MicroRNA-155在T细胞耗竭中的作用及其机制研究
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摘要
T淋巴细胞是介导适应性免疫应答的主要效应细胞，在各类免疫性疾病的发生及防治中发挥重要作用。通常情况下，在外来抗原的刺激下，T细胞迅速增殖扩增成为效应性T细胞；当抗原消失后，大部分细胞发生凋亡，小部分细胞分化成为记忆性T细胞，在再次免疫应答中发挥重要作用。然而，在慢性抗原持续刺激的情况下，如肿瘤，慢性感染性疾病以及自身免疫性疾病，抗原特异性T细胞会持续存在相当长的时间，同时伴随效应功能逐渐衰竭，最终成为耗竭性T细胞。耗竭性T细胞是一种效应性T细胞，其特征是细胞因子的表达减少，包括IFN-γ，TNF-α及IL-2等表达降低，以及细胞效应功能减弱，包括细胞毒性作用及细胞增殖等功能障碍。耗竭性T细胞免疫保护以及免疫监视等功能发生障碍，最终将导致慢性病原体感染性疾病以及肿瘤的发生。
MicroRNAs (miRNAs)是存在于真核生物中的一类内源性的具有调控功能的非编码蛋白质的RNA，长约20~25个核苷酸。miRNAs通过与靶mRNA3’UTR互补结合，诱导靶mRNA降解或抑制靶mRNA的翻译，从而实现转录后基因调控作用。目前共发现1000多个miRNAs，其中与免疫系统相关的就有100多个。miRNAs广泛参与各类免疫应答与多种生物学行为，如免疫细胞的分化发育、细胞的增殖与凋亡，并且在各类病原体感染性疾病、自身免疫性疾病以及多种肿瘤的发生发展中都发挥重要的调节作用。
在众多miRNAs中，miR-155与免疫调控的关系最为密切。miR-155基因位于人类21号染色体B细胞非编码集合基因簇(BIC)的第三个外显子中。miR-155是第一个被报道与癌症相关的miRNAs。研究表明，miR-155与免疫细胞的发育分化密切相关。miR-155影响B细胞的成熟以及其转化成浆细胞分泌抗体的能力。miR-155调控T细胞的成熟，促进Th1及Th17细胞的分化。 miR-155参与Treg细胞的分化及其维持内环境稳定的功能。此外，miR-155广泛参与介导炎症性疾病及肿瘤的发生。总之，miR-155对免疫系统的调控具有复杂性和网络性，对不同的细胞类型、在细胞不同的分化阶段的调控都表现出明显的差异性，其具体机制还不是很清楚。此外，miR-155是否参与T细胞耗竭的过程，还未曾报道。阐明miR-155在T细胞耗竭中的作用及机制，可以进一步丰富对miR-155生物活性的认识，为研究及治疗其介导的慢性疾病提供新思路。
【研究目的】
1.利用抗原慢性持续性刺激小鼠模型，探索耗竭性CD4~+T细胞的功能及其免疫调控机制。
2.筛选并鉴定与CD4~+T细胞耗竭相关的miRNAs，探讨其对CD4~+T细胞耗竭的影响。
3.鉴定在耗竭性CD4~+T细胞中miR-155的靶标分子，并研究其在CD4~+T细胞耗竭中的作用。
4．利用实验性自身免疫性脑脊髓炎(EAE)模型，进一步研究miR-155与其靶标分子血红素加氧酶-1(HO-1)的相互调节作用。
【研究方法】
1. CD4~+T细胞耗竭模型的建立及与CD4~+T细胞耗竭相关miRNAs的筛选鉴定
利用TcR转基因小鼠Rag2~(-/-)Marilyn的CD4~+T细胞作为供体细胞，此种T细胞的受体可以特异性识别雄性H-Y肽段。将雌性Rag2~(-/-)Marilyn CD4~+T细胞腹腔过继转移至雄性Rag2~(-/-)IL-2Rγc~(-/-)受体小鼠体内。过继转移21天后处死小鼠，从受体小鼠脾淋巴细胞中分离纯化Marilyn CD4~+T细胞，采用miRNA芯片技术比较过继前后细胞miRNAs表达谱的变化。此外，收集受体小鼠脾混合淋巴细胞，并进行体外培养，同时加入抗PDL-1抗体阻断PD-1/PDL-1通路，初步探讨PD-1在CD4~+T细胞耗竭中的作用。抗CD3/CD28抗体体外刺激过继的Marilyn CD4~+T细胞，在与PD-1配体PDL-1Ig或同型Ig结合后，ELISA检测细胞培养上清中IFN-γ的变化。
2. miR-155在CD4~+T细胞耗竭中的作用及其机制研究
分别过继转移miR-155~(-/-)Marilyn CD4~+T细胞与miR-155~+/~+Marilyn CD4~+T细胞至Rag2~(-/-)IL-2Rγc~(-/-)受体小鼠体内，并在过继转移后14天开始用抗PDL-1抗体体内阻断PD-1/PDL-1通路，每2天注射一次，21天后处死小鼠。采用免疫荧光染色技术，分析CD4~+T细胞在各靶器官中的浸润变化；采用流式细胞技术分析脾Th细胞的应答变化；同时，利用ELISA技术检测体外培养脾混合淋巴细胞以及经anti-CD3/CD28刺激的CD4~+T细胞，培养上清中IFN-γ分泌的变化；采用mRNA芯片技术对比过继的miR-155~(-/-)Marilyn CD4~+T细胞与过继的miR-155~+/~+Marilyn CD4~+T细胞mRNA表达谱的区别。通过对比分析mRNAs芯片结果与靶标预测软件结果，筛选miR-155的靶标。采用荧光定量PCR及western blot技术进一步鉴定miR-155的靶标。此外，应用RNA免疫共沉淀技术研究miR-155与AGO2形成的蛋白复合体与靶标mRNA之间的相互结合。在此基础上，通过双荧光素酶报告基因实验检测miR-155与靶标3’UTR之间的相互作用。
3. HO-1对耗竭性miR-155~(-/-)CD4~+T细胞的作用及机制研究
在确定血红素加氧酶-1(HO-1, encoded by Hmox1)是miR-155靶标的基础上，研究其功能。将miR-155~(-/-)Marilyn CD4~+T细胞过继转移至Rag2~(-/-)IL-2Rγc~(-/-)受体小鼠体内，从过继前一天开始，每2天腹腔注射HO-1抑制剂ZnPP，同时设置对照组。21天后处死小鼠。采用免疫荧光染色技术，分析ZnPP处理组与对照组miR-155~(-/-)Marilyn CD4~+T细胞在受体小鼠各靶器官的浸润变化；采用流式细胞技术分析受体小鼠脾中Th细胞应答变化。将经抗CD3/CD28抗体刺激的初始性miR-155~(-/-)CD4~+T细胞与ZnPP体外共培养，ELISA检测培养上清中IL-2及IFN-γ的分泌情况。
4. HO-1在小鼠EAE模型中的作用及机制的初步探讨
利用小鼠EAE模型研究HO-1的功能。共设置以下4组小鼠实验：B6~+Vehicle对照组；B6~+CoPP组；miR-155~(-/-)~+Vehicle对照组；miR-155~(-/-)~+ZnPP组。从MOG35-55皮下免疫第一天开始，每2天腹腔注射HO-1诱导剂CoPP或HO-1抑制剂ZnPP，同时设置Vehicle对照组。每天进行EAE评分，免疫后23天宰杀小鼠，分别取脾，腹股沟淋巴结，脑组织淋巴细胞。用流式细胞技术检测CD3~+，B220~+，CD11b~+细胞的浸润情况以及Th细胞应答的变化。
【研究结果】
1.过继的Marilyn CD4~+T细胞基因表达谱与耗竭性CD8~+T细胞的基因表达谱相似。PD-1可以调控耗竭性CD4~+T细胞的功能，抗PDL-1抗体体内阻断PD-1/PDL-1信号通路后，Marilyn CD4~+T细胞在受体小鼠的脾，结肠，肺，肝脏，肾脏等器官中的浸润明显增加。体外抗PDL-1抗体阻断后，可以恢复耗竭性Marilyn CD4~+T细胞分泌IFN-γ的功能。在TCR与PD-1交联的情况下，耗竭性Marilyn CD4~+T细胞IFN-γ的分泌受到抑制。
2. miRNA芯片的结果显示，耗竭性Marilyn CD4~+T细胞伴随miR-155高表达。过继转移21天后，miR-155~(-/-)Marilyn CD4~+T细胞在受体小鼠的脾，结肠，肺，肝脏，肾脏器官中的浸润程度以及脾中Th1细胞应答明显少于miR-155~+/~+Marilyn CD4~+T细胞。体外经anti-CD3/CD28刺激后，过继的miR-155~(-/-)Marilyn CD4~+T细胞IFN-γ的分泌显著少于miR-155~+/~+Marilyn CD4~+T细胞。过继的miR-155~(-/-)Marilyn CD4~+T细胞同样表达PD-1，但是与过继的miR-155~+/~+Marilyn CD4~+T细胞不同的是，抗PDL-1抗体体内及体外阻断PD-1/PDL-1信号通路并不能恢复耗竭性miR-155~(-/-)Marilyn CD4~+T细胞的增殖及IFN-γ分泌功能。通过分析对比mRNA芯片结果与MicroCosm计算方法预测结果，Hmox1是miR-155潜在靶点。荧光定量PCR及western blot结果进一步证实了HO-1在耗竭性miR-155~(-/-)Marilyn CD4~+T细胞高表达。在此基础上，双荧光素酶报告基因荧光素酶活性检测结果为：miR-155Mimic与Hmox13’UTR荧光报告载体共转染HEK293T细胞组相对荧光素酶活性比miRNA Mimic control和Hmox13’UTR荧光报告载体共转染组明显降低。RNA免疫共沉淀实验结果表明，miR-155与AGO2形成蛋白复合体并结合Hmox1mRNA导致其表达降低。
3. ZnPP处理后，受体小鼠脾总淋巴细胞数以及miR-155~(-/-)Marilyn CD4~+T细胞的数量都明显高于Vehicle对照组。免疫荧光染色的结果显示：在结肠，肺，肝脏，肾脏，ZnPP处理组的miR-155~(-/-)Mariyln CD4~+T细胞浸润明显增加。但是ZnPP处理组与Vehicle对照组相比，Th1细胞应答并没有明显差异。抗CD3/CD28抗体刺激的初始性miR-155~(-/-)CD4~+T细胞，体外ZnPP处理将增加IL-2的分泌。
4.在诱导EAE的4组小鼠模型中，B6组小鼠全部发病，免疫后14天开始发病，20天左右达高峰；在B6小鼠中，CoPP处理组临床评分明显低于Vehicle对照组小鼠；在miR-155~(-/-)小鼠中，Vehicle对照组小鼠只有少数小鼠发病，平均临床评分<0.5分，ZnPP处理组小鼠临床评分高于Vehicle对照组。此外，流式细胞技术检测发现，miR-155~(-/-)对照组高峰期小鼠中枢神经组织中CD3~+，CD11b~+及B220~+细胞浸润明显少于其他组，而在脾及腹股沟淋巴结中，4组之间细胞浸润则无显著差异。在中枢神经组织中，miR-155~(-/-)组的Th1及Th17细胞应答明显少于miR-155~+/~+组，当注射ZnPP后，miR-155~(-/-)组Th1及Th17细胞应答水平显著增加。
【主要结论】
1.慢性持续性抗原刺激可以诱导CD4~+T细胞耗竭。耗竭性CD4~+T细胞高表达Th1细胞相关基因以及抑制性共刺激分子。在抑制性共刺激分子中，PD-1表达最高，并且PD-1可以调控耗竭性CD4~+T细胞的增殖，IFN-γ的分泌等免疫活性。
2.耗竭性CD4~+T细胞伴随miR-155高表达。耗竭性miR-155~(-/-)CD4~+T细胞的增殖能力及Th1细胞应答明显弱于耗竭性miR-155~+/~+CD4~+T细胞。miR-155对于CD4~+T细胞耗竭并不是必需的，但是阻断PD-1/PDL-1信号通路恢复耗竭性T细胞免疫功能需要有miR-155的表达。
3.在CD4~+T细胞耗竭模型中，Hmox1是miR-155的靶基因。HO-1可以调控耗竭性miR-155~(-/-)CD4~+T细胞的增殖功能。
4.抑制HO-1的活性可以恢复miR-155~(-/-)小鼠对EAE的易感性，并且伴随中枢神经系统CD3~+细胞浸润以及Th1/Th17细胞应答增加。
【研究意义】
1.本研究成功构建了CD4~+T细胞耗竭模型。运用mRNAs芯片与miRNAs芯片技术全面分析了耗竭性CD4~+T细胞的表达谱，为深入研究T细胞耗竭奠定了基础。
2.首次全面阐述了Hmox1是miR-155的一个新靶标，为了解研究miR-155的生物活性及功能提供了新线索。
3.本研究初步探讨HO-1与miR-155在T细胞耗竭中的相互调控机制，为研究及治疗相关疾病，如：肿瘤，慢性感染性疾病等提供新思路。HO-1可能成为治疗相关疾病的新靶点。
T lymphocytes are a crucial part of the immune system and are the major cellsinvolved in the adaptive immune response. Usually, T cells expand rapidly in response toantigenic stimulation, and then, as a result of antigen clearance, they die by apoptosis orbecome memeory T cells. However, in situations of chronic antigenic exposure, such asthose observed in cancer, chronic infections or autoimmunity diseases, antigen-specific Tcells may persist for extended periods of time and these conditions are often associated withfunctional exhaustion. Exhausted T cells are characterized by decreased cytokineexpression and dysfunction.
MicroRNAs (miRNA) are small genome-encoded RNAs that regulate gene expressionby targeting complementary messenger RNAs (mRNA) and resulting in gene expressionsilencing through translational repression or target degradation. There are over1000miRNAs reported in humans, which may target about60%of mammalian genes. MiRNAsare associated with the pathogenesis and developement of many diseases, and miRNAs areinvolved in establishing and maintaining cell fate as well as regulating innate and adaptiveimmune systems.
Among miRNAs the most present in immune cells, miR-155is shown to be critical forthe maturation and differentiation of several cell types, such as B cells, DCs and Th cells.MiR-155regulates CD4~+T cell function by suppressing the expression of its target genes.MiR-155has been shown to promote Th cell-driven inflammation, however, the exactmolecular mechanism by which miR-155promotes Th cell-driven inflammation isunknown. The involvement of miR-155in the phenomenon of T cell exhaustion has yet tobe investigated.
[Objectives]
1. Study the function of CD4~+T cells after exposure to persistent systemic antigen.
2. Identify the miRNAs which influence CD4~+T cell exhaustion.
3. Investigate the role of miR-155in the regulation of CD4~+T cells subjected to apersistent antigenic stimulation.
4. Explore the target of miR-155and its function in the CD4~+T cell exhaustion model.
[Methods]
1. Purifed female Rag2~(-/-)Marilyn CD4~+T cells, which are transgenic for a TCR specificfor the male H-Y peptide, were injected i.p into male Rag2~(-/-)IL-2Rγc~(-/-)recipient.Lymphocytes of spleen were collected21days after transfer. To identify the photype of thetransferred CD4~+T cells, transferred CD4~+T cells and na ve CD4~+T cells were purified formicroarrays. IFN-γ secretion from culture supernatant of mixed splenocytes oranti-CD3/CD28stimulated CD4~+T cells was evaluated by ELISA.
2. MiR-155~(-/-)Rag2~(-/-)Marilyn mice were genenated by crossing breeding Rag2~(-/-)Marilynmice with miR-155~(-/-)B6mice. MiR-155~(-/-)Rag2~(-/-)Marilyn hemozygote mice were obtainedafter4generations. CD4~+T cells from female miR-155~+/~+Rag2~(-/-)Marilyn andmiR-155~(-/-)Rag2~(-/-)Marilyn mice were i.p adoptive transferred into male Rag2~(-/-)IL-2Rγc~(-/-)recipient respectively. Lymphocytes of recipient spleen were collected21days aftertransfer. Antigen-specific CD4~+T cell expansion and Th responses in spleen were detectedby FACS. IFN-γ secretion from culture supernant was evaluated by ELISA.Antigen-specific CD4~+T cell infiltration in target organs were detected byimmunofluorescense. Moreover, CD4~+T cells from the two goups were used formicroarrays. The potential miR-155target was further confirmed by real-time PCR,western blot and RNA immunopreciptation. In addition, a luciferase report plasmid whichcontained Hmox13’UTR was co-transfected with miR-155-Mimic or miR-Mimic controlinto HEK293T cells. The interation between Hmox1and miR-155was determined by dualluciferase assay.
3. MiR-155~(-/-)Rag2~(-/-)Marilyn CD4~+T cells were injected i.p into male Rag2~(-/-)IL-2Rγc~(-/-)recipient. Recipient mice were administrated i.p with HO-1inhibitor ZnPP every two daysfrom one day before the adoptive transfer. Mice injected with vehicle were used as controls.Spleen, heart, liver, lung, kidney and large intestine were collected21days post transfer.Antigen-specific CD4~+T cells infiltration in target organs were evaluated by immunofluorecence. Antigen-specific CD4~+T cells proliferation and Th cell responses inspleen were examined by FACS. Na ve miR-155~(-/-)CD4~+T cells were activated byanti-CD3/anti-CD28simulation plus ZnPP or vehicle treatment for24h. IFN-γ and IL-2secretion from the supernant were evaluated by ELISA.
4. B6and miR-155~(-/-)B6mice were immunized with MOG35-55peptide to induceexperimental autoimmune encephalomyelitis (EAE) respectively. Mice were injected i.pwith CoPP or ZnPP every two days from the immunization. Mice injected with vehiclewere used as controls. Spleen, draining lymph node, brain were collected at the indicatedtime post immunization. Infiltrated cell types and Th responses were detected and analyzedby FACS.
[Results]
1. Compared with na ve CD4~+T cells, transferred CD4~+T cells aquired a geneexpression profile similar to exhausted CD8~+T cells. The exhausted CD4~+T cells highlyexpressed Th1genes and inhibitory receptors, such as IFN-γ, STAT1, T-bet and PD-1.Blocking PD-1/PDL-1interation to the culture of splenocytes isolated from recipient micerestored T cell effector function, as assessed by IFN-γ production. Purified transferredCD4~+T cells stimulated with anti-CD3/anti-CD28plus PD-1pathway engagement lowerIFN-γ production.
2. Microarray results indicated that exhausted CD4~+T cell expressed high level ofmiR-155. Transferred miR-155~(-/-)Marilyn CD4~+T cells also expressed PD-1asmiR-155~+/~+counterpart, however, unlike exhausted miR-155~+/~+CD4~+T cells, blockade ofPD-1/PD-L1interaction did not restore the function of exhausted miR-155~(-/-)CD4~+T cells.Hmox1(The gene encodes HO-1) was one of the genes which were up-regulated inexhausted miR-155~(-/-)CD4~+T cells. Compared with exhausted miR-155~+/~+CD4~+T cells,Hmox1mRNA and HO-1protein level were highly expressed in exhaustedmiR-155~(-/-)CD4~+T cells. RNA immunopreciptation results suggested that miR-155andhmox1mRNA could be coimmunopreciptated by anti-Argonaute2(anti-AGO2) antibody.Furthermore, in the dual luciferase assay experiment, cotransfected miR-155-Mimicrepressed expression of luciferase fused to Hmox13’UTR, while miR-Mimic control failedto repress luciferase expression.
3. ZnPP treatment enhanced the expansion of miR-155~(-/-)CD4~+T cells transferred intomale recipients. Moreover, T cell infiltrates were also significantly increased in severalorgans after treatment with ZnPP. This revealed a role of HO-1for maintaining immuneunresponsiveness in exhausted miR-155~(-/-)CD4~+T cells. HO-1inhibition with ZnPPincreased IL-2secretion from na ve miR-155~(-/-)CD4~+T cells after in vitro stimulation withanti-CD3/CD28antibodies, however, HO-1inhibition did not improve the capacity ofexhausted miR-155~(-/-)CD4~+T cells to produce IFN-γ. HO-1activity could account for T cellunresponsiveness in our system.
4. B6with CoPP treatment lowered the clinal signs of EAE. ZnPP inhibition worsedthe clinical signs of EAE in miR-155~(-/-)mice with more CD3~+T cell infiltrated into the brain.Th1and Th17cell responses in miR-155~(-/-)mice were lower than that in the other groups.
[Conclusion]
1. Exposure to persistent systemic antigen stimulation leads to T cell exhaustion,whose activity is controlled by PD-1.
2. MiR-155is not required for T cell exhaustion, but it is indispensable for restoring Tcell function in the absence of PD-1inhibition.
3. Hmox1is a direct target of miR-155. HO-1is responsible for maintaining immuneunresponsiveness in exhausted miR-155~(-/-)CD4~+T cells.
4. Inhibition of HO-1rescues susceptibility to EAE in miR-155~(-/-)mice.
[Significance]
1. We developed a CD4~+T cell exhaustion model, which could be used for furtherstudy of T cell exhaustion.
2. Our work has revealed one novel pathway in which miR-155, by targeting Hmox1,promotes T cell mediated inflammation.
3. Inhibition HO-1could rescue the proliferative capacity of exhausted CD4~+T cells,which could be essential for the development of innovative immunotherapies in chronicimmunological diseases.
MicroRNAs (miRNAs)是存在于真核生物中的一类内源性的具有调控功能的非编码蛋白质的RNA，长约20~25个核苷酸。miRNAs通过与靶mRNA3’UTR互补结合，诱导靶mRNA降解或抑制靶mRNA的翻译，从而实现转录后基因调控作用。目前共发现1000多个miRNAs，其中与免疫系统相关的就有100多个。miRNAs广泛参与各类免疫应答与多种生物学行为，如免疫细胞的分化发育、细胞的增殖与凋亡，并且在各类病原体感染性疾病、自身免疫性疾病以及多种肿瘤的发生发展中都发挥重要的调节作用。
在众多miRNAs中，miR-155与免疫调控的关系最为密切。miR-155基因位于人类21号染色体B细胞非编码集合基因簇(BIC)的第三个外显子中。miR-155是第一个被报道与癌症相关的miRNAs。研究表明，miR-155与免疫细胞的发育分化密切相关。miR-155影响B细胞的成熟以及其转化成浆细胞分泌抗体的能力。miR-155调控T细胞的成熟，促进Th1及Th17细胞的分化。 miR-155参与Treg细胞的分化及其维持内环境稳定的功能。此外，miR-155广泛参与介导炎症性疾病及肿瘤的发生。总之，miR-155对免疫系统的调控具有复杂性和网络性，对不同的细胞类型、在细胞不同的分化阶段的调控都表现出明显的差异性，其具体机制还不是很清楚。此外，miR-155是否参与T细胞耗竭的过程，还未曾报道。阐明miR-155在T细胞耗竭中的作用及机制，可以进一步丰富对miR-155生物活性的认识，为研究及治疗其介导的慢性疾病提供新思路。
【研究目的】
1.利用抗原慢性持续性刺激小鼠模型，探索耗竭性CD4~+T细胞的功能及其免疫调控机制。
2.筛选并鉴定与CD4~+T细胞耗竭相关的miRNAs，探讨其对CD4~+T细胞耗竭的影响。
3.鉴定在耗竭性CD4~+T细胞中miR-155的靶标分子，并研究其在CD4~+T细胞耗竭中的作用。
4．利用实验性自身免疫性脑脊髓炎(EAE)模型，进一步研究miR-155与其靶标分子血红素加氧酶-1(HO-1)的相互调节作用。
【研究方法】
1. CD4~+T细胞耗竭模型的建立及与CD4~+T细胞耗竭相关miRNAs的筛选鉴定
利用TcR转基因小鼠Rag2~(-/-)Marilyn的CD4~+T细胞作为供体细胞，此种T细胞的受体可以特异性识别雄性H-Y肽段。将雌性Rag2~(-/-)Marilyn CD4~+T细胞腹腔过继转移至雄性Rag2~(-/-)IL-2Rγc~(-/-)受体小鼠体内。过继转移21天后处死小鼠，从受体小鼠脾淋巴细胞中分离纯化Marilyn CD4~+T细胞，采用miRNA芯片技术比较过继前后细胞miRNAs表达谱的变化。此外，收集受体小鼠脾混合淋巴细胞，并进行体外培养，同时加入抗PDL-1抗体阻断PD-1/PDL-1通路，初步探讨PD-1在CD4~+T细胞耗竭中的作用。抗CD3/CD28抗体体外刺激过继的Marilyn CD4~+T细胞，在与PD-1配体PDL-1Ig或同型Ig结合后，ELISA检测细胞培养上清中IFN-γ的变化。
2. miR-155在CD4~+T细胞耗竭中的作用及其机制研究
分别过继转移miR-155~(-/-)Marilyn CD4~+T细胞与miR-155~+/~+Marilyn CD4~+T细胞至Rag2~(-/-)IL-2Rγc~(-/-)受体小鼠体内，并在过继转移后14天开始用抗PDL-1抗体体内阻断PD-1/PDL-1通路，每2天注射一次，21天后处死小鼠。采用免疫荧光染色技术，分析CD4~+T细胞在各靶器官中的浸润变化；采用流式细胞技术分析脾Th细胞的应答变化；同时，利用ELISA技术检测体外培养脾混合淋巴细胞以及经anti-CD3/CD28刺激的CD4~+T细胞，培养上清中IFN-γ分泌的变化；采用mRNA芯片技术对比过继的miR-155~(-/-)Marilyn CD4~+T细胞与过继的miR-155~+/~+Marilyn CD4~+T细胞mRNA表达谱的区别。通过对比分析mRNAs芯片结果与靶标预测软件结果，筛选miR-155的靶标。采用荧光定量PCR及western blot技术进一步鉴定miR-155的靶标。此外，应用RNA免疫共沉淀技术研究miR-155与AGO2形成的蛋白复合体与靶标mRNA之间的相互结合。在此基础上，通过双荧光素酶报告基因实验检测miR-155与靶标3’UTR之间的相互作用。
3. HO-1对耗竭性miR-155~(-/-)CD4~+T细胞的作用及机制研究
在确定血红素加氧酶-1(HO-1, encoded by Hmox1)是miR-155靶标的基础上，研究其功能。将miR-155~(-/-)Marilyn CD4~+T细胞过继转移至Rag2~(-/-)IL-2Rγc~(-/-)受体小鼠体内，从过继前一天开始，每2天腹腔注射HO-1抑制剂ZnPP，同时设置对照组。21天后处死小鼠。采用免疫荧光染色技术，分析ZnPP处理组与对照组miR-155~(-/-)Marilyn CD4~+T细胞在受体小鼠各靶器官的浸润变化；采用流式细胞技术分析受体小鼠脾中Th细胞应答变化。将经抗CD3/CD28抗体刺激的初始性miR-155~(-/-)CD4~+T细胞与ZnPP体外共培养，ELISA检测培养上清中IL-2及IFN-γ的分泌情况。
4. HO-1在小鼠EAE模型中的作用及机制的初步探讨
利用小鼠EAE模型研究HO-1的功能。共设置以下4组小鼠实验：B6~+Vehicle对照组；B6~+CoPP组；miR-155~(-/-)~+Vehicle对照组；miR-155~(-/-)~+ZnPP组。从MOG35-55皮下免疫第一天开始，每2天腹腔注射HO-1诱导剂CoPP或HO-1抑制剂ZnPP，同时设置Vehicle对照组。每天进行EAE评分，免疫后23天宰杀小鼠，分别取脾，腹股沟淋巴结，脑组织淋巴细胞。用流式细胞技术检测CD3~+，B220~+，CD11b~+细胞的浸润情况以及Th细胞应答的变化。
【研究结果】
1.过继的Marilyn CD4~+T细胞基因表达谱与耗竭性CD8~+T细胞的基因表达谱相似。PD-1可以调控耗竭性CD4~+T细胞的功能，抗PDL-1抗体体内阻断PD-1/PDL-1信号通路后，Marilyn CD4~+T细胞在受体小鼠的脾，结肠，肺，肝脏，肾脏等器官中的浸润明显增加。体外抗PDL-1抗体阻断后，可以恢复耗竭性Marilyn CD4~+T细胞分泌IFN-γ的功能。在TCR与PD-1交联的情况下，耗竭性Marilyn CD4~+T细胞IFN-γ的分泌受到抑制。
2. miRNA芯片的结果显示，耗竭性Marilyn CD4~+T细胞伴随miR-155高表达。过继转移21天后，miR-155~(-/-)Marilyn CD4~+T细胞在受体小鼠的脾，结肠，肺，肝脏，肾脏器官中的浸润程度以及脾中Th1细胞应答明显少于miR-155~+/~+Marilyn CD4~+T细胞。体外经anti-CD3/CD28刺激后，过继的miR-155~(-/-)Marilyn CD4~+T细胞IFN-γ的分泌显著少于miR-155~+/~+Marilyn CD4~+T细胞。过继的miR-155~(-/-)Marilyn CD4~+T细胞同样表达PD-1，但是与过继的miR-155~+/~+Marilyn CD4~+T细胞不同的是，抗PDL-1抗体体内及体外阻断PD-1/PDL-1信号通路并不能恢复耗竭性miR-155~(-/-)Marilyn CD4~+T细胞的增殖及IFN-γ分泌功能。通过分析对比mRNA芯片结果与MicroCosm计算方法预测结果，Hmox1是miR-155潜在靶点。荧光定量PCR及western blot结果进一步证实了HO-1在耗竭性miR-155~(-/-)Marilyn CD4~+T细胞高表达。在此基础上，双荧光素酶报告基因荧光素酶活性检测结果为：miR-155Mimic与Hmox13’UTR荧光报告载体共转染HEK293T细胞组相对荧光素酶活性比miRNA Mimic control和Hmox13’UTR荧光报告载体共转染组明显降低。RNA免疫共沉淀实验结果表明，miR-155与AGO2形成蛋白复合体并结合Hmox1mRNA导致其表达降低。
3. ZnPP处理后，受体小鼠脾总淋巴细胞数以及miR-155~(-/-)Marilyn CD4~+T细胞的数量都明显高于Vehicle对照组。免疫荧光染色的结果显示：在结肠，肺，肝脏，肾脏，ZnPP处理组的miR-155~(-/-)Mariyln CD4~+T细胞浸润明显增加。但是ZnPP处理组与Vehicle对照组相比，Th1细胞应答并没有明显差异。抗CD3/CD28抗体刺激的初始性miR-155~(-/-)CD4~+T细胞，体外ZnPP处理将增加IL-2的分泌。
4.在诱导EAE的4组小鼠模型中，B6组小鼠全部发病，免疫后14天开始发病，20天左右达高峰；在B6小鼠中，CoPP处理组临床评分明显低于Vehicle对照组小鼠；在miR-155~(-/-)小鼠中，Vehicle对照组小鼠只有少数小鼠发病，平均临床评分<0.5分，ZnPP处理组小鼠临床评分高于Vehicle对照组。此外，流式细胞技术检测发现，miR-155~(-/-)对照组高峰期小鼠中枢神经组织中CD3~+，CD11b~+及B220~+细胞浸润明显少于其他组，而在脾及腹股沟淋巴结中，4组之间细胞浸润则无显著差异。在中枢神经组织中，miR-155~(-/-)组的Th1及Th17细胞应答明显少于miR-155~+/~+组，当注射ZnPP后，miR-155~(-/-)组Th1及Th17细胞应答水平显著增加。
【主要结论】
1.慢性持续性抗原刺激可以诱导CD4~+T细胞耗竭。耗竭性CD4~+T细胞高表达Th1细胞相关基因以及抑制性共刺激分子。在抑制性共刺激分子中，PD-1表达最高，并且PD-1可以调控耗竭性CD4~+T细胞的增殖，IFN-γ的分泌等免疫活性。
2.耗竭性CD4~+T细胞伴随miR-155高表达。耗竭性miR-155~(-/-)CD4~+T细胞的增殖能力及Th1细胞应答明显弱于耗竭性miR-155~+/~+CD4~+T细胞。miR-155对于CD4~+T细胞耗竭并不是必需的，但是阻断PD-1/PDL-1信号通路恢复耗竭性T细胞免疫功能需要有miR-155的表达。
3.在CD4~+T细胞耗竭模型中，Hmox1是miR-155的靶基因。HO-1可以调控耗竭性miR-155~(-/-)CD4~+T细胞的增殖功能。
4.抑制HO-1的活性可以恢复miR-155~(-/-)小鼠对EAE的易感性，并且伴随中枢神经系统CD3~+细胞浸润以及Th1/Th17细胞应答增加。
【研究意义】
1.本研究成功构建了CD4~+T细胞耗竭模型。运用mRNAs芯片与miRNAs芯片技术全面分析了耗竭性CD4~+T细胞的表达谱，为深入研究T细胞耗竭奠定了基础。
2.首次全面阐述了Hmox1是miR-155的一个新靶标，为了解研究miR-155的生物活性及功能提供了新线索。
3.本研究初步探讨HO-1与miR-155在T细胞耗竭中的相互调控机制，为研究及治疗相关疾病，如：肿瘤，慢性感染性疾病等提供新思路。HO-1可能成为治疗相关疾病的新靶点。
T lymphocytes are a crucial part of the immune system and are the major cellsinvolved in the adaptive immune response. Usually, T cells expand rapidly in response toantigenic stimulation, and then, as a result of antigen clearance, they die by apoptosis orbecome memeory T cells. However, in situations of chronic antigenic exposure, such asthose observed in cancer, chronic infections or autoimmunity diseases, antigen-specific Tcells may persist for extended periods of time and these conditions are often associated withfunctional exhaustion. Exhausted T cells are characterized by decreased cytokineexpression and dysfunction.
MicroRNAs (miRNA) are small genome-encoded RNAs that regulate gene expressionby targeting complementary messenger RNAs (mRNA) and resulting in gene expressionsilencing through translational repression or target degradation. There are over1000miRNAs reported in humans, which may target about60%of mammalian genes. MiRNAsare associated with the pathogenesis and developement of many diseases, and miRNAs areinvolved in establishing and maintaining cell fate as well as regulating innate and adaptiveimmune systems.
Among miRNAs the most present in immune cells, miR-155is shown to be critical forthe maturation and differentiation of several cell types, such as B cells, DCs and Th cells.MiR-155regulates CD4~+T cell function by suppressing the expression of its target genes.MiR-155has been shown to promote Th cell-driven inflammation, however, the exactmolecular mechanism by which miR-155promotes Th cell-driven inflammation isunknown. The involvement of miR-155in the phenomenon of T cell exhaustion has yet tobe investigated.
[Objectives]
1. Study the function of CD4~+T cells after exposure to persistent systemic antigen.
2. Identify the miRNAs which influence CD4~+T cell exhaustion.
3. Investigate the role of miR-155in the regulation of CD4~+T cells subjected to apersistent antigenic stimulation.
4. Explore the target of miR-155and its function in the CD4~+T cell exhaustion model.
[Methods]
1. Purifed female Rag2~(-/-)Marilyn CD4~+T cells, which are transgenic for a TCR specificfor the male H-Y peptide, were injected i.p into male Rag2~(-/-)IL-2Rγc~(-/-)recipient.Lymphocytes of spleen were collected21days after transfer. To identify the photype of thetransferred CD4~+T cells, transferred CD4~+T cells and na ve CD4~+T cells were purified formicroarrays. IFN-γ secretion from culture supernatant of mixed splenocytes oranti-CD3/CD28stimulated CD4~+T cells was evaluated by ELISA.
2. MiR-155~(-/-)Rag2~(-/-)Marilyn mice were genenated by crossing breeding Rag2~(-/-)Marilynmice with miR-155~(-/-)B6mice. MiR-155~(-/-)Rag2~(-/-)Marilyn hemozygote mice were obtainedafter4generations. CD4~+T cells from female miR-155~+/~+Rag2~(-/-)Marilyn andmiR-155~(-/-)Rag2~(-/-)Marilyn mice were i.p adoptive transferred into male Rag2~(-/-)IL-2Rγc~(-/-)recipient respectively. Lymphocytes of recipient spleen were collected21days aftertransfer. Antigen-specific CD4~+T cell expansion and Th responses in spleen were detectedby FACS. IFN-γ secretion from culture supernant was evaluated by ELISA.Antigen-specific CD4~+T cell infiltration in target organs were detected byimmunofluorescense. Moreover, CD4~+T cells from the two goups were used formicroarrays. The potential miR-155target was further confirmed by real-time PCR,western blot and RNA immunopreciptation. In addition, a luciferase report plasmid whichcontained Hmox13’UTR was co-transfected with miR-155-Mimic or miR-Mimic controlinto HEK293T cells. The interation between Hmox1and miR-155was determined by dualluciferase assay.
3. MiR-155~(-/-)Rag2~(-/-)Marilyn CD4~+T cells were injected i.p into male Rag2~(-/-)IL-2Rγc~(-/-)recipient. Recipient mice were administrated i.p with HO-1inhibitor ZnPP every two daysfrom one day before the adoptive transfer. Mice injected with vehicle were used as controls.Spleen, heart, liver, lung, kidney and large intestine were collected21days post transfer.Antigen-specific CD4~+T cells infiltration in target organs were evaluated by immunofluorecence. Antigen-specific CD4~+T cells proliferation and Th cell responses inspleen were examined by FACS. Na ve miR-155~(-/-)CD4~+T cells were activated byanti-CD3/anti-CD28simulation plus ZnPP or vehicle treatment for24h. IFN-γ and IL-2secretion from the supernant were evaluated by ELISA.
4. B6and miR-155~(-/-)B6mice were immunized with MOG35-55peptide to induceexperimental autoimmune encephalomyelitis (EAE) respectively. Mice were injected i.pwith CoPP or ZnPP every two days from the immunization. Mice injected with vehiclewere used as controls. Spleen, draining lymph node, brain were collected at the indicatedtime post immunization. Infiltrated cell types and Th responses were detected and analyzedby FACS.
[Results]
1. Compared with na ve CD4~+T cells, transferred CD4~+T cells aquired a geneexpression profile similar to exhausted CD8~+T cells. The exhausted CD4~+T cells highlyexpressed Th1genes and inhibitory receptors, such as IFN-γ, STAT1, T-bet and PD-1.Blocking PD-1/PDL-1interation to the culture of splenocytes isolated from recipient micerestored T cell effector function, as assessed by IFN-γ production. Purified transferredCD4~+T cells stimulated with anti-CD3/anti-CD28plus PD-1pathway engagement lowerIFN-γ production.
2. Microarray results indicated that exhausted CD4~+T cell expressed high level ofmiR-155. Transferred miR-155~(-/-)Marilyn CD4~+T cells also expressed PD-1asmiR-155~+/~+counterpart, however, unlike exhausted miR-155~+/~+CD4~+T cells, blockade ofPD-1/PD-L1interaction did not restore the function of exhausted miR-155~(-/-)CD4~+T cells.Hmox1(The gene encodes HO-1) was one of the genes which were up-regulated inexhausted miR-155~(-/-)CD4~+T cells. Compared with exhausted miR-155~+/~+CD4~+T cells,Hmox1mRNA and HO-1protein level were highly expressed in exhaustedmiR-155~(-/-)CD4~+T cells. RNA immunopreciptation results suggested that miR-155andhmox1mRNA could be coimmunopreciptated by anti-Argonaute2(anti-AGO2) antibody.Furthermore, in the dual luciferase assay experiment, cotransfected miR-155-Mimicrepressed expression of luciferase fused to Hmox13’UTR, while miR-Mimic control failedto repress luciferase expression.
3. ZnPP treatment enhanced the expansion of miR-155~(-/-)CD4~+T cells transferred intomale recipients. Moreover, T cell infiltrates were also significantly increased in severalorgans after treatment with ZnPP. This revealed a role of HO-1for maintaining immuneunresponsiveness in exhausted miR-155~(-/-)CD4~+T cells. HO-1inhibition with ZnPPincreased IL-2secretion from na ve miR-155~(-/-)CD4~+T cells after in vitro stimulation withanti-CD3/CD28antibodies, however, HO-1inhibition did not improve the capacity ofexhausted miR-155~(-/-)CD4~+T cells to produce IFN-γ. HO-1activity could account for T cellunresponsiveness in our system.
4. B6with CoPP treatment lowered the clinal signs of EAE. ZnPP inhibition worsedthe clinical signs of EAE in miR-155~(-/-)mice with more CD3~+T cell infiltrated into the brain.Th1and Th17cell responses in miR-155~(-/-)mice were lower than that in the other groups.
[Conclusion]
1. Exposure to persistent systemic antigen stimulation leads to T cell exhaustion,whose activity is controlled by PD-1.
2. MiR-155is not required for T cell exhaustion, but it is indispensable for restoring Tcell function in the absence of PD-1inhibition.
3. Hmox1is a direct target of miR-155. HO-1is responsible for maintaining immuneunresponsiveness in exhausted miR-155~(-/-)CD4~+T cells.
4. Inhibition of HO-1rescues susceptibility to EAE in miR-155~(-/-)mice.
[Significance]
1. We developed a CD4~+T cell exhaustion model, which could be used for furtherstudy of T cell exhaustion.
2. Our work has revealed one novel pathway in which miR-155, by targeting Hmox1,promotes T cell mediated inflammation.
3. Inhibition HO-1could rescue the proliferative capacity of exhausted CD4~+T cells,which could be essential for the development of innovative immunotherapies in chronicimmunological diseases.
引文
1Wherry EJ (2011) T cell exhaustion. Nat Immunol12:492-499.
2Francisco LM, Sage PT, Sharpe AH (2010) The PD-1pathway in tolerance and autoimmunity. Immunol Rev236:219-242.
3Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T (1994) Structure and chromosomal localization of thehuman PD-1gene (PDCD1). Genomics23:704-706.
4Ishida Y, Agata Y, Shibahara K, Honjo T (1992) Induced expression of PD-1, a novel member of the immunoglobulingene superfamily, upon programmed cell death. EMBO J11:3887-3895.
1Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, et al.(2006) Restoring function in exhausted CD8T cellsduring chronic viral infection. Nature439:682-687.
2Ambros V (2004) The functions of animal microRNAs. Nature431:350-355.
Muljo SA, Ansel KM, Kanellopoulou C, Livingston DM, Rao A, et al.(2005) Aberrant T cell differentiation in theabsence of Dicer. J Exp Med202:261-269.
4Cobb BS, Nesterova TB, Thompson E, Hertweck A, O'Connor E, et al.(2005) T cell lineage choice and differentiationin the absence of the RNase III enzyme Dicer. J Exp Med201:1367-1373.
5Guo S, Lu J, Schlanger R, Zhang H, Wang JY, et al.(2010) MicroRNA miR-125a controls hematopoietic stem cellnumber. Proc Natl Acad Sci U S A107:14229-14234.
6Koralov SB, Muljo SA, Galler GR, Krek A, Chakraborty T, et al.(2008) Dicer ablation affects antibody diversity and
7cell survival in the B lymphocyte lineage. Cell132:860-874.Liston A, Lu LF, O'Carroll D, Tarakhovsky A, Rudensky AY (2008) Dicer-dependent microRNA pathway safeguardsregulatory T cell function. J Exp Med205:1993-2004.
8Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, et al.(2009) Cutting edge: the Foxp3target miR-155contributes to the development of regulatory T cells. J Immunol182:2578-2582.
9Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, et al.(2009) Foxp3-dependent microRNA155confers competitivefitness to regulatory T cells by targeting SOCS1protein. Immunity30:80-91.
10O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al.(2010) MicroRNA-155promotes autoimmuneinflammation by enhancing inflammatory T cell development. Immunity33:607-619.
Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, et al.(2007) Regulation of the germinal center response bymicroRNA-155. Science316:604-608.
1Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL (2010) Micro-RNA-155inhibits IFN-gammasignaling in CD4+T cells. Eur J Immunol40:225-231.
2Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, et al.(2007) microRNA-155regulates the generation ofimmunoglobulin class-switched plasma cells. Immunity27:847-859.
Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, et al.(2007) Regulation of the germinal center response bymicroRNA-155. Science316:604-608.
1Noval Rivas M, Weatherly K, Hazzan M, Vokaer B, Dremier S, et al.(2009) Reviving function in CD4+T cellsadapted to persistent systemic antigen. J Immunol183:4284-4291.
1Noval Rivas M, Weatherly K, Hazzan M, Vokaer B, Dremier S, et al.(2009) Reviving function in CD4+T cellsadapted to persistent systemic antigen. J Immunol183:4284-4291.
Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R (2003) Viral persistence alters CD8T-cellimmunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol77:4911-4927.
1Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, et al.(2006) Restoring function in exhausted CD8T cellsduring chronic viral infection. Nature439:682-687.
1Wherry EJ (2011) T cell exhaustion. Nat Immunol12:492-499.
2Noval Rivas M, Weatherly K, Hazzan M, Vokaer B, Dremier S, et al.(2009) Reviving function in CD4+T cellsadapted to persistent systemic antigen. J Immunol183:4284-4291.
Noval Rivas M, Weatherly K, Hazzan M, Vokaer B, Dremier S, et al.(2009) Reviving function in CD4+T cellsadapted to persistent systemic antigen. J Immunol183:4284-4291.
1Noval Rivas M, Weatherly K, Hazzan M, Vokaer B, Dremier S, et al.(2009) Reviving function in CD4+T cellsadapted to persistent systemic antigen. J Immunol183:4284-4291.
2Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, et al.(1998) Viral immune evasion due topersistence of activated T cells without effector function. J Exp Med188:2205-2213.
3Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R (2003) Viral persistence alters CD8T-cellimmunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol77:4911-4927.
4Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, et al.(2006) HIV nonprogressors preferentially maintainhighly functional HIV-specific CD8+T cells. Blood107:4781-4789.
5Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, et al.(2000) Analysis of successful immune responses inpersons infected with hepatitis C virus. J Exp Med191:1499-1512.
6Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, et al.(2006) Restoring function in exhausted CD8T cellsduring chronic viral infection. Nature439:682-687.
7Nishimura H, Agata Y, Kawasaki A, Sato M, Imamura S, et al.(1996) Developmentally regulated expression of thePD-1protein on the surface of double-negative (CD4-CD8-) thymocytes. Int Immunol8:773-780.
8Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1and its ligands in tolerance and immunity. Annu RevImmunol26:677-704.
9Polanczyk MJ, Hopke C, Vandenbark AA, Offner H (2006) Estrogen-mediated immunomodulation involves reducedactivation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1costimulatory pathway. JNeurosci Res84:370-378.
1Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, et al.(1996) Expression of the PD-1antigen on the surfaceof stimulated mouse T and B lymphocytes. Int Immunol8:765-772.
2Freeman GJ, Wherry EJ, Ahmed R, Sharpe AH (2006) Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1ligand blockade. J Exp Med203:2223-2227.
3Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, et al.(2008) The common gamma-chain cytokines IL-2, IL-7,IL-15, and IL-21induce the expression of programmed death-1and its ligands. J Immunol181:6738-6746.
4Oestreich KJ, Yoon H, Ahmed R, Boss JM (2008) NFATc1regulates PD-1expression upon T cell activation. JImmunol181:4832-4839.
5Cho HY, Lee SW, Seo SK, Choi IW, Choi I (2008) Interferon-sensitive response element (ISRE) is mainly responsiblefor IFN-alpha-induced upregulation of programmed death-1(PD-1) in macrophages. Biochim Biophys Acta1779:811-819.
6Yao S, Wang S, Zhu Y, Luo L, Zhu G, et al.(2009) PD-1on dendritic cells impedes innate immunity against bacterialinfection. Blood113:5811-5818.
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, et al.(2000) Engagement of the PD-1immunoinhibitoryreceptor by a novel B7family member leads to negative regulation of lymphocyte activation. J Exp Med192:1027-1034.
8Francisco LM, Sage PT, Sharpe AH (2010) The PD-1pathway in tolerance and autoimmunity. Immunol Rev236:219-242.
9Blank C, Mackensen A (2007) Contribution of the PD-L1/PD-1pathway to T-cell exhaustion: an update onimplications for chronic infections and tumor evasion. Cancer Immunol Immunother56:739-745.
10Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, et al.(2004) PD-1inhibits T-cell receptor inducedphosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett574:37-41.
Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, et al.(2005) CTLA-4and PD-1receptors inhibitT-cell activation by distinct mechanisms. Mol Cell Biol25:9543-9553.
1Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, et al.(2005) CTLA-4and PD-1receptors inhibitT-cell activation by distinct mechanisms. Mol Cell Biol25:9543-9553.
2Bennett F, Luxenberg D, Ling V, Wang IM, Marquette K, et al.(2003) Program death-1engagement upon TCRactivation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21,but not CD28, IL-7, and IL-15responses. J Immunol170:711-718.
3Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, et al.(2006) Upregulation of PD-1expression onHIV-specific CD8+T cells leads to reversible immune dysfunction. Nat Med12:1198-1202.
4Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, et al.(2006) Restoring function in exhausted CD8T cellsduring chronic viral infection. Nature439:682-687.
5Freeman GJ, Wherry EJ, Ahmed R, Sharpe AH (2006) Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1ligand blockade. J Exp Med203:2223-2227.
Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, et al.(2004) PD-L1/B7H-1inhibits the effector phase of tumorrejection by T cell receptor (TCR) transgenic CD8+T cells. Cancer Res64:1140-1145.
1O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al.(2010) MicroRNA-155promotes autoimmuneinflammation by enhancing inflammatory T cell development. Immunity33:607-619.
1Ambros V (2004) The functions of animal microRNAs. Nature431:350-355.
2Cai X, Hagedorn CH, Cullen BR (2004) Human microRNAs are processed from capped, polyadenylated transcriptsthat can also function as mRNAs. RNA10:1957-1966.
3Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004) Processing of primary microRNAs by theMicroprocessor complex. Nature432:231-235.
4Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U (2004) Nuclear export of microRNA precursors. Science303:95-98.
Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4encodes small RNAs with antisensecomplementarity to lin-14. Cell75:843-854.
1Muljo SA, Ansel KM, Kanellopoulou C, Livingston DM, Rao A, et al.(2005) Aberrant T cell differentiation in theabsence of Dicer. J Exp Med202:261-269.
2Cobb BS, Nesterova TB, Thompson E, Hertweck A, O'Connor E, et al.(2005) T cell lineage choice and differentiationin the absence of the RNase III enzyme Dicer. J Exp Med201:1367-1373.
3Guo S, Lu J, Schlanger R, Zhang H, Wang JY, et al.(2010) MicroRNA miR-125a controls hematopoietic stem cellnumber. Proc Natl Acad Sci U S A107:14229-14234.
4Koralov SB, Muljo SA, Galler GR, Krek A, Chakraborty T, et al.(2008) Dicer ablation affects antibody diversity andcell survival in the B lymphocyte lineage. Cell132:860-874.
Bronevetsky Y, Villarino AV, Eisley CJ, Barbeau R, Barczak AJ, et al.(2013) T cell activation induces proteasomaldegradation of Argonaute and rapid remodeling of the microRNA repertoire. J Exp Med210:417-432.
6Liston A, Lu LF, O'Carroll D, Tarakhovsky A, Rudensky AY (2008) Dicer-dependent microRNA pathway safeguardsregulatory T cell function. J Exp Med205:1993-2004.
7Liston A, Lu LF, O'Carroll D, Tarakhovsky A, Rudensky AY (2008) Dicer-dependent microRNA pathway safeguardsregulatory T cell function. J Exp Med205:1993-2004.
8Li QJ, Chau J, Ebert PJ, Sylvester G, Min H, et al.(2007) miR-181a is an intrinsic modulator of T cell sensitivity andselection. Cell129:147-161.
Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, et al.(2010) Function of miR-146a in controlling Tregcell-mediated regulation of Th1responses. Cell142:914-929.
1Stittrich AB, Haftmann C, Sgouroudis E, Kuhl AA, Hegazy AN, et al.(2010) The microRNA miR-182is induced byIL-2and promotes clonal expansion of activated helper T lymphocytes. Nat Immunol11:1057-1062.
2Mattes J, Collison A, Plank M, Phipps S, Foster PS (2009) Antagonism of microRNA-126suppresses the effectorfunction of TH2cells and the development of allergic airways disease. Proc Natl Acad Sci U S A106:18704-18709.
3Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, et al.(2007) Requirement of bic/microRNA-155for normalimmune function. Science316:608-611.
Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, et al.(2009) Foxp3-dependent microRNA155confers competitivefitness to regulatory T cells by targeting SOCS1protein. Immunity30:80-91.
5Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs:are the answers in sight? Nat Rev Genet9:102-114.
6Bronevetsky Y, Villarino AV, Eisley CJ, Barbeau R, Barczak AJ, et al.(2013) T cell activation induces proteasomaldegradation of Argonaute and rapid remodeling of the microRNA repertoire. J Exp Med210:417-432.
7Jiang S, Li C, Olive V, Lykken E, Feng F, et al.(2011) Molecular dissection of the miR-17-92cluster's critical dualroles in promoting Th1responses and preventing inducible Treg differentiation. Blood118:5487-5497.
Ma F, Xu S, Liu X, Zhang Q, Xu X, et al.(2011) The microRNA miR-29controls innate and adaptive immuneresponses to intracellular bacterial infection by targeting interferon-gamma. Nat Immunol12:861-869.
1Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, et al.(2009) Foxp3-dependent microRNA155confers competitivefitness to regulatory T cells by targeting SOCS1protein. Immunity30:80-91.
2Takahashi R, Nishimoto S, Muto G, Sekiya T, Tamiya T, et al.(2011) SOCS1is essential for regulatory T cellfunctions by preventing loss of Foxp3expression as well as IFN-{gamma} and IL-17A production. J Exp Med208:2055-2067.
1O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al.(2010) MicroRNA-155promotes autoimmuneinflammation by enhancing inflammatory T cell development. Immunity33:607-619.
1Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, et al.(2007) A mammalian microRNA expression atlas based onsmall RNA library sequencing. Cell129:1401-1414.
2Eis PS, Tam W, Sun L, Chadburn A, Li Z, et al.(2005) Accumulation of miR-155and BIC RNA in human B celllymphomas. Proc Natl Acad Sci U S A102:3627-3632.
Kutty RK, Nagineni CN, Samuel W, Vijayasarathy C, Hooks JJ, et al.(2010) Inflammatory cytokines regulatemicroRNA-155expression in human retinal pigment epithelial cells by activating JAK/STAT pathway. Biochem BiophysRes Commun402:390-395.
4O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D (2007) MicroRNA-155is induced during themacrophage inflammatory response. Proc Natl Acad Sci U S A104:1604-1609.
5Haasch D, Chen YW, Reilly RM, Chiou XG, Koterski S, et al.(2002) T cell activation induces a noncoding RNAtranscript sensitive to inhibition by immunosuppressant drugs and encoded by the proto-oncogene, BIC. Cell Immunol217:78-86.
Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, et al.(2007) Requirement of bic/microRNA-155for normalimmune function. Science316:608-611.
1Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer6:857-866.
2Metzler M, Wilda M, Busch K, Viehmann S, Borkhardt A (2004) High expression of precursor microRNA-155/BICRNA in children with Burkitt lymphoma. Genes Chromosomes Cancer39:167-169.
3Eis PS, Tam W, Sun L, Chadburn A, Li Z, et al.(2005) Accumulation of miR-155and BIC RNA in human B celllymphomas. Proc Natl Acad Sci U S A102:3627-3632.
4O'Connell RM, Rao DS, Chaudhuri AA, Boldin MP, Taganov KD, et al.(2008) Sustained expression ofmicroRNA-155in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med205:585-594.
O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al.(2010) MicroRNA-155promotes autoimmuneinflammation by enhancing inflammatory T cell development. Immunity33:607-619.
6Bluml S, Bonelli M, Niederreiter B, Puchner A, Mayr G, et al.(2011) Essential role of microRNA-155in thepathogenesis of autoimmune arthritis in mice. Arthritis Rheum63:1281-1288.
7Oertli M, Engler DB, Kohler E, Koch M, Meyer TF, et al.(2011) MicroRNA-155is essential for the T cell-mediatedcontrol of Helicobacter pylori infection and for the induction of chronic Gastritis and Colitis. J Immunol187:3578-3586.
8Dudda JC, Salaun B, Ji Y, Palmer DC, Monnot GC, et al.(2013) MicroRNA-155is required for effector CD8+T cellresponses to virus infection and cancer. Immunity38:742-753.
Clare S, John V, Walker AW, Hill JL, Abreu-Goodger C, et al.(2013) Enhanced susceptibility to Citrobacterrodentium infection in microRNA-155-deficient mice. Infect Immun81:723-732.
1Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, et al.(2007) Requirement of bic/microRNA-155for normalimmune function. Science316:608-611.
2Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, et al.(2007) Regulation of the germinal center response bymicroRNA-155. Science316:604-608.
3Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, et al.(2007) microRNA-155regulates the generation ofimmunoglobulin class-switched plasma cells. Immunity27:847-859.
4Ramiro AR, Jankovic M, Eisenreich T, Difilippantonio S, Chen-Kiang S, et al.(2004) AID is required for c-myc/IgHchromosome translocations in vivo. Cell118:431-438.
5Cobb BS, Hertweck A, Smith J, O'Connor E, Graf D, et al.(2006) A role for Dicer in immune regulation. J Exp Med203:2519-2527.
6Niimoto T, Nakasa T, Ishikawa M, Okuhara A, Izumi B, et al.(2010) MicroRNA-146a expresses in interleukin-17producing T cells in rheumatoid arthritis patients. BMC Musculoskelet Disord11:209.
7Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, et al.(2009) Cutting edge: the Foxp3target miR-155contributes to the development of regulatory T cells. J Immunol182:2578-2582.
8Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, et al.(2009) Foxp3-dependent microRNA155confers competitivefitness to regulatory T cells by targeting SOCS1protein. Immunity30:80-91.
9Yao R, Ma YL, Liang W, Li HH, Ma ZJ, et al.(2012) MicroRNA-155modulates Treg and Th17cells differentiationand Th17cell function by targeting SOCS1. PLoS One7: e46082.
10Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, et al.(2007) Regulation of the germinal center response bymicroRNA-155. Science316:604-608.
11Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL (2010) Micro-RNA-155inhibits IFN-gammasignaling in CD4+T cells. Eur J Immunol40:225-231.
12Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, et al.(2007) Requirement of bic/microRNA-155for normalimmune function. Science316:608-611.
O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al.(2010) MicroRNA-155promotes autoimmuneinflammation by enhancing inflammatory T cell development. Immunity33:607-619.
1Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, et al.(2009) Foxp3-dependent microRNA155confers competitivefitness to regulatory T cells by targeting SOCS1protein. Immunity30:80-91.
1Ramiro AR, Jankovic M, Eisenreich T, Difilippantonio S, Chen-Kiang S, et al.(2004) AID is required for c-myc/IgHchromosome translocations in vivo. Cell118:431-438.
2Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, et al.(2007) microRNA-155regulates the generation ofimmunoglobulin class-switched plasma cells. Immunity27:847-859.
3Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, et al.(2009) Cutting edge: the Foxp3target miR-155contributes to the development of regulatory T cells. J Immunol182:2578-2582.
4Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, et al.(2009) Foxp3-dependent microRNA155confers competitivefitness to regulatory T cells by targeting SOCS1protein. Immunity30:80-91.
Dudda JC, Salaun B, Ji Y, Palmer DC, Monnot GC, et al.(2013) MicroRNA-155is required for effector CD8+T cellresponses to virus infection and cancer. Immunity38:742-753.
6Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, et al.(2007) Regulation of the germinal center response bymicroRNA-155. Science316:604-608.
7Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL (2010) Micro-RNA-155inhibits IFN-gammasignaling in CD4+T cells. Eur J Immunol40:225-231.
8O'Connell RM, Chaudhuri AA, Rao DS, Baltimore D (2009) Inositol phosphatase SHIP1is a primary target ofmiR-155. Proc Natl Acad Sci U S A106:7113-7118.
Tenhunen R, Marver HS, Schmid R (1968) The enzymatic conversion of heme to bilirubin by microsomal hemeoxygenase. Proc Natl Acad Sci U S A61:748-755.
1Jozkowicz A, Was H, Dulak J (2007) Heme oxygenase-1in tumors: is it a false friend? Antioxid Redox Signal9:2099-2117.
2Panchenko MV, Farber HW, Korn JH (2000) Induction of heme oxygenase-1by hypoxia and free radicals in humandermal fibroblasts. Am J Physiol Cell Physiol278: C92-C101.
3Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, et al.(1992) Ferritin: a cytoprotective antioxidant strategem ofendothelium. J Biol Chem267:18148-18153.
Yet SF, Layne MD, Liu X, Chen YH, Ith B, et al.(2003) Absence of heme oxygenase-1exacerbates atheroscleroticlesion formation and vascular remodeling. FASEB J17:1759-1761.
5Zenke-Kawasaki Y, Dohi Y, Katoh Y, Ikura T, Ikura M, et al.(2007) Heme induces ubiquitination and degradation ofthe transcription factor Bach1. Mol Cell Biol27:6962-6971.
6Hira S, Tomita T, Matsui T, Igarashi K, Ikeda-Saito M (2007) Bach1, a heme-dependent transcription factor, revealspresence of multiple heme binding sites with distinct coordination structure. IUBMB Life59:542-551.
7Zenke-Kawasaki Y, Dohi Y, Katoh Y, Ikura T, Ikura M, et al.(2007) Heme induces ubiquitination and degradation ofthe transcription factor Bach1. Mol Cell Biol27:6962-6971.
Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, et al.(1999) Nrf2, a Cap'n'Collar transcription factor,regulates induction of the heme oxygenase-1gene. J Biol Chem274:26071-26078.
1Tenhunen R, Marver HS, Schmid R (1968) The enzymatic conversion of heme to bilirubin by microsomal hemeoxygenase. Proc Natl Acad Sci U S A61:748-755.
2Wilks A (2002) Heme oxygenase: evolution, structure, and mechanism. Antioxid Redox Signal4:603-614.
3Jozkowicz A, Was H, Dulak J (2007) Heme oxygenase-1in tumors: is it a false friend? Antioxid Redox Signal9:2099-2117.
4Brouard S, Otterbein LE, Anrather J, Tobiasch E, Bach FH, et al.(2000) Carbon monoxide generated by hemeoxygenase1suppresses endothelial cell apoptosis. J Exp Med192:1015-1026.
5Gozzelino R, Jeney V, Soares MP (2010) Mechanisms of cell protection by heme oxygenase-1. Annu Rev PharmacolToxicol50:323-354.
6Bilban M, Bach FH, Otterbein SL, Ifedigbo E, d'Avila JC, et al.(2006) Carbon monoxide orchestrates a protectiveresponse through PPARgamma. Immunity24:601-610.
7Nakao A, Kimizuka K, Stolz DB, Neto JS, Kaizu T, et al.(2003) Carbon monoxide inhalation protects rat intestinalgrafts from ischemia/reperfusion injury. Am J Pathol163:1587-1598.
8Chin BY, Jiang G, Wegiel B, Wang HJ, Macdonald T, et al.(2007) Hypoxia-inducible factor1alpha stabilization bycarbon monoxide results in cytoprotective preconditioning. Proc Natl Acad Sci U S A104:5109-5114.
9Brouard S, Berberat PO, Tobiasch E, Seldon MP, Bach FH, et al.(2002) Heme oxygenase-1-derived carbon monoxiderequires the activation of transcription factor NF-kappa B to protect endothelial cells from tumor necrosisfactor-alpha-mediated apoptosis. J Biol Chem277:17950-17961.
10Ferris CD, Jaffrey SR, Sawa A, Takahashi M, Brady SD, et al.(1999) Haem oxygenase-1prevents cell death byregulating cellular iron. Nat Cell Biol1:152-157.
Ferris CD, Jaffrey SR, Sawa A, Takahashi M, Brady SD, et al.(1999) Haem oxygenase-1prevents cell death byregulating cellular iron. Nat Cell Biol1:152-157.
1Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, et al.(2004) Ferritin heavy chain upregulation by NF-kappaBinhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species. Cell119:529-542.
2Brouard S, Berberat PO, Tobiasch E, Seldon MP, Bach FH, et al.(2002) Heme oxygenase-1-derived carbon monoxiderequires the activation of transcription factor NF-kappa B to protect endothelial cells from tumor necrosisfactor-alpha-mediated apoptosis. J Biol Chem277:17950-17961.
3Maghzal GJ, Leck MC, Collinson E, Li C, Stocker R (2009) Limited role for the bilirubin-biliverdin redoxamplification cycle in the cellular antioxidant protection by biliverdin reductase. J Biol Chem284:29251-29259.
4Fondevila C, Shen XD, Tsuchiyashi S, Yamashita K, Csizmadia E, et al.(2004) Biliverdin therapy protects rat liversfrom ischemia and reperfusion injury. Hepatology40:1333-1341.
5Wang H, Lee SS, Dell'Agnello C, Tchipashvili V, d'Avila JC, et al.(2006) Bilirubin can induce tolerance to isletallografts. Endocrinology147:762-768.
6Fondevila C, Shen XD, Tsuchiyashi S, Yamashita K, Csizmadia E, et al.(2004) Biliverdin therapy protects rat liversfrom ischemia and reperfusion injury. Hepatology40:1333-1341.
7Hu CM, Lin HH, Chiang MT, Chang PF, Chau LY (2007) Systemic expression of heme oxygenase-1ameliorates type1diabetes in NOD mice. Diabetes56:1240-1247.
8Chora AA, Fontoura P, Cunha A, Pais TF, Cardoso S, et al.(2007) Heme oxygenase-1and carbon monoxide suppressautoimmune neuroinflammation. J Clin Invest117:438-447.
9Lehmann E, El-Tantawy WH, Ocker M, Bartenschlager R, Lohmann V, et al.(2010) The heme oxygenase1productbiliverdin interferes with hepatitis C virus replication by increasing antiviral interferon response. Hepatology51:398-404.
10Protzer U, Seyfried S, Quasdorff M, Sass G, Svorcova M, et al.(2007) Antiviral activity and hepatoprotection byheme oxygenase-1in hepatitis B virus infection. Gastroenterology133:1156-1165.
11Silva-Gomes S, Appelberg R, Larsen R, Soares MP, Gomes MS (2013) Heme catabolism by heme oxygenase-11c2onfers host resistance to Mycobacterium infection. Infect Immun81:2536-2545.
Pamplona A, Ferreira A, Balla J, Jeney V, Balla G, et al.(2007) Heme oxygenase-1and carbon monoxide suppress thepathogenesis of experimental cerebral malaria. Nat Med13:703-710.
13Doi K, Akaike T, Fujii S, Tanaka S, Ikebe N, et al.(1999) Induction of haem oxygenase-1nitric oxide and ischaemiain experimental solid tumours and implications for tumour growth. Br J Cancer80:1945-1954
14Deininger MH, Meyermann R, Trautmann K, Duffner F, Grote EH, et al.(2000) Heme oxygenase (HO)-1expressingmacrophages/microglial cells accumulate during oligodendroglioma progression. Brain Res882:1-8
15Torisu-Itakura H, Furue M, Kuwano M, Ono M (2000) Co-expression of thymidine phosphorylase and hemeoxygenase-1in macrophages in human malignant vertical growth melanomas. Jpn J Cancer Res91:906-910.
Tsuji MH, Yanagawa T, Iwasa S, Tabuchi K, Onizawa K, et al.(1999) Heme oxygenase-1expression in oralsquamous cell carcinoma as involved in lymph node metastasis. Cancer Lett138:53-59.
1Pae HO, Oh GS, Choi BM, Chae SC, Kim YM, et al.(2004) Carbon monoxide produced by heme oxygenase-1suppresses T cell proliferation via inhibition of IL-2production. J Immunol172:4744-4751.
1Burt TD, Seu L, Mold JE, Kappas A, McCune JM (2010) Naive human T cells are activated and proliferate in responseto the heme oxygenase-1inhibitor tin mesoporphyrin. J Immunol185:5279-5288.
1Soares MP, Bach FH (2009) Heme oxygenase-1: from biology to therapeutic potential. Trends Mol Med15:50-58.
2Exner M, Minar E, Wagner O, Schillinger M (2004) The role of heme oxygenase-1promoter polymorphisms in humandisease. Free Radic Biol Med37:1097-1104.
Hengartner MO, Horvitz HR (1994) Programmed cell death in Caenorhabditis elegans. Curr Opin Genet Dev4:581-586.
1Soares MP, Lin Y, Anrather J, Csizmadia E, Takigami K, et al.(1998) Expression of heme oxygenase-1can determinecardiac xenograft survival. Nat Med4:1073-1077.
2Tartaglia LA, Rothe M, Hu YF, Goeddel DV (1993) Tumor necrosis factor's cytotoxic activity is signaled by the p55TNF receptor. Cell73:213-216.
3Soares MP, Seldon MP, Gregoire IP, Vassilevskaia T, Berberat PO, et al.(2004) Heme oxygenase-1modulates theexpression of adhesion molecules associated with endothelial cell activation. J Immunol172:3553-3563.
4Mahoney DJ, Cheung HH, Mrad RL, Plenchette S, Simard C, et al.(2008) Both cIAP1and cIAP2regulateTNFalpha-mediated NF-kappaB activation. Proc Natl Acad Sci U S A105:11778-11783.
5Micheau O, Tschopp J (2003) Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.Cell114:181-190.
6Perkins ND (2007) Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol8:49-62.
7Perkins ND (2007) Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol8:49-62.
8Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U (1995) Control of I kappa B-alpha proteolysis bysite-specific, signal-induced phosphorylation. Science267:1485-1488.
9Chen Z, Hagler J, Palombella VJ, Melandri F, Scherer D, et al.(1995) Signal-induced site-specific phosphorylationtargets I kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev9:1586-1597.
10Henkel T, Machleidt T, Alkalay I, Kronke M, Ben-Neriah Y, et al.(1993) Rapid proteolysis of I kappa B-alpha isnecessary for activation of transcription factor NF-kappa B. Nature365:182-185.
11Brouard S, Berberat PO, Tobiasch E, Seldon MP, Bach FH, et al.(2002) Heme oxygenase-1-derived carbon monoxiderequires the activation of transcription factor NF-kappa B to protect endothelial cells from tumor necrosisfactor-alpha-mediated apoptosis. J Biol Chem277:17950-17961.
12Brouard S, Berberat PO, Tobiasch E, Seldon MP, Bach FH, et al.(2002) Heme oxygenase-1-derived carbon monoxiderequires the activation of transcription factor NF-kappa B to protect endothelial cells from tumor necrosisfactor-alpha-mediated apoptosis. J Biol Chem277:17950-17961.
13Seldon MP, Silva G, Pejanovic N, Larsen R, Gregoire IP, et al.(2007) Heme oxygenase-1inhibits the expression ofadhesion molecules associated with endothelial cell activation via inhibition of NF-kappaB RelA phosphorylation atserine276. J Immunol179:7840-7851.
Micheau O, Tschopp J (2003) Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.Cell114:181-190.
1Fiers W, Beyaert R, Declercq W, Vandenabeele P (1999) More than one way to die: apoptosis, necrosis and reactiveoxygen damage. Oncogene18:7719-7730.
2Brouard S, Otterbein LE, Anrather J, Tobiasch E, Bach FH, et al.(2000) Carbon monoxide generated by hemeoxygenase1suppresses endothelial cell apoptosis. J Exp Med192:1015-1026.
3Arruda MA, Rossi AG, de Freitas MS, Barja-Fidalgo C, Graca-Souza AV (2004) Heme inhibits human neutrophilapoptosis: involvement of phosphoinositide3-kinase, MAPK, and NF-kappaB. J Immunol173:2023-2030.
4Wada T, Penninger JM (2004) Mitogen-activated protein kinases in apoptosis regulation. Oncogene23:2838-2849.
5Silva G, Cunha A, Gregoire IP, Seldon MP, Soares MP (2006) The antiapoptotic effect of heme oxygenase-1inendothelial cells involves the degradation of p38alpha MAPK isoform. J Immunol177:1894-1903.
6Zhang X, Shan P, Alam J, Fu XY, Lee PJ (2005) Carbon monoxide differentially modulates STAT1and STAT3andinhibits apoptosis via a phosphatidylinositol3-kinase/Akt and p38kinase-dependent STAT3pathway duringanoxia-reoxygenation injury. J Biol Chem280:8714-8721.
7Salinas M, Wang J, Rosa de Sagarra M, Martin D, Rojo AI, et al.(2004) Protein kinase Akt/PKB phosphorylates hemeoxygenase-1in vitro and in vivo. FEBS Lett578:90-94.
8Katori M, Buelow R, Ke B, Ma J, Coito AJ, et al.(2002) Heme oxygenase-1overexpression protects rat hearts fromcold ischemia/reperfusion injury via an antiapoptotic pathway. Transplantation73:287-292.
Pae HO, Oh GS, Choi BM, Chae SC, Kim YM, et al.(2004) Carbon monoxide produced by heme oxygenase-1suppresses T cell proliferation via inhibition of IL-2production. J Immunol172:4744-4751.
1McDaid J, Yamashita K, Chora A, Ollinger R, Strom TB, et al.(2005) Heme oxygenase-1modulates the allo-immuneresponse by promoting activation-induced cell death of T cells. FASEB J19:458-460.
1Urban JL, Kumar V, Kono DH, Gomez C, Horvath SJ, et al.(1988) Restricted use of T cell receptor V genes in murineautoimmune encephalomyelitis raises possibilities for antibody therapy. Cell54:577-592.
1Mendel I, Kerlero de Rosbo N, Ben-Nun A (1995) A myelin oligodendrocyte glycoprotein peptide induces typicalchronic experimental autoimmune encephalomyelitis in H-2b mice: fine specificity and T cell receptor V beta expressionof encephalitogenic T cells. Eur J Immunol25:1951-1959.
2Jones MV, Nguyen TT, Deboy CA, Griffin JW, Whartenby KA, et al.(2008) Behavioral and pathological outcomes inMOG35-55experimental autoimmune encephalomyelitis. J Neuroimmunol199:83-93.
3Brostoff SW, Mason DW (1984) Experimental allergic encephalomyelitis: successful treatment in vivo with amonoclonal antibody that recognizes T helper cells. J Immunol133:1938-1942.
4Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol23:683-747.
1Hafler DA (2004) Multiple sclerosis. J Clin Invest113:788-794.
2Gocke AR, Cravens PD, Ben LH, Hussain RZ, Northrop SC, et al.(2007) T-bet regulates the fate of Th1and Th17lymphocytes in autoimmunity. J Immunol178:1341-1348.
3Heremans H, Dillen C, Groenen M, Martens E, Billiau A (1996) Chronic relapsing experimental autoimmuneencephalomyelitis (CREAE) in mice: enhancement by monoclonal antibodies against interferon-gamma. Eur J Immunol
426:2393-2398.Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, et al.(2003) Interleukin-23rather than interleukin-12is the criticalcytokine for autoimmune inflammation of the brain. Nature421:744-748.
5Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, et al.(2005) IL-23drives a pathogenic T cellpopulation that induces autoimmune inflammation. J Exp Med201:233-240.
6Eugster HP, Frei K, Kopf M, Lassmann H, Fontana A (1998) IL-6-deficient mice resist myelin oligodendrocyteglycoprotein-induced autoimmune encephalomyelitis. Eur J Immunol28:2178-2187.
7Park H, Li Z, Yang XO, Chang SH, Nurieva R, et al.(2005) A distinct lineage of CD4T cells regulates tissueinflammation by producing interleukin17. Nat Immunol6:1133-1141.
Du C, Liu C, Kang J, Zhao G, Ye Z, et al.(2009) MicroRNA miR-326regulates TH-17differentiation and is associatedwith the pathogenesis of multiple sclerosis. Nat Immunol10:1252-1259.
9Mycko MP, Cichalewska M, Machlanska A, Cwiklinska H, Mariasiewicz M, et al.(2012) MicroRNA-301a regulationof a T-helper17immune response controls autoimmune demyelination. Proc Natl Acad Sci U S A109: E1248-1257.
10O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al.(2010) MicroRNA-155promotes autoimmuneinflammation by enhancing inflammatory T cell development. Immunity33:607-619.
11Laatsch RH (1962) Glycerol phosphate dehydrogenase activity of developing rat central nervous system. J Neurochem192:487-492.
Chora AA, Fontoura P, Cunha A, Pais TF, Cardoso S, et al.(2007) Heme oxygenase-1and carbon monoxide suppressautoimmune neuroinflammation. J Clin Invest117:438-447.
1So AY, Garcia-Flores Y, Minisandram A, Martin A, Taganov K, et al.(2012) Regulation of APC development,immune response, and autoimmunity by Bach1/HO-1pathway in mice. Blood120:2428-2437.
1Kusters, J.G., van Vliet, A.H.&Kuipers, E.J.(2006) Pathogenesis of Helicobacter pylori infection. Clin Microbiol Rev19,449-490.
2Pappo, J., et al.(1999) Helicobacter pylori infection in immunized mice lacking major histocompatibility complexclass I and class II functions. Infect Immun67,337-341
3Dong, C.(2008) TH17cells in development: an updated view of their molecular identity and genetic programming. NatRev Immunol8,337-348.
4Shi, Y., et al.(2010) Helicobacter pylori-induced Th17responses modulate Th1cell responses, benefit bacterial growth,
5and contribute to pathology in mice. J Immunol184,5121-5129.Andersen, L.P.(2007) Colonization and infection by Helicobacter pylori in humans. Helicobacter12Suppl2,12-15.
6Tan, S.&Berg, D.E.(2004) Motility of urease-deficient derivatives of Helicobacter pylori. J Bacteriol186,885-888.
1Andrutis, K.A., et al.(1995) Inability of an isogenic urease-negative mutant stain of Helicobacter mustelae to colonizethe ferret stomach. Infect Immun63,3722-3725.
2Harris, P.R., Mobley, H.L., Perez-Perez, G.I., Blaser, M.J.&Smith, P.D.(1996) Helicobacter pylori urease is a potentstimulus of mononuclear phagocyte activation and inflammatory cytokine production. Gastroenterology111,419-425.
DeLyria, E.S., Redline, R.W.&Blanchard, T.G.(2009) Vaccination of mice against H pylori induces a strong Th-17response and immunity that is neutrophil dependent. Gastroenterology136,247-256.
1Lu, D.S., et al.(2003)[Recombinant Helicobacter pylori urease B subunit and its biological properties]. Di Yi Jun YiDa Xue Xue Bao23,549-552.
1Oppmann, B., et al.(2000) Novel p19protein engages IL-12p40to form a cytokine, IL-23, with biological activitiessimilar as well as distinct from IL-12. Immunity13,715-725.
2Kryczek, I., et al.(2007) Cutting edge: opposite effects of IL-1and IL-2on the regulation of IL-17+T cell pool IL-1subverts IL-2-mediated suppression. J Immunol179,1423-1426.
3Ivanov, II, et al.(2006) The orphan nuclear receptor RORgammat directs the differentiation program ofproinflammatory IL-17+T helper cells. Cell126,1121-1133.
Zhou, L., et al.(2007) IL-6programs T(H)-17cell differentiation by promoting sequential engagement of the IL-21andIL-23pathways. Nat Immunol8,967-974.
1Ambros V (2004) The functions of animal microRNAs. Nature431:350-355.
2Cai X, Hagedorn CH, Cullen BR (2004) Human microRNAs are processed from capped, polyadenylated transcriptsthat can also function as mRNAs. RNA10:1957-1966.
3Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004) Processing of primary microRNAs by theMicroprocessor complex. Nature432:231-235.
4Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U (2004) Nuclear export of microRNA precursors. Science303:95-98.
5Haasch D, Chen YW, Reilly RM, Chiou XG, Koterski S, et al.(2002) T cell activation induces a noncoding RNAtranscript sensitive to inhibition by immunosuppressant drugs and encoded by the proto-oncogene, BIC. Cell Immunol217:78-86.
1Kutty RK, Nagineni CN, Samuel W, Vijayasarathy C, Hooks JJ, et al.(2010) Inflammatory cytokines regulatemicroRNA-155expression in human retinal pigment epithelial cells by activating JAK/STAT pathway. Biochem BiophysRes Commun402:390-395.
2O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D (2007) MicroRNA-155is induced during themacrophage inflammatory response. Proc Natl Acad Sci U S A104:1604-1609.
3Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer6:857-866.
4Martinez-Nunez RT, Louafi F, Sanchez-Elsner T (2011) The interleukin13(IL-13) pathway in human macrophages ismodulated by microRNA-155via direct targeting of interleukin13receptor alpha1(IL13Ralpha1). J Biol Chem286:1786-1794.
5Worm J, Stenvang J, Petri A, Frederiksen KS, Obad S, et al.(2009) Silencing of microRNA-155in mice during acuteinflammatory response leads to derepression of c/ebp Beta and down-regulation of G-CSF. Nucleic Acids Res37:5784-5792.
Louafi F, Martinez-Nunez RT, Sanchez-Elsner T (2010) MicroRNA-155targets SMAD2and modulates the responseof macrophages to transforming growth factor-{beta}. J Biol Chem285:41328-41336.
1Nazari-Jahantigh M, Wei Y, Noels H, Akhtar S, Zhou Z, et al.(2012) MicroRNA-155promotes atherosclerosis byrepressing Bcl6in macrophages. J Clin Invest122:4190-4202.
2Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, et al.(2007) Requirement of bic/microRNA-155for normalimmune function. Science316:608-611.
Dunand-Sauthier I, Santiago-Raber ML, Capponi L, Vejnar CE, Schaad O, et al.(2011) Silencing of c-Fos expressionby microRNA-155is critical for dendritic cell maturation and function. Blood117:4490-4500.
4Ceppi M, Pereira PM, Dunand-Sauthier I, Barras E, Reith W, et al.(2009) MicroRNA-155modulates the interleukin-1signaling pathway in activated human monocyte-derived dendritic cells. Proc Natl Acad Sci U S A106:2735-2740.
5Chen T, Yan H, Li Z, Jing T, Zhu W, et al.(2011) MicroRNA-155regulates lipid uptake, adhesion/chemokine markersecretion and SCG2expression in oxLDL-stimulated dendritic cells/macrophages. Int J Cardiol147:446-447.
6Ramiro AR, Jankovic M, Eisenreich T, Difilippantonio S, Chen-Kiang S, et al.(2004) AID is required for c-myc/IgHchromosome translocations in vivo. Cell118:431-438.
Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, et al.(2007) microRNA-155regulates the generation ofimmunoglobulin class-switched plasma cells. Immunity27:847-859.
1Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, et al.(2007) Regulation of the germinal center response bymicroRNA-155. Science316:604-608.
2Tili E, Croce CM, Michaille JJ (2009) miR-155: on the crosstalk between inflammation and cancer. Int Rev Immunol28:264-284.
3Pedersen IM, Otero D, Kao E, Miletic AV, Hother C, et al.(2009) Onco-miR-155targets SHIP1to promoteTNFalpha-dependent growth of B cell lymphomas. EMBO Mol Med1:288-295.
4Eis PS, Tam W, Sun L, Chadburn A, Li Z, et al.(2005) Accumulation of miR-155and BIC RNA in human B celllymphomas. Proc Natl Acad Sci U S A102:3627-3632.
O'Connell RM, Chaudhuri AA, Rao DS, Baltimore D (2009) Inositol phosphatase SHIP1is a primary target ofmiR-155. Proc Natl Acad Sci U S A106:7113-7118.
6Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, et al.(2007) Regulation of the germinal center response bymicroRNA-155. Science316:604-608.
7Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL (2010) Micro-RNA-155inhibits IFN-gammasignaling in CD4+T cells. Eur J Immunol40:225-231.
8Dudda JC, Salaun B, Ji Y, Palmer DC, Monnot GC, et al.(2013) MicroRNA-155is required for effector CD8+T cellresponses to virus infection and cancer. Immunity38:742-753.
Oertli M, Engler DB, Kohler E, Koch M, Meyer TF, et al.(2011) MicroRNA-155is essential for the T cell-mediatedcontrol of Helicobacter pylori infection and for the induction of chronic Gastritis and Colitis. J Immunol187:3578-3586.
1O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al.(2010) MicroRNA-155promotes autoimmune
2inflammation by enhancing inflammatory T cell development. Immunity33:607-619.Gracias DT, Stelekati E, Hope JL, Boesteanu AC, Doering TA, et al.(2013) The microRNA miR-155controls CD8(+)T cell responses by regulating interferon signaling. Nat Immunol14:593-602.
3Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, et al.(2009) Cutting edge: the Foxp3target miR-155contributes to the development of regulatory T cells. J Immunol182:2578-2582.
4Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, et al.(2009) Foxp3-dependent microRNA155confers competitivefitness to regulatory T cells by targeting SOCS1protein. Immunity30:80-91.
5Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, et al.(2009) Cutting edge: the Foxp3target miR-155contributes to the development of regulatory T cells. J Immunol182:2578-2582.
Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, et al.(2009) Cutting edge: the Foxp3target miR-155contributes to the development of regulatory T cells. J Immunol182:2578-2582.
[1] Wherry EJ (2011) T cell exhaustion. Nat Immunol12:492-499.
[2] Blackburn SD, Wherry EJ (2007) IL-10, T cell exhaustion and viral persistence.Trends Microbiol15:143-146.
[3] Francisco LM, Sage PT, Sharpe AH (2010) The PD-1pathway in tolerance andautoimmunity. Immunol Rev236:219-242.
[4] Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T (1994) Structure andchromosomal localization of the human PD-1gene (PDCD1). Genomics23:704-706.
[5] Ishida Y, Agata Y, Shibahara K, Honjo T (1992) Induced expression of PD-1, a novelmember of the immunoglobulin gene superfamily, upon programmed cell death.EMBO J11:3887-3895.
[6] Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, et al.(2006) Restoringfunction in exhausted CD8T cells during chronic viral infection. Nature439:682-687.
[7] Curran MA, Montalvo W, Yagita H, Allison JP (2010) PD-1and CTLA-4combination blockade expands infiltrating T cells and reduces regulatory T andmyeloid cells within B16melanoma tumors. Proc Natl Acad Sci U S A107:4275-4280.
[8] Noval Rivas M, Weatherly K, Hazzan M, Vokaer B, Dremier S, et al.(2009)Reviving function in CD4+T cells adapted to persistent systemic antigen. J Immunol183:4284-4291.
[9] Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, et al.(2010) TargetingTim-3and PD-1pathways to reverse T cell exhaustion and restore anti-tumorimmunity. J Exp Med207:2187-2194.
[10] Ambros V (2004) The functions of animal microRNAs. Nature431:350-355.
[11] Muljo SA, Ansel KM, Kanellopoulou C, Livingston DM, Rao A, et al.(2005)Aberrant T cell differentiation in the absence of Dicer. J Exp Med202:261-269.
[12] Cobb BS, Nesterova TB, Thompson E, Hertweck A, O'Connor E, et al.(2005) T celllineage choice and differentiation in the absence of the RNase III enzyme Dicer. JExp Med201:1367-1373.
[13] Guo S, Lu J, Schlanger R, Zhang H, Wang JY, et al.(2010) MicroRNA miR-125acontrols hematopoietic stem cell number. Proc Natl Acad Sci U S A107:14229-14234.
[14] Koralov SB, Muljo SA, Galler GR, Krek A, Chakraborty T, et al.(2008) Dicerablation affects antibody diversity and cell survival in the B lymphocyte lineage. Cell132:860-874.
[15] Liston A, Lu LF, O'Carroll D, Tarakhovsky A, Rudensky AY (2008) Dicer-dependentmicroRNA pathway safeguards regulatory T cell function. J Exp Med205:1993-2004.
[16] Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, et al.(2009)Cutting edge: the Foxp3target miR-155contributes to the development of regulatoryT cells. J Immunol182:2578-2582.
[17] Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, et al.(2009) Foxp3-dependentmicroRNA155confers competitive fitness to regulatory T cells by targeting SOCS1protein. Immunity30:80-91.
[18] O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al.(2010)MicroRNA-155promotes autoimmune inflammation by enhancing inflammatory Tcell development. Immunity33:607-619.
[19] Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, et al.(2007) Regulation of thegerminal center response by microRNA-155. Science316:604-608.
[20] Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL (2010)Micro-RNA-155inhibits IFN-gamma signaling in CD4+T cells. Eur J Immunol40:225-231.
[21] Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, et al.(2007)microRNA-155regulates the generation of immunoglobulin class-switched plasmacells. Immunity27:847-859.
[22] Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, et al.(1998) Viralimmune evasion due to persistence of activated T cells without effector function. JExp Med188:2205-2213.
[23] Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R (2003) Viralpersistence alters CD8T-cell immunodominance and tissue distribution and results indistinct stages of functional impairment. J Virol77:4911-4927.
[24] Moskophidis D, Lechner F, Pircher H, Zinkernagel RM (1993) Virus persistence inacutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effectorT cells. Nature362:758-761.
[25] Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, et al.(2006) HIVnonprogressors preferentially maintain highly functional HIV-specific CD8+T cells.Blood107:4781-4789.
[26] Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, et al.(2000) Analysis ofsuccessful immune responses in persons infected with hepatitis C virus. J Exp Med191:1499-1512.
[27] Nishimura H, Agata Y, Kawasaki A, Sato M, Imamura S, et al.(1996)Developmentally regulated expression of the PD-1protein on the surface ofdouble-negative (CD4-CD8-) thymocytes. Int Immunol8:773-780.
[28] Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1and its ligands in toleranceand immunity. Annu Rev Immunol26:677-704.
[29] Polanczyk MJ, Hopke C, Vandenbark AA, Offner H (2006) Estrogen-mediatedimmunomodulation involves reduced activation of effector T cells, potentiation ofTreg cells, and enhanced expression of the PD-1costimulatory pathway. J NeurosciRes84:370-378.
[30] Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, et al.(1996) Expression ofthe PD-1antigen on the surface of stimulated mouse T and B lymphocytes. IntImmunol8:765-772.
[31] Freeman GJ, Wherry EJ, Ahmed R, Sharpe AH (2006) Reinvigorating exhaustedHIV-specific T cells via PD-1-PD-1ligand blockade. J Exp Med203:2223-2227.
[32] Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, et al.(2008) The commongamma-chain cytokines IL-2, IL-7, IL-15, and IL-21induce the expression ofprogrammed death-1and its ligands. J Immunol181:6738-6746.
[33] Oestreich KJ, Yoon H, Ahmed R, Boss JM (2008) NFATc1regulates PD-1expression upon T cell activation. J Immunol181:4832-4839.
[34] Cho HY, Lee SW, Seo SK, Choi IW, Choi I (2008) Interferon-sensitive responseelement (ISRE) is mainly responsible for IFN-alpha-induced upregulation ofprogrammed death-1(PD-1) in macrophages. Biochim Biophys Acta1779:811-819.
[35] Yao S, Wang S, Zhu Y, Luo L, Zhu G, et al.(2009) PD-1on dendritic cells impedesinnate immunity against bacterial infection. Blood113:5811-5818.
[36] Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, et al.(2000) Engagement ofthe PD-1immunoinhibitory receptor by a novel B7family member leads to negativeregulation of lymphocyte activation. J Exp Med192:1027-1034.
[37] Blank C, Mackensen A (2007) Contribution of the PD-L1/PD-1pathway to T-cellexhaustion: an update on implications for chronic infections and tumor evasion.Cancer Immunol Immunother56:739-745.
[38] Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, et al.(2004) PD-1inhibitsT-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome anddownstream signaling to PKCtheta. FEBS Lett574:37-41.
[39] Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, et al.(2005)CTLA-4and PD-1receptors inhibit T-cell activation by distinct mechanisms. MolCell Biol25:9543-9553.
[40] Bennett F, Luxenberg D, Ling V, Wang IM, Marquette K, et al.(2003) Programdeath-1engagement upon TCR activation has distinct effects on costimulation andcytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28,IL-7, and IL-15responses. J Immunol170:711-718.
[41] Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, et al.(2006)Upregulation of PD-1expression on HIV-specific CD8+T cells leads to reversibleimmune dysfunction. Nat Med12:1198-1202.
[42] Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, et al.(2004) PD-L1/B7H-1inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenicCD8+T cells. Cancer Res64:1140-1145.
[43] Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, et al.(2002) Involvement of PD-L1on tumor cells in the escape from host immune system and tumor immunotherapy byPD-L1blockade. Proc Natl Acad Sci U S A99:12293-12297.
[44] Cai X, Hagedorn CH, Cullen BR (2004) Human microRNAs are processed fromcapped, polyadenylated transcripts that can also function as mRNAs. RNA10:1957-1966.
[45] Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004) Processing ofprimary microRNAs by the Microprocessor complex. Nature432:231-235.
[46] Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U (2004) Nuclear export ofmicroRNA precursors. Science303:95-98.
[47] Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4encodes small RNAs with antisense complementarity to lin-14. Cell75:843-854.
[48] Belver L, Papavasiliou FN, Ramiro AR (2011) MicroRNA control of lymphocytedifferentiation and function. Curr Opin Immunol23:368-373.
[49] Bronevetsky Y, Villarino AV, Eisley CJ, Barbeau R, Barczak AJ, et al.(2013) T cellactivation induces proteasomal degradation of Argonaute and rapid remodeling of themicroRNA repertoire. J Exp Med210:417-432.
[50] Zhou X, Jeker LT, Fife BT, Zhu S, Anderson MS, et al.(2008) Selective miRNAdisruption in T reg cells leads to uncontrolled autoimmunity. J Exp Med205:1983-1991.
[51] Li QJ, Chau J, Ebert PJ, Sylvester G, Min H, et al.(2007) miR-181a is an intrinsicmodulator of T cell sensitivity and selection. Cell129:147-161.
[52] Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, et al.(2010) Function ofmiR-146a in controlling Treg cell-mediated regulation of Th1responses. Cell142:914-929.
[53] Stittrich AB, Haftmann C, Sgouroudis E, Kuhl AA, Hegazy AN, et al.(2010) ThemicroRNA miR-182is induced by IL-2and promotes clonal expansion of activatedhelper T lymphocytes. Nat Immunol11:1057-1062.
[54] Mattes J, Collison A, Plank M, Phipps S, Foster PS (2009) Antagonism ofmicroRNA-126suppresses the effector function of TH2cells and the development ofallergic airways disease. Proc Natl Acad Sci U S A106:18704-18709.
[55] Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, et al.(2007) Requirementof bic/microRNA-155for normal immune function. Science316:608-611.
[56] Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms ofpost-transcriptional regulation by microRNAs: are the answers in sight? Nat RevGenet9:102-114.
[57] Jiang S, Li C, Olive V, Lykken E, Feng F, et al.(2011) Molecular dissection of themiR-17-92cluster's critical dual roles in promoting Th1responses and preventinginducible Treg differentiation. Blood118:5487-5497.
[58] Ma F, Xu S, Liu X, Zhang Q, Xu X, et al.(2011) The microRNA miR-29controlsinnate and adaptive immune responses to intracellular bacterial infection by targetinginterferon-gamma. Nat Immunol12:861-869.
[59] Takahashi R, Nishimoto S, Muto G, Sekiya T, Tamiya T, et al.(2011) SOCS1isessential for regulatory T cell functions by preventing loss of Foxp3expression aswell as IFN-{gamma} and IL-17A production. J Exp Med208:2055-2067.
[60] Dudda JC, Salaun B, Ji Y, Palmer DC, Monnot GC, et al.(2013) MicroRNA-155isrequired for effector CD8+T cell responses to virus infection and cancer. Immunity38:742-753.
[61] Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, et al.(2007) A mammalianmicroRNA expression atlas based on small RNA library sequencing. Cell129:1401-1414.
[62] Eis PS, Tam W, Sun L, Chadburn A, Li Z, et al.(2005) Accumulation of miR-155andBIC RNA in human B cell lymphomas. Proc Natl Acad Sci U S A102:3627-3632.
[63] O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D (2007)MicroRNA-155is induced during the macrophage inflammatory response. Proc NatlAcad Sci U S A104:1604-1609.
[64] Kutty RK, Nagineni CN, Samuel W, Vijayasarathy C, Hooks JJ, et al.(2010)Inflammatory cytokines regulate microRNA-155expression in human retinal pigmentepithelial cells by activating JAK/STAT pathway. Biochem Biophys Res Commun402:390-395.
[65] Haasch D, Chen YW, Reilly RM, Chiou XG, Koterski S, et al.(2002) T cellactivation induces a noncoding RNA transcript sensitive to inhibition byimmunosuppressant drugs and encoded by the proto-oncogene, BIC. Cell Immunol217:78-86.
[66] Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat RevCancer6:857-866.
[67] Metzler M, Wilda M, Busch K, Viehmann S, Borkhardt A (2004) High expression ofprecursor microRNA-155/BIC RNA in children with Burkitt lymphoma. GenesChromosomes Cancer39:167-169.
[68] van den Berg A, Kroesen BJ, Kooistra K, de Jong D, Briggs J, et al.(2003) Highexpression of B-cell receptor inducible gene BIC in all subtypes of Hodgkinlymphoma. Genes Chromosomes Cancer37:20-28.
[69] O'Connell RM, Rao DS, Chaudhuri AA, Boldin MP, Taganov KD, et al.(2008)Sustained expression of microRNA-155in hematopoietic stem cells causes amyeloproliferative disorder. J Exp Med205:585-594.
[70] Bluml S, Bonelli M, Niederreiter B, Puchner A, Mayr G, et al.(2011) Essential roleof microRNA-155in the pathogenesis of autoimmune arthritis in mice. ArthritisRheum63:1281-1288.
[71] Oertli M, Engler DB, Kohler E, Koch M, Meyer TF, et al.(2011) MicroRNA-155isessential for the T cell-mediated control of Helicobacter pylori infection and for theinduction of chronic Gastritis and Colitis. J Immunol187:3578-3586.
[72] Clare S, John V, Walker AW, Hill JL, Abreu-Goodger C, et al.(2013) Enhancedsusceptibility to Citrobacter rodentium infection in microRNA-155-deficient mice.Infect Immun81:723-732.
[73] Ramiro AR, Jankovic M, Eisenreich T, Difilippantonio S, Chen-Kiang S, et al.(2004)AID is required for c-myc/IgH chromosome translocations in vivo. Cell118:431-438.
[74] Cobb BS, Hertweck A, Smith J, O'Connor E, Graf D, et al.(2006) A role for Dicer inimmune regulation. J Exp Med203:2519-2527.
[75] Niimoto T, Nakasa T, Ishikawa M, Okuhara A, Izumi B, et al.(2010)MicroRNA-146a expresses in interleukin-17producing T cells in rheumatoid arthritispatients. BMC Musculoskelet Disord11:209.
[76] Yoshimura A, Naka T, Kubo M (2007) SOCS proteins, cytokine signalling andimmune regulation. Nat Rev Immunol7:454-465.
[77] Yao R, Ma YL, Liang W, Li HH, Ma ZJ, et al.(2012) MicroRNA-155modulatesTreg and Th17cells differentiation and Th17cell function by targeting SOCS1. PLoSOne7: e46082.
[78] Dunand-Sauthier I, Santiago-Raber ML, Capponi L, Vejnar CE, Schaad O, et al.(2011) Silencing of c-Fos expression by microRNA-155is critical for dendritic cellmaturation and function. Blood117:4490-4500.
[79] O'Connell RM, Chaudhuri AA, Rao DS, Baltimore D (2009) Inositol phosphataseSHIP1is a primary target of miR-155. Proc Natl Acad Sci U S A106:7113-7118.
[80] Tenhunen R, Marver HS, Schmid R (1968) The enzymatic conversion of heme tobilirubin by microsomal heme oxygenase. Proc Natl Acad Sci U S A61:748-755.
[81] Jozkowicz A, Was H, Dulak J (2007) Heme oxygenase-1in tumors: is it a false friend?Antioxid Redox Signal9:2099-2117.
[82] Panchenko MV, Farber HW, Korn JH (2000) Induction of heme oxygenase-1byhypoxia and free radicals in human dermal fibroblasts. Am J Physiol Cell Physiol278:C92-C101.
[83] Christou H, Bailey N, Kluger MS, Mitsialis SA, Kourembanas S (2005) Extracellularacidosis induces heme oxygenase-1expression in vascular smooth muscle cells. Am JPhysiol Heart Circ Physiol288: H2647-2652.
[84] Ferreira A, Balla J, Jeney V, Balla G, Soares MP (2008) A central role for free hemein the pathogenesis of severe malaria: the missing link? J Mol Med (Berl)86:1097-1111.
[85] Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, et al.(1992) Ferritin: acytoprotective antioxidant strategem of endothelium. J Biol Chem267:18148-18153.
[86] Poss KD, Tonegawa S (1997) Reduced stress defense in heme oxygenase1-deficientcells. Proc Natl Acad Sci U S A94:10925-10930.
[87] Yet SF, Layne MD, Liu X, Chen YH, Ith B, et al.(2003) Absence of hemeoxygenase-1exacerbates atherosclerotic lesion formation and vascular remodeling.FASEB J17:1759-1761.
[88] Zenke-Kawasaki Y, Dohi Y, Katoh Y, Ikura T, Ikura M, et al.(2007) Heme inducesubiquitination and degradation of the transcription factor Bach1. Mol Cell Biol27:6962-6971.
[89] Hira S, Tomita T, Matsui T, Igarashi K, Ikeda-Saito M (2007) Bach1, aheme-dependent transcription factor, reveals presence of multiple heme binding siteswith distinct coordination structure. IUBMB Life59:542-551.
[90] Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, et al.(1999) Nrf2, aCap'n'Collar transcription factor, regulates induction of the heme oxygenase-1gene. JBiol Chem274:26071-26078.
[91] Wilks A (2002) Heme oxygenase: evolution, structure, and mechanism. AntioxidRedox Signal4:603-614.
[92] Brouard S, Otterbein LE, Anrather J, Tobiasch E, Bach FH, et al.(2000) Carbonmonoxide generated by heme oxygenase1suppresses endothelial cell apoptosis. JExp Med192:1015-1026.
[93] Gozzelino R, Jeney V, Soares MP (2010) Mechanisms of cell protection by hemeoxygenase-1. Annu Rev Pharmacol Toxicol50:323-354.
[94] Zuckerbraun BS, Chin BY, Bilban M, d'Avila JC, Rao J, et al.(2007) Carbonmonoxide signals via inhibition of cytochrome c oxidase and generation ofmitochondrial reactive oxygen species. FASEB J21:1099-1106.
[95] Bilban M, Bach FH, Otterbein SL, Ifedigbo E, d'Avila JC, et al.(2006) Carbonmonoxide orchestrates a protective response through PPARgamma. Immunity24:601-610.
[96] Nakao A, Kimizuka K, Stolz DB, Neto JS, Kaizu T, et al.(2003) Carbon monoxideinhalation protects rat intestinal grafts from ischemia/reperfusion injury. Am J Pathol163:1587-1598.
[97] Chin BY, Jiang G, Wegiel B, Wang HJ, Macdonald T, et al.(2007)Hypoxia-inducible factor1alpha stabilization by carbon monoxide results incytoprotective preconditioning. Proc Natl Acad Sci U S A104:5109-5114.
[98] Brouard S, Berberat PO, Tobiasch E, Seldon MP, Bach FH, et al.(2002) Hemeoxygenase-1-derived carbon monoxide requires the activation of transcription factorNF-kappa B to protect endothelial cells from tumor necrosis factor-alpha-mediatedapoptosis. J Biol Chem277:17950-17961.
[99] Ferris CD, Jaffrey SR, Sawa A, Takahashi M, Brady SD, et al.(1999) Haemoxygenase-1prevents cell death by regulating cellular iron. Nat Cell Biol1:152-157.
[100] Baker HM, Anderson BF, Baker EN (2003) Dealing with iron: common structuralprinciples in proteins that transport iron and heme. Proc Natl Acad Sci U S A100:3579-3583.
[101] Cozzi A, Levi S, Corsi B, Santambrogio P, Campanella A, et al.(2003) Role of ironand ferritin in TNFalpha-induced apoptosis in HeLa cells. FEBS Lett537:187-192.
[102] Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, et al.(2004) Ferritin heavy chainupregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressingreactive oxygen species. Cell119:529-542.
[103] Maghzal GJ, Leck MC, Collinson E, Li C, Stocker R (2009) Limited role for thebilirubin-biliverdin redox amplification cycle in the cellular antioxidant protection bybiliverdin reductase. J Biol Chem284:29251-29259.
[104] Reiter TA, Pang B, Dedon P, Demple B (2006) Resistance to nitric oxide-inducednecrosis in heme oxygenase-1overexpressing pulmonary epithelial cells associatedwith decreased lipid peroxidation. J Biol Chem281:36603-36612.
[105] Fondevila C, Shen XD, Tsuchiyashi S, Yamashita K, Csizmadia E, et al.(2004)Biliverdin therapy protects rat livers from ischemia and reperfusion injury.Hepatology40:1333-1341.
[106] Wang H, Lee SS, Dell'Agnello C, Tchipashvili V, d'Avila JC, et al.(2006) Bilirubincan induce tolerance to islet allografts. Endocrinology147:762-768.
[107] Overhaus M, Moore BA, Barbato JE, Behrendt FF, Doering JG, et al.(2006)Biliverdin protects against polymicrobial sepsis by modulating inflammatorymediators. Am J Physiol Gastrointest Liver Physiol290: G695-703.
[108] Hu CM, Lin HH, Chiang MT, Chang PF, Chau LY (2007) Systemic expression ofheme oxygenase-1ameliorates type1diabetes in NOD mice. Diabetes56:1240-1247.
[109] Chora AA, Fontoura P, Cunha A, Pais TF, Cardoso S, et al.(2007) Hemeoxygenase-1and carbon monoxide suppress autoimmune neuroinflammation. J ClinInvest117:438-447.
[110] Lehmann E, El-Tantawy WH, Ocker M, Bartenschlager R, Lohmann V, et al.(2010)The heme oxygenase1product biliverdin interferes with hepatitis C virus replicationby increasing antiviral interferon response. Hepatology51:398-404.
[111] Protzer U, Seyfried S, Quasdorff M, Sass G, Svorcova M, et al.(2007) Antiviralactivity and hepatoprotection by heme oxygenase-1in hepatitis B virus infection.Gastroenterology133:1156-1165.
[112] Silva-Gomes S, Appelberg R, Larsen R, Soares MP, Gomes MS (2013) Hemecatabolism by heme oxygenase-1confers host resistance to Mycobacterium infection.Infect Immun81:2536-2545.
[113] Pamplona A, Ferreira A, Balla J, Jeney V, Balla G, et al.(2007) Heme oxygenase-1and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. NatMed13:703-710.
[114] Doi K, Akaike T, Fujii S, Tanaka S, Ikebe N, et al.(1999) Induction of haemoxygenase-1nitric oxide and ischaemia in experimental solid tumours andimplications for tumour growth. Br J Cancer80:1945-1954.
[115] Deininger MH, Meyermann R, Trautmann K, Duffner F, Grote EH, et al.(2000)Heme oxygenase (HO)-1expressing macrophages/microglial cells accumulate duringoligodendroglioma progression. Brain Res882:1-8.
[116] Torisu-Itakura H, Furue M, Kuwano M, Ono M (2000) Co-expression of thymidinephosphorylase and heme oxygenase-1in macrophages in human malignant verticalgrowth melanomas. Jpn J Cancer Res91:906-910.
[117] Maines MD, Abrahamsson PA (1996) Expression of heme oxygenase-1(HSP32) inhuman prostate: normal, hyperplastic, and tumor tissue distribution. Urology47:727-733.
[118] Tsuji MH, Yanagawa T, Iwasa S, Tabuchi K, Onizawa K, et al.(1999) Hemeoxygenase-1expression in oral squamous cell carcinoma as involved in lymph nodemetastasis. Cancer Lett138:53-59.
[119] Berberat PO, Dambrauskas Z, Gulbinas A, Giese T, Giese N, et al.(2005) Inhibitionof heme oxygenase-1increases responsiveness of pancreatic cancer cells to anticancertreatment. Clin Cancer Res11:3790-3798.
[120] Pae HO, Oh GS, Choi BM, Chae SC, Kim YM, et al.(2004) Carbon monoxideproduced by heme oxygenase-1suppresses T cell proliferation via inhibition of IL-2production. J Immunol172:4744-4751.
[121] Burt TD, Seu L, Mold JE, Kappas A, McCune JM (2010) Naive human T cells areactivated and proliferate in response to the heme oxygenase-1inhibitor tinmesoporphyrin. J Immunol185:5279-5288.
[122] Soares MP, Bach FH (2009) Heme oxygenase-1: from biology to therapeutic potential.Trends Mol Med15:50-58.
[123] Exner M, Minar E, Wagner O, Schillinger M (2004) The role of heme oxygenase-1promoter polymorphisms in human disease. Free Radic Biol Med37:1097-1104.
[124] Hengartner MO, Horvitz HR (1994) Programmed cell death in Caenorhabditis elegans.Curr Opin Genet Dev4:581-586.
[125] Soares MP, Lin Y, Anrather J, Csizmadia E, Takigami K, et al.(1998) Expression ofheme oxygenase-1can determine cardiac xenograft survival. Nat Med4:1073-1077.
[126] Tartaglia LA, Rothe M, Hu YF, Goeddel DV (1993) Tumor necrosis factor's cytotoxicactivity is signaled by the p55TNF receptor. Cell73:213-216.
[127] Soares MP, Seldon MP, Gregoire IP, Vassilevskaia T, Berberat PO, et al.(2004)Heme oxygenase-1modulates the expression of adhesion molecules associated withendothelial cell activation. J Immunol172:3553-3563.
[128] Mahoney DJ, Cheung HH, Mrad RL, Plenchette S, Simard C, et al.(2008) BothcIAP1and cIAP2regulate TNFalpha-mediated NF-kappaB activation. Proc Natl AcadSci U S A105:11778-11783.
[129] Micheau O, Tschopp J (2003) Induction of TNF receptor I-mediated apoptosis viatwo sequential signaling complexes. Cell114:181-190.
[130] Perkins ND (2007) Integrating cell-signalling pathways with NF-kappaB and IKKfunction. Nat Rev Mol Cell Biol8:49-62.
[131] Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U (1995) Control of Ikappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science267:1485-1488.
[132] Chen Z, Hagler J, Palombella VJ, Melandri F, Scherer D, et al.(1995) Signal-inducedsite-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasomepathway. Genes Dev9:1586-1597.
[133] Henkel T, Machleidt T, Alkalay I, Kronke M, Ben-Neriah Y, et al.(1993) Rapidproteolysis of I kappa B-alpha is necessary for activation of transcription factorNF-kappa B. Nature365:182-185.
[134] Seldon MP, Silva G, Pejanovic N, Larsen R, Gregoire IP, et al.(2007) Hemeoxygenase-1inhibits the expression of adhesion molecules associated withendothelial cell activation via inhibition of NF-kappaB RelA phosphorylation atserine276. J Immunol179:7840-7851.
[135] Fiers W, Beyaert R, Declercq W, Vandenabeele P (1999) More than one way to die:apoptosis, necrosis and reactive oxygen damage. Oncogene18:7719-7730.
[136] Wada T, Penninger JM (2004) Mitogen-activated protein kinases in apoptosisregulation. Oncogene23:2838-2849.
[137] Silva G, Cunha A, Gregoire IP, Seldon MP, Soares MP (2006) The antiapoptoticeffect of heme oxygenase-1in endothelial cells involves the degradation of p38alphaMAPK isoform. J Immunol177:1894-1903.
[138] Arruda MA, Rossi AG, de Freitas MS, Barja-Fidalgo C, Graca-Souza AV (2004)Heme inhibits human neutrophil apoptosis: involvement of phosphoinositide3-kinase,MAPK, and NF-kappaB. J Immunol173:2023-2030.
[139] Zhang X, Shan P, Alam J, Fu XY, Lee PJ (2005) Carbon monoxide differentiallymodulates STAT1and STAT3and inhibits apoptosis via a phosphatidylinositol3-kinase/Akt and p38kinase-dependent STAT3pathway during anoxia-reoxygenationinjury. J Biol Chem280:8714-8721.
[140] Brunt KR, Fenrich KK, Kiani G, Tse MY, Pang SC, et al.(2006) Protection of humanvascular smooth muscle cells from H2O2-induced apoptosis through functionalcodependence between HO-1and AKT. Arterioscler Thromb Vasc Biol26:2027-2034.
[141] Salinas M, Wang J, Rosa de Sagarra M, Martin D, Rojo AI, et al.(2004) Proteinkinase Akt/PKB phosphorylates heme oxygenase-1in vitro and in vivo. FEBS Lett578:90-94.
[142] Tang YL, Tang Y, Zhang YC, Qian K, Shen L, et al.(2004) Protection from ischemicheart injury by a vigilant heme oxygenase-1plasmid system. Hypertension43:746-751.
[143] Katori M, Buelow R, Ke B, Ma J, Coito AJ, et al.(2002) Heme oxygenase-1overexpression protects rat hearts from cold ischemia/reperfusion injury via anantiapoptotic pathway. Transplantation73:287-292.
[144] McDaid J, Yamashita K, Chora A, Ollinger R, Strom TB, et al.(2005) Hemeoxygenase-1modulates the allo-immune response by promoting activation-inducedcell death of T cells. FASEB J19:458-460.
[145] Urban JL, Kumar V, Kono DH, Gomez C, Horvath SJ, et al.(1988) Restricted use ofT cell receptor V genes in murine autoimmune encephalomyelitis raises possibilitiesfor antibody therapy. Cell54:577-592.
[146] Laatsch RH (1962) Glycerol phosphate dehydrogenase activity of developing ratcentral nervous system. J Neurochem9:487-492.
[147] Mendel I, Kerlero de Rosbo N, Ben-Nun A (1995) A myelin oligodendrocyteglycoprotein peptide induces typical chronic experimental autoimmuneencephalomyelitis in H-2b mice: fine specificity and T cell receptor V beta expressionof encephalitogenic T cells. Eur J Immunol25:1951-1959.
[148] Tuohy VK, Lu Z, Sobel RA, Laursen RA, Lees MB (1989) Identification of anencephalitogenic determinant of myelin proteolipid protein for SJL mice. J Immunol142:1523-1527.
[149] Jones MV, Nguyen TT, Deboy CA, Griffin JW, Whartenby KA, et al.(2008)Behavioral and pathological outcomes in MOG35-55experimental autoimmuneencephalomyelitis. J Neuroimmunol199:83-93.
[150] Brostoff SW, Mason DW (1984) Experimental allergic encephalomyelitis: successfultreatment in vivo with a monoclonal antibody that recognizes T helper cells. JImmunol133:1938-1942.
[151] Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol23:683-747.
[152] Hafler DA (2004) Multiple sclerosis. J Clin Invest113:788-794.
[153] Yura M, Takahashi I, Serada M, Koshio T, Nakagami K, et al.(2001) Role ofMOG-stimulated Th1type "light up"(GFP+) CD4+T cells for the development ofexperimental autoimmune encephalomyelitis (EAE). J Autoimmun17:17-25.
[154] Gocke AR, Cravens PD, Ben LH, Hussain RZ, Northrop SC, et al.(2007) T-betregulates the fate of Th1and Th17lymphocytes in autoimmunity. J Immunol178:1341-1348.
[155] Lublin FD, Knobler RL, Kalman B, Goldhaber M, Marini J, et al.(1993) Monoclonalanti-gamma interferon antibodies enhance experimental allergic encephalomyelitis.Autoimmunity16:267-274.
[156] Heremans H, Dillen C, Groenen M, Martens E, Billiau A (1996) Chronic relapsingexperimental autoimmune encephalomyelitis (CREAE) in mice: enhancement bymonoclonal antibodies against interferon-gamma. Eur J Immunol26:2393-2398.
[157] Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, et al.(2003) Interleukin-23ratherthan interleukin-12is the critical cytokine for autoimmune inflammation of the brain.Nature421:744-748.
[158] Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, et al.(2005) IL-23drives a pathogenic T cell population that induces autoimmune inflammation. J ExpMed201:233-240.
[159] Eugster HP, Frei K, Kopf M, Lassmann H, Fontana A (1998) IL-6-deficient miceresist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis.Eur J Immunol28:2178-2187.
[160] Park H, Li Z, Yang XO, Chang SH, Nurieva R, et al.(2005) A distinct lineage of CD4T cells regulates tissue inflammation by producing interleukin17. Nat Immunol6:1133-1141.
[161] Hu Y, Ota N, Peng I, Refino CJ, Danilenko DM, et al.(2010) IL-17RC is required forIL-17A-and IL-17F-dependent signaling and the pathogenesis of experimentalautoimmune encephalomyelitis. J Immunol184:4307-4316.
[162] Du C, Liu C, Kang J, Zhao G, Ye Z, et al.(2009) MicroRNA miR-326regulatesTH-17differentiation and is associated with the pathogenesis of multiple sclerosis.Nat Immunol10:1252-1259.
[163] Mycko MP, Cichalewska M, Machlanska A, Cwiklinska H, Mariasiewicz M, et al.(2012) MicroRNA-301a regulation of a T-helper17immune response controlsautoimmune demyelination. Proc Natl Acad Sci U S A109: E1248-1257.
[164] Murugaiyan G, Beynon V, Mittal A, Joller N, Weiner HL (2011) SilencingmicroRNA-155ameliorates experimental autoimmune encephalomyelitis. J Immunol187:2213-2221.
[165] So AY, Garcia-Flores Y, Minisandram A, Martin A, Taganov K, et al.(2012)Regulation of APC development, immune response, and autoimmunity byBach1/HO-1pathway in mice. Blood120:2428-2437.
[166] Kusters, J.G., van Vliet, A.H.&Kuipers, E.J.(2006) Pathogenesis of Helicobacterpylori infection. Clin Microbiol Rev19,449-490.
[167] Pappo, J., et al.(1999) Helicobacter pylori infection in immunized mice lacking majorhistocompatibility complex class I and class II functions. Infect Immun67,337-341.
[168] Dong, C.(2008) TH17cells in development: an updated view of their molecularidentity and genetic programming. Nat Rev Immunol8,337-348.
[169] Shi, Y., et al.(2010) Helicobacter pylori-induced Th17responses modulate Th1cellresponses, benefit bacterial growth, and contribute to pathology in mice. J Immunol184,5121-5129.
[170] Caruso, R., et al.(2008) IL-23-mediated regulation of IL-17production inHelicobacter pylori-infected gastric mucosa. Eur J Immunol38,470-478.
[171] Andersen, L.P.(2007) Colonization and infection by Helicobacter pylori in humans.Helicobacter12Suppl2,12-15.
[172] Tan, S.&Berg, D.E.(2004) Motility of urease-deficient derivatives of Helicobacterpylori. J Bacteriol186,885-888.
[173] Andrutis, K.A., et al.(1995) Inability of an isogenic urease-negative mutant stain ofHelicobacter mustelae to colonize the ferret stomach. Infect Immun63,3722-3725.
[174] Harris, P.R., Mobley, H.L., Perez-Perez, G.I., Blaser, M.J.&Smith, P.D.(1996)Helicobacter pylori urease is a potent stimulus of mononuclear phagocyte activationand inflammatory cytokine production. Gastroenterology111,419-425.
[175] DeLyria, E.S., Redline, R.W.&Blanchard, T.G.(2009) Vaccination of mice againstH pylori induces a strong Th-17response and immunity that is neutrophil dependent.Gastroenterology136,247-256.
[176] Lu, D.S., et al.(2003)[Recombinant Helicobacter pylori urease B subunit and itsbiological properties]. Di Yi Jun Yi Da Xue Xue Bao23,549-552.
[177] Oppmann, B., et al.(2000) Novel p19protein engages IL-12p40to form a cytokine,IL-23, with biological activities similar as well as distinct from IL-12. Immunity13,715-725.
[178] Kryczek, I., et al.(2007) Cutting edge: opposite effects of IL-1and IL-2on theregulation of IL-17+T cell pool IL-1subverts IL-2-mediated suppression. J Immunol179,1423-1426.
[179] Ivanov, II, et al.(2006) The orphan nuclear receptor RORgammat directs thedifferentiation program of proinflammatory IL-17+T helper cells. Cell126,1121-1133.
[180] Korn, T., et al.(2007) IL-21initiates an alternative pathway to induceproinflammatory T(H)17cells. Nature448,484-487.
[181] Zhou, L., et al.(2007) IL-6programs T(H)-17cell differentiation by promotingsequential engagement of the IL-21and IL-23pathways. Nat Immunol8,967-974.
[1] Ambros V (2004) The functions of animal microRNAs. Nature431:350-355.
[2] Cai X, Hagedorn CH, Cullen BR (2004) Human microRNAs are processed fromcapped, polyadenylated transcripts that can also function as mRNAs. RNA10:1957-1966.
[3] Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004) Processing ofprimary microRNAs by the Microprocessor complex. Nature432:231-235.
[4] Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U (2004) Nuclear export ofmicroRNA precursors. Science303:95-98.
[5] Haasch D, Chen YW, Reilly RM, Chiou XG, Koterski S, et al.(2002) T cellactivation induces a noncoding RNA transcript sensitive to inhibition byimmunosuppressant drugs and encoded by the proto-oncogene, BIC. Cell Immunol217:78-86.
[6] Kutty RK, Nagineni CN, Samuel W, Vijayasarathy C, Hooks JJ, et al.(2010)Inflammatory cytokines regulate microRNA-155expression in human retinal pigmentepithelial cells by activating JAK/STAT pathway. Biochem Biophys Res Commun402:390-395.
[7] O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D (2007)MicroRNA-155is induced during the macrophage inflammatory response. Proc NatlAcad Sci U S A104:1604-1609.
[8] Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat RevCancer6:857-866.
[9] Martinez-Nunez RT, Louafi F, Sanchez-Elsner T (2011) The interleukin13(IL-13)pathway in human macrophages is modulated by microRNA-155via direct targetingof interleukin13receptor alpha1(IL13Ralpha1). J Biol Chem286:1786-1794.
[10] Worm J, Stenvang J, Petri A, Frederiksen KS, Obad S, et al.(2009) Silencing ofmicroRNA-155in mice during acute inflammatory response leads to derepression ofc/ebp Beta and down-regulation of G-CSF. Nucleic Acids Res37:5784-5792.
[11] Louafi F, Martinez-Nunez RT, Sanchez-Elsner T (2010) MicroRNA-155targetsSMAD2and modulates the response of macrophages to transforming growthfactor-{beta}. J Biol Chem285:41328-41336.
[12] Nazari-Jahantigh M, Wei Y, Noels H, Akhtar S, Zhou Z, et al.(2012) MicroRNA-155promotes atherosclerosis by repressing Bcl6in macrophages. J Clin Invest122:4190-4202.
[13] Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, et al.(2007) Requirementof bic/microRNA-155for normal immune function. Science316:608-611.
[14] Dunand-Sauthier I, Santiago-Raber ML, Capponi L, Vejnar CE, Schaad O, et al.(2011) Silencing of c-Fos expression by microRNA-155is critical for dendritic cellmaturation and function. Blood117:4490-4500.
[15] Ceppi M, Pereira PM, Dunand-Sauthier I, Barras E, Reith W, et al.(2009)MicroRNA-155modulates the interleukin-1signaling pathway in activated humanmonocyte-derived dendritic cells. Proc Natl Acad Sci U S A106:2735-2740.
[16] Chen T, Yan H, Li Z, Jing T, Zhu W, et al.(2011) MicroRNA-155regulates lipiduptake, adhesion/chemokine marker secretion and SCG2expression inoxLDL-stimulated dendritic cells/macrophages. Int J Cardiol147:446-447.
[17] Ramiro AR, Jankovic M, Eisenreich T, Difilippantonio S, Chen-Kiang S, et al.(2004)AID is required for c-myc/IgH chromosome translocations in vivo. Cell118:431-438.
[18] Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, et al.(2007)microRNA-155regulates the generation of immunoglobulin class-switched plasmacells. Immunity27:847-859.
[19] Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, et al.(2007) Regulation of thegerminal center response by microRNA-155. Science316:604-608.
[20] Tili E, Croce CM, Michaille JJ (2009) miR-155: on the crosstalk betweeninflammation and cancer. Int Rev Immunol28:264-284.
[21] Pedersen IM, Otero D, Kao E, Miletic AV, Hother C, et al.(2009) Onco-miR-155targets SHIP1to promote TNFalpha-dependent growth of B cell lymphomas. EMBOMol Med1:288-295.
[22] Eis PS, Tam W, Sun L, Chadburn A, Li Z, et al.(2005) Accumulation of miR-155andBIC RNA in human B cell lymphomas. Proc Natl Acad Sci U S A102:3627-3632.
[23] O'Connell RM, Chaudhuri AA, Rao DS, Baltimore D (2009) Inositol phosphataseSHIP1is a primary target of miR-155. Proc Natl Acad Sci U S A106:7113-7118.
[24] Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL (2010)Micro-RNA-155inhibits IFN-gamma signaling in CD4+T cells. Eur J Immunol40:225-231.
[25] Dudda JC, Salaun B, Ji Y, Palmer DC, Monnot GC, et al.(2013) MicroRNA-155isrequired for effector CD8+T cell responses to virus infection and cancer. Immunity38:742-753.
[26] Oertli M, Engler DB, Kohler E, Koch M, Meyer TF, et al.(2011) MicroRNA-155isessential for the T cell-mediated control of Helicobacter pylori infection and for theinduction of chronic Gastritis and Colitis. J Immunol187:3578-3586.
[27] O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al.(2010)MicroRNA-155promotes autoimmune inflammation by enhancing inflammatory Tcell development. Immunity33:607-619.
[28] Gracias DT, Stelekati E, Hope JL, Boesteanu AC, Doering TA, et al.(2013) ThemicroRNA miR-155controls CD8(+) T cell responses by regulating interferonsignaling. Nat Immunol14:593-602.
[29] Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, et al.(2009)Cutting edge: the Foxp3target miR-155contributes to the development of regulatoryT cells. J Immunol182:2578-2582.
[30] Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, et al.(2009) Foxp3-dependentmicroRNA155confers competitive fitness to regulatory T cells by targeting SOCS1protein. Immunity30:80-91.
2Francisco LM, Sage PT, Sharpe AH (2010) The PD-1pathway in tolerance and autoimmunity. Immunol Rev236:219-242.
3Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T (1994) Structure and chromosomal localization of thehuman PD-1gene (PDCD1). Genomics23:704-706.
4Ishida Y, Agata Y, Shibahara K, Honjo T (1992) Induced expression of PD-1, a novel member of the immunoglobulingene superfamily, upon programmed cell death. EMBO J11:3887-3895.
1Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, et al.(2006) Restoring function in exhausted CD8T cellsduring chronic viral infection. Nature439:682-687.
2Ambros V (2004) The functions of animal microRNAs. Nature431:350-355.
Muljo SA, Ansel KM, Kanellopoulou C, Livingston DM, Rao A, et al.(2005) Aberrant T cell differentiation in theabsence of Dicer. J Exp Med202:261-269.
4Cobb BS, Nesterova TB, Thompson E, Hertweck A, O'Connor E, et al.(2005) T cell lineage choice and differentiationin the absence of the RNase III enzyme Dicer. J Exp Med201:1367-1373.
5Guo S, Lu J, Schlanger R, Zhang H, Wang JY, et al.(2010) MicroRNA miR-125a controls hematopoietic stem cellnumber. Proc Natl Acad Sci U S A107:14229-14234.
6Koralov SB, Muljo SA, Galler GR, Krek A, Chakraborty T, et al.(2008) Dicer ablation affects antibody diversity and
7cell survival in the B lymphocyte lineage. Cell132:860-874.Liston A, Lu LF, O'Carroll D, Tarakhovsky A, Rudensky AY (2008) Dicer-dependent microRNA pathway safeguardsregulatory T cell function. J Exp Med205:1993-2004.
8Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, et al.(2009) Cutting edge: the Foxp3target miR-155contributes to the development of regulatory T cells. J Immunol182:2578-2582.
9Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, et al.(2009) Foxp3-dependent microRNA155confers competitivefitness to regulatory T cells by targeting SOCS1protein. Immunity30:80-91.
10O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al.(2010) MicroRNA-155promotes autoimmuneinflammation by enhancing inflammatory T cell development. Immunity33:607-619.
Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, et al.(2007) Regulation of the germinal center response bymicroRNA-155. Science316:604-608.
1Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL (2010) Micro-RNA-155inhibits IFN-gammasignaling in CD4+T cells. Eur J Immunol40:225-231.
2Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, et al.(2007) microRNA-155regulates the generation ofimmunoglobulin class-switched plasma cells. Immunity27:847-859.
Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, et al.(2007) Regulation of the germinal center response bymicroRNA-155. Science316:604-608.
1Noval Rivas M, Weatherly K, Hazzan M, Vokaer B, Dremier S, et al.(2009) Reviving function in CD4+T cellsadapted to persistent systemic antigen. J Immunol183:4284-4291.
1Noval Rivas M, Weatherly K, Hazzan M, Vokaer B, Dremier S, et al.(2009) Reviving function in CD4+T cellsadapted to persistent systemic antigen. J Immunol183:4284-4291.
Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R (2003) Viral persistence alters CD8T-cellimmunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol77:4911-4927.
1Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, et al.(2006) Restoring function in exhausted CD8T cellsduring chronic viral infection. Nature439:682-687.
1Wherry EJ (2011) T cell exhaustion. Nat Immunol12:492-499.
2Noval Rivas M, Weatherly K, Hazzan M, Vokaer B, Dremier S, et al.(2009) Reviving function in CD4+T cellsadapted to persistent systemic antigen. J Immunol183:4284-4291.
Noval Rivas M, Weatherly K, Hazzan M, Vokaer B, Dremier S, et al.(2009) Reviving function in CD4+T cellsadapted to persistent systemic antigen. J Immunol183:4284-4291.
1Noval Rivas M, Weatherly K, Hazzan M, Vokaer B, Dremier S, et al.(2009) Reviving function in CD4+T cellsadapted to persistent systemic antigen. J Immunol183:4284-4291.
2Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, et al.(1998) Viral immune evasion due topersistence of activated T cells without effector function. J Exp Med188:2205-2213.
3Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R (2003) Viral persistence alters CD8T-cellimmunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol77:4911-4927.
4Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, et al.(2006) HIV nonprogressors preferentially maintainhighly functional HIV-specific CD8+T cells. Blood107:4781-4789.
5Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, et al.(2000) Analysis of successful immune responses inpersons infected with hepatitis C virus. J Exp Med191:1499-1512.
6Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, et al.(2006) Restoring function in exhausted CD8T cellsduring chronic viral infection. Nature439:682-687.
7Nishimura H, Agata Y, Kawasaki A, Sato M, Imamura S, et al.(1996) Developmentally regulated expression of thePD-1protein on the surface of double-negative (CD4-CD8-) thymocytes. Int Immunol8:773-780.
8Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1and its ligands in tolerance and immunity. Annu RevImmunol26:677-704.
9Polanczyk MJ, Hopke C, Vandenbark AA, Offner H (2006) Estrogen-mediated immunomodulation involves reducedactivation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1costimulatory pathway. JNeurosci Res84:370-378.
1Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, et al.(1996) Expression of the PD-1antigen on the surfaceof stimulated mouse T and B lymphocytes. Int Immunol8:765-772.
2Freeman GJ, Wherry EJ, Ahmed R, Sharpe AH (2006) Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1ligand blockade. J Exp Med203:2223-2227.
3Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, et al.(2008) The common gamma-chain cytokines IL-2, IL-7,IL-15, and IL-21induce the expression of programmed death-1and its ligands. J Immunol181:6738-6746.
4Oestreich KJ, Yoon H, Ahmed R, Boss JM (2008) NFATc1regulates PD-1expression upon T cell activation. JImmunol181:4832-4839.
5Cho HY, Lee SW, Seo SK, Choi IW, Choi I (2008) Interferon-sensitive response element (ISRE) is mainly responsiblefor IFN-alpha-induced upregulation of programmed death-1(PD-1) in macrophages. Biochim Biophys Acta1779:811-819.
6Yao S, Wang S, Zhu Y, Luo L, Zhu G, et al.(2009) PD-1on dendritic cells impedes innate immunity against bacterialinfection. Blood113:5811-5818.
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, et al.(2000) Engagement of the PD-1immunoinhibitoryreceptor by a novel B7family member leads to negative regulation of lymphocyte activation. J Exp Med192:1027-1034.
8Francisco LM, Sage PT, Sharpe AH (2010) The PD-1pathway in tolerance and autoimmunity. Immunol Rev236:219-242.
9Blank C, Mackensen A (2007) Contribution of the PD-L1/PD-1pathway to T-cell exhaustion: an update onimplications for chronic infections and tumor evasion. Cancer Immunol Immunother56:739-745.
10Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, et al.(2004) PD-1inhibits T-cell receptor inducedphosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett574:37-41.
Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, et al.(2005) CTLA-4and PD-1receptors inhibitT-cell activation by distinct mechanisms. Mol Cell Biol25:9543-9553.
1Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, et al.(2005) CTLA-4and PD-1receptors inhibitT-cell activation by distinct mechanisms. Mol Cell Biol25:9543-9553.
2Bennett F, Luxenberg D, Ling V, Wang IM, Marquette K, et al.(2003) Program death-1engagement upon TCRactivation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21,but not CD28, IL-7, and IL-15responses. J Immunol170:711-718.
3Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, et al.(2006) Upregulation of PD-1expression onHIV-specific CD8+T cells leads to reversible immune dysfunction. Nat Med12:1198-1202.
4Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, et al.(2006) Restoring function in exhausted CD8T cellsduring chronic viral infection. Nature439:682-687.
5Freeman GJ, Wherry EJ, Ahmed R, Sharpe AH (2006) Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1ligand blockade. J Exp Med203:2223-2227.
Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, et al.(2004) PD-L1/B7H-1inhibits the effector phase of tumorrejection by T cell receptor (TCR) transgenic CD8+T cells. Cancer Res64:1140-1145.
1O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al.(2010) MicroRNA-155promotes autoimmuneinflammation by enhancing inflammatory T cell development. Immunity33:607-619.
1Ambros V (2004) The functions of animal microRNAs. Nature431:350-355.
2Cai X, Hagedorn CH, Cullen BR (2004) Human microRNAs are processed from capped, polyadenylated transcriptsthat can also function as mRNAs. RNA10:1957-1966.
3Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004) Processing of primary microRNAs by theMicroprocessor complex. Nature432:231-235.
4Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U (2004) Nuclear export of microRNA precursors. Science303:95-98.
Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4encodes small RNAs with antisensecomplementarity to lin-14. Cell75:843-854.
1Muljo SA, Ansel KM, Kanellopoulou C, Livingston DM, Rao A, et al.(2005) Aberrant T cell differentiation in theabsence of Dicer. J Exp Med202:261-269.
2Cobb BS, Nesterova TB, Thompson E, Hertweck A, O'Connor E, et al.(2005) T cell lineage choice and differentiationin the absence of the RNase III enzyme Dicer. J Exp Med201:1367-1373.
3Guo S, Lu J, Schlanger R, Zhang H, Wang JY, et al.(2010) MicroRNA miR-125a controls hematopoietic stem cellnumber. Proc Natl Acad Sci U S A107:14229-14234.
4Koralov SB, Muljo SA, Galler GR, Krek A, Chakraborty T, et al.(2008) Dicer ablation affects antibody diversity andcell survival in the B lymphocyte lineage. Cell132:860-874.
Bronevetsky Y, Villarino AV, Eisley CJ, Barbeau R, Barczak AJ, et al.(2013) T cell activation induces proteasomaldegradation of Argonaute and rapid remodeling of the microRNA repertoire. J Exp Med210:417-432.
6Liston A, Lu LF, O'Carroll D, Tarakhovsky A, Rudensky AY (2008) Dicer-dependent microRNA pathway safeguardsregulatory T cell function. J Exp Med205:1993-2004.
7Liston A, Lu LF, O'Carroll D, Tarakhovsky A, Rudensky AY (2008) Dicer-dependent microRNA pathway safeguardsregulatory T cell function. J Exp Med205:1993-2004.
8Li QJ, Chau J, Ebert PJ, Sylvester G, Min H, et al.(2007) miR-181a is an intrinsic modulator of T cell sensitivity andselection. Cell129:147-161.
Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, et al.(2010) Function of miR-146a in controlling Tregcell-mediated regulation of Th1responses. Cell142:914-929.
1Stittrich AB, Haftmann C, Sgouroudis E, Kuhl AA, Hegazy AN, et al.(2010) The microRNA miR-182is induced byIL-2and promotes clonal expansion of activated helper T lymphocytes. Nat Immunol11:1057-1062.
2Mattes J, Collison A, Plank M, Phipps S, Foster PS (2009) Antagonism of microRNA-126suppresses the effectorfunction of TH2cells and the development of allergic airways disease. Proc Natl Acad Sci U S A106:18704-18709.
3Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, et al.(2007) Requirement of bic/microRNA-155for normalimmune function. Science316:608-611.
Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, et al.(2009) Foxp3-dependent microRNA155confers competitivefitness to regulatory T cells by targeting SOCS1protein. Immunity30:80-91.
5Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs:are the answers in sight? Nat Rev Genet9:102-114.
6Bronevetsky Y, Villarino AV, Eisley CJ, Barbeau R, Barczak AJ, et al.(2013) T cell activation induces proteasomaldegradation of Argonaute and rapid remodeling of the microRNA repertoire. J Exp Med210:417-432.
7Jiang S, Li C, Olive V, Lykken E, Feng F, et al.(2011) Molecular dissection of the miR-17-92cluster's critical dualroles in promoting Th1responses and preventing inducible Treg differentiation. Blood118:5487-5497.
Ma F, Xu S, Liu X, Zhang Q, Xu X, et al.(2011) The microRNA miR-29controls innate and adaptive immuneresponses to intracellular bacterial infection by targeting interferon-gamma. Nat Immunol12:861-869.
1Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, et al.(2009) Foxp3-dependent microRNA155confers competitivefitness to regulatory T cells by targeting SOCS1protein. Immunity30:80-91.
2Takahashi R, Nishimoto S, Muto G, Sekiya T, Tamiya T, et al.(2011) SOCS1is essential for regulatory T cellfunctions by preventing loss of Foxp3expression as well as IFN-{gamma} and IL-17A production. J Exp Med208:2055-2067.
1O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al.(2010) MicroRNA-155promotes autoimmuneinflammation by enhancing inflammatory T cell development. Immunity33:607-619.
1Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, et al.(2007) A mammalian microRNA expression atlas based onsmall RNA library sequencing. Cell129:1401-1414.
2Eis PS, Tam W, Sun L, Chadburn A, Li Z, et al.(2005) Accumulation of miR-155and BIC RNA in human B celllymphomas. Proc Natl Acad Sci U S A102:3627-3632.
Kutty RK, Nagineni CN, Samuel W, Vijayasarathy C, Hooks JJ, et al.(2010) Inflammatory cytokines regulatemicroRNA-155expression in human retinal pigment epithelial cells by activating JAK/STAT pathway. Biochem BiophysRes Commun402:390-395.
4O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D (2007) MicroRNA-155is induced during themacrophage inflammatory response. Proc Natl Acad Sci U S A104:1604-1609.
5Haasch D, Chen YW, Reilly RM, Chiou XG, Koterski S, et al.(2002) T cell activation induces a noncoding RNAtranscript sensitive to inhibition by immunosuppressant drugs and encoded by the proto-oncogene, BIC. Cell Immunol217:78-86.
Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, et al.(2007) Requirement of bic/microRNA-155for normalimmune function. Science316:608-611.
1Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer6:857-866.
2Metzler M, Wilda M, Busch K, Viehmann S, Borkhardt A (2004) High expression of precursor microRNA-155/BICRNA in children with Burkitt lymphoma. Genes Chromosomes Cancer39:167-169.
3Eis PS, Tam W, Sun L, Chadburn A, Li Z, et al.(2005) Accumulation of miR-155and BIC RNA in human B celllymphomas. Proc Natl Acad Sci U S A102:3627-3632.
4O'Connell RM, Rao DS, Chaudhuri AA, Boldin MP, Taganov KD, et al.(2008) Sustained expression ofmicroRNA-155in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med205:585-594.
O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al.(2010) MicroRNA-155promotes autoimmuneinflammation by enhancing inflammatory T cell development. Immunity33:607-619.
6Bluml S, Bonelli M, Niederreiter B, Puchner A, Mayr G, et al.(2011) Essential role of microRNA-155in thepathogenesis of autoimmune arthritis in mice. Arthritis Rheum63:1281-1288.
7Oertli M, Engler DB, Kohler E, Koch M, Meyer TF, et al.(2011) MicroRNA-155is essential for the T cell-mediatedcontrol of Helicobacter pylori infection and for the induction of chronic Gastritis and Colitis. J Immunol187:3578-3586.
8Dudda JC, Salaun B, Ji Y, Palmer DC, Monnot GC, et al.(2013) MicroRNA-155is required for effector CD8+T cellresponses to virus infection and cancer. Immunity38:742-753.
Clare S, John V, Walker AW, Hill JL, Abreu-Goodger C, et al.(2013) Enhanced susceptibility to Citrobacterrodentium infection in microRNA-155-deficient mice. Infect Immun81:723-732.
1Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, et al.(2007) Requirement of bic/microRNA-155for normalimmune function. Science316:608-611.
2Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, et al.(2007) Regulation of the germinal center response bymicroRNA-155. Science316:604-608.
3Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, et al.(2007) microRNA-155regulates the generation ofimmunoglobulin class-switched plasma cells. Immunity27:847-859.
4Ramiro AR, Jankovic M, Eisenreich T, Difilippantonio S, Chen-Kiang S, et al.(2004) AID is required for c-myc/IgHchromosome translocations in vivo. Cell118:431-438.
5Cobb BS, Hertweck A, Smith J, O'Connor E, Graf D, et al.(2006) A role for Dicer in immune regulation. J Exp Med203:2519-2527.
6Niimoto T, Nakasa T, Ishikawa M, Okuhara A, Izumi B, et al.(2010) MicroRNA-146a expresses in interleukin-17producing T cells in rheumatoid arthritis patients. BMC Musculoskelet Disord11:209.
7Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, et al.(2009) Cutting edge: the Foxp3target miR-155contributes to the development of regulatory T cells. J Immunol182:2578-2582.
8Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, et al.(2009) Foxp3-dependent microRNA155confers competitivefitness to regulatory T cells by targeting SOCS1protein. Immunity30:80-91.
9Yao R, Ma YL, Liang W, Li HH, Ma ZJ, et al.(2012) MicroRNA-155modulates Treg and Th17cells differentiationand Th17cell function by targeting SOCS1. PLoS One7: e46082.
10Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, et al.(2007) Regulation of the germinal center response bymicroRNA-155. Science316:604-608.
11Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL (2010) Micro-RNA-155inhibits IFN-gammasignaling in CD4+T cells. Eur J Immunol40:225-231.
12Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, et al.(2007) Requirement of bic/microRNA-155for normalimmune function. Science316:608-611.
O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al.(2010) MicroRNA-155promotes autoimmuneinflammation by enhancing inflammatory T cell development. Immunity33:607-619.
1Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, et al.(2009) Foxp3-dependent microRNA155confers competitivefitness to regulatory T cells by targeting SOCS1protein. Immunity30:80-91.
1Ramiro AR, Jankovic M, Eisenreich T, Difilippantonio S, Chen-Kiang S, et al.(2004) AID is required for c-myc/IgHchromosome translocations in vivo. Cell118:431-438.
2Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, et al.(2007) microRNA-155regulates the generation ofimmunoglobulin class-switched plasma cells. Immunity27:847-859.
3Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, et al.(2009) Cutting edge: the Foxp3target miR-155contributes to the development of regulatory T cells. J Immunol182:2578-2582.
4Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, et al.(2009) Foxp3-dependent microRNA155confers competitivefitness to regulatory T cells by targeting SOCS1protein. Immunity30:80-91.
Dudda JC, Salaun B, Ji Y, Palmer DC, Monnot GC, et al.(2013) MicroRNA-155is required for effector CD8+T cellresponses to virus infection and cancer. Immunity38:742-753.
6Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, et al.(2007) Regulation of the germinal center response bymicroRNA-155. Science316:604-608.
7Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL (2010) Micro-RNA-155inhibits IFN-gammasignaling in CD4+T cells. Eur J Immunol40:225-231.
8O'Connell RM, Chaudhuri AA, Rao DS, Baltimore D (2009) Inositol phosphatase SHIP1is a primary target ofmiR-155. Proc Natl Acad Sci U S A106:7113-7118.
Tenhunen R, Marver HS, Schmid R (1968) The enzymatic conversion of heme to bilirubin by microsomal hemeoxygenase. Proc Natl Acad Sci U S A61:748-755.
1Jozkowicz A, Was H, Dulak J (2007) Heme oxygenase-1in tumors: is it a false friend? Antioxid Redox Signal9:2099-2117.
2Panchenko MV, Farber HW, Korn JH (2000) Induction of heme oxygenase-1by hypoxia and free radicals in humandermal fibroblasts. Am J Physiol Cell Physiol278: C92-C101.
3Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, et al.(1992) Ferritin: a cytoprotective antioxidant strategem ofendothelium. J Biol Chem267:18148-18153.
Yet SF, Layne MD, Liu X, Chen YH, Ith B, et al.(2003) Absence of heme oxygenase-1exacerbates atheroscleroticlesion formation and vascular remodeling. FASEB J17:1759-1761.
5Zenke-Kawasaki Y, Dohi Y, Katoh Y, Ikura T, Ikura M, et al.(2007) Heme induces ubiquitination and degradation ofthe transcription factor Bach1. Mol Cell Biol27:6962-6971.
6Hira S, Tomita T, Matsui T, Igarashi K, Ikeda-Saito M (2007) Bach1, a heme-dependent transcription factor, revealspresence of multiple heme binding sites with distinct coordination structure. IUBMB Life59:542-551.
7Zenke-Kawasaki Y, Dohi Y, Katoh Y, Ikura T, Ikura M, et al.(2007) Heme induces ubiquitination and degradation ofthe transcription factor Bach1. Mol Cell Biol27:6962-6971.
Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, et al.(1999) Nrf2, a Cap'n'Collar transcription factor,regulates induction of the heme oxygenase-1gene. J Biol Chem274:26071-26078.
1Tenhunen R, Marver HS, Schmid R (1968) The enzymatic conversion of heme to bilirubin by microsomal hemeoxygenase. Proc Natl Acad Sci U S A61:748-755.
2Wilks A (2002) Heme oxygenase: evolution, structure, and mechanism. Antioxid Redox Signal4:603-614.
3Jozkowicz A, Was H, Dulak J (2007) Heme oxygenase-1in tumors: is it a false friend? Antioxid Redox Signal9:2099-2117.
4Brouard S, Otterbein LE, Anrather J, Tobiasch E, Bach FH, et al.(2000) Carbon monoxide generated by hemeoxygenase1suppresses endothelial cell apoptosis. J Exp Med192:1015-1026.
5Gozzelino R, Jeney V, Soares MP (2010) Mechanisms of cell protection by heme oxygenase-1. Annu Rev PharmacolToxicol50:323-354.
6Bilban M, Bach FH, Otterbein SL, Ifedigbo E, d'Avila JC, et al.(2006) Carbon monoxide orchestrates a protectiveresponse through PPARgamma. Immunity24:601-610.
7Nakao A, Kimizuka K, Stolz DB, Neto JS, Kaizu T, et al.(2003) Carbon monoxide inhalation protects rat intestinalgrafts from ischemia/reperfusion injury. Am J Pathol163:1587-1598.
8Chin BY, Jiang G, Wegiel B, Wang HJ, Macdonald T, et al.(2007) Hypoxia-inducible factor1alpha stabilization bycarbon monoxide results in cytoprotective preconditioning. Proc Natl Acad Sci U S A104:5109-5114.
9Brouard S, Berberat PO, Tobiasch E, Seldon MP, Bach FH, et al.(2002) Heme oxygenase-1-derived carbon monoxiderequires the activation of transcription factor NF-kappa B to protect endothelial cells from tumor necrosisfactor-alpha-mediated apoptosis. J Biol Chem277:17950-17961.
10Ferris CD, Jaffrey SR, Sawa A, Takahashi M, Brady SD, et al.(1999) Haem oxygenase-1prevents cell death byregulating cellular iron. Nat Cell Biol1:152-157.
Ferris CD, Jaffrey SR, Sawa A, Takahashi M, Brady SD, et al.(1999) Haem oxygenase-1prevents cell death byregulating cellular iron. Nat Cell Biol1:152-157.
1Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, et al.(2004) Ferritin heavy chain upregulation by NF-kappaBinhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species. Cell119:529-542.
2Brouard S, Berberat PO, Tobiasch E, Seldon MP, Bach FH, et al.(2002) Heme oxygenase-1-derived carbon monoxiderequires the activation of transcription factor NF-kappa B to protect endothelial cells from tumor necrosisfactor-alpha-mediated apoptosis. J Biol Chem277:17950-17961.
3Maghzal GJ, Leck MC, Collinson E, Li C, Stocker R (2009) Limited role for the bilirubin-biliverdin redoxamplification cycle in the cellular antioxidant protection by biliverdin reductase. J Biol Chem284:29251-29259.
4Fondevila C, Shen XD, Tsuchiyashi S, Yamashita K, Csizmadia E, et al.(2004) Biliverdin therapy protects rat liversfrom ischemia and reperfusion injury. Hepatology40:1333-1341.
5Wang H, Lee SS, Dell'Agnello C, Tchipashvili V, d'Avila JC, et al.(2006) Bilirubin can induce tolerance to isletallografts. Endocrinology147:762-768.
6Fondevila C, Shen XD, Tsuchiyashi S, Yamashita K, Csizmadia E, et al.(2004) Biliverdin therapy protects rat liversfrom ischemia and reperfusion injury. Hepatology40:1333-1341.
7Hu CM, Lin HH, Chiang MT, Chang PF, Chau LY (2007) Systemic expression of heme oxygenase-1ameliorates type1diabetes in NOD mice. Diabetes56:1240-1247.
8Chora AA, Fontoura P, Cunha A, Pais TF, Cardoso S, et al.(2007) Heme oxygenase-1and carbon monoxide suppressautoimmune neuroinflammation. J Clin Invest117:438-447.
9Lehmann E, El-Tantawy WH, Ocker M, Bartenschlager R, Lohmann V, et al.(2010) The heme oxygenase1productbiliverdin interferes with hepatitis C virus replication by increasing antiviral interferon response. Hepatology51:398-404.
10Protzer U, Seyfried S, Quasdorff M, Sass G, Svorcova M, et al.(2007) Antiviral activity and hepatoprotection byheme oxygenase-1in hepatitis B virus infection. Gastroenterology133:1156-1165.
11Silva-Gomes S, Appelberg R, Larsen R, Soares MP, Gomes MS (2013) Heme catabolism by heme oxygenase-11c2onfers host resistance to Mycobacterium infection. Infect Immun81:2536-2545.
Pamplona A, Ferreira A, Balla J, Jeney V, Balla G, et al.(2007) Heme oxygenase-1and carbon monoxide suppress thepathogenesis of experimental cerebral malaria. Nat Med13:703-710.
13Doi K, Akaike T, Fujii S, Tanaka S, Ikebe N, et al.(1999) Induction of haem oxygenase-1nitric oxide and ischaemiain experimental solid tumours and implications for tumour growth. Br J Cancer80:1945-1954
14Deininger MH, Meyermann R, Trautmann K, Duffner F, Grote EH, et al.(2000) Heme oxygenase (HO)-1expressingmacrophages/microglial cells accumulate during oligodendroglioma progression. Brain Res882:1-8
15Torisu-Itakura H, Furue M, Kuwano M, Ono M (2000) Co-expression of thymidine phosphorylase and hemeoxygenase-1in macrophages in human malignant vertical growth melanomas. Jpn J Cancer Res91:906-910.
Tsuji MH, Yanagawa T, Iwasa S, Tabuchi K, Onizawa K, et al.(1999) Heme oxygenase-1expression in oralsquamous cell carcinoma as involved in lymph node metastasis. Cancer Lett138:53-59.
1Pae HO, Oh GS, Choi BM, Chae SC, Kim YM, et al.(2004) Carbon monoxide produced by heme oxygenase-1suppresses T cell proliferation via inhibition of IL-2production. J Immunol172:4744-4751.
1Burt TD, Seu L, Mold JE, Kappas A, McCune JM (2010) Naive human T cells are activated and proliferate in responseto the heme oxygenase-1inhibitor tin mesoporphyrin. J Immunol185:5279-5288.
1Soares MP, Bach FH (2009) Heme oxygenase-1: from biology to therapeutic potential. Trends Mol Med15:50-58.
2Exner M, Minar E, Wagner O, Schillinger M (2004) The role of heme oxygenase-1promoter polymorphisms in humandisease. Free Radic Biol Med37:1097-1104.
Hengartner MO, Horvitz HR (1994) Programmed cell death in Caenorhabditis elegans. Curr Opin Genet Dev4:581-586.
1Soares MP, Lin Y, Anrather J, Csizmadia E, Takigami K, et al.(1998) Expression of heme oxygenase-1can determinecardiac xenograft survival. Nat Med4:1073-1077.
2Tartaglia LA, Rothe M, Hu YF, Goeddel DV (1993) Tumor necrosis factor's cytotoxic activity is signaled by the p55TNF receptor. Cell73:213-216.
3Soares MP, Seldon MP, Gregoire IP, Vassilevskaia T, Berberat PO, et al.(2004) Heme oxygenase-1modulates theexpression of adhesion molecules associated with endothelial cell activation. J Immunol172:3553-3563.
4Mahoney DJ, Cheung HH, Mrad RL, Plenchette S, Simard C, et al.(2008) Both cIAP1and cIAP2regulateTNFalpha-mediated NF-kappaB activation. Proc Natl Acad Sci U S A105:11778-11783.
5Micheau O, Tschopp J (2003) Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.Cell114:181-190.
6Perkins ND (2007) Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol8:49-62.
7Perkins ND (2007) Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol8:49-62.
8Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U (1995) Control of I kappa B-alpha proteolysis bysite-specific, signal-induced phosphorylation. Science267:1485-1488.
9Chen Z, Hagler J, Palombella VJ, Melandri F, Scherer D, et al.(1995) Signal-induced site-specific phosphorylationtargets I kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev9:1586-1597.
10Henkel T, Machleidt T, Alkalay I, Kronke M, Ben-Neriah Y, et al.(1993) Rapid proteolysis of I kappa B-alpha isnecessary for activation of transcription factor NF-kappa B. Nature365:182-185.
11Brouard S, Berberat PO, Tobiasch E, Seldon MP, Bach FH, et al.(2002) Heme oxygenase-1-derived carbon monoxiderequires the activation of transcription factor NF-kappa B to protect endothelial cells from tumor necrosisfactor-alpha-mediated apoptosis. J Biol Chem277:17950-17961.
12Brouard S, Berberat PO, Tobiasch E, Seldon MP, Bach FH, et al.(2002) Heme oxygenase-1-derived carbon monoxiderequires the activation of transcription factor NF-kappa B to protect endothelial cells from tumor necrosisfactor-alpha-mediated apoptosis. J Biol Chem277:17950-17961.
13Seldon MP, Silva G, Pejanovic N, Larsen R, Gregoire IP, et al.(2007) Heme oxygenase-1inhibits the expression ofadhesion molecules associated with endothelial cell activation via inhibition of NF-kappaB RelA phosphorylation atserine276. J Immunol179:7840-7851.
Micheau O, Tschopp J (2003) Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.Cell114:181-190.
1Fiers W, Beyaert R, Declercq W, Vandenabeele P (1999) More than one way to die: apoptosis, necrosis and reactiveoxygen damage. Oncogene18:7719-7730.
2Brouard S, Otterbein LE, Anrather J, Tobiasch E, Bach FH, et al.(2000) Carbon monoxide generated by hemeoxygenase1suppresses endothelial cell apoptosis. J Exp Med192:1015-1026.
3Arruda MA, Rossi AG, de Freitas MS, Barja-Fidalgo C, Graca-Souza AV (2004) Heme inhibits human neutrophilapoptosis: involvement of phosphoinositide3-kinase, MAPK, and NF-kappaB. J Immunol173:2023-2030.
4Wada T, Penninger JM (2004) Mitogen-activated protein kinases in apoptosis regulation. Oncogene23:2838-2849.
5Silva G, Cunha A, Gregoire IP, Seldon MP, Soares MP (2006) The antiapoptotic effect of heme oxygenase-1inendothelial cells involves the degradation of p38alpha MAPK isoform. J Immunol177:1894-1903.
6Zhang X, Shan P, Alam J, Fu XY, Lee PJ (2005) Carbon monoxide differentially modulates STAT1and STAT3andinhibits apoptosis via a phosphatidylinositol3-kinase/Akt and p38kinase-dependent STAT3pathway duringanoxia-reoxygenation injury. J Biol Chem280:8714-8721.
7Salinas M, Wang J, Rosa de Sagarra M, Martin D, Rojo AI, et al.(2004) Protein kinase Akt/PKB phosphorylates hemeoxygenase-1in vitro and in vivo. FEBS Lett578:90-94.
8Katori M, Buelow R, Ke B, Ma J, Coito AJ, et al.(2002) Heme oxygenase-1overexpression protects rat hearts fromcold ischemia/reperfusion injury via an antiapoptotic pathway. Transplantation73:287-292.
Pae HO, Oh GS, Choi BM, Chae SC, Kim YM, et al.(2004) Carbon monoxide produced by heme oxygenase-1suppresses T cell proliferation via inhibition of IL-2production. J Immunol172:4744-4751.
1McDaid J, Yamashita K, Chora A, Ollinger R, Strom TB, et al.(2005) Heme oxygenase-1modulates the allo-immuneresponse by promoting activation-induced cell death of T cells. FASEB J19:458-460.
1Urban JL, Kumar V, Kono DH, Gomez C, Horvath SJ, et al.(1988) Restricted use of T cell receptor V genes in murineautoimmune encephalomyelitis raises possibilities for antibody therapy. Cell54:577-592.
1Mendel I, Kerlero de Rosbo N, Ben-Nun A (1995) A myelin oligodendrocyte glycoprotein peptide induces typicalchronic experimental autoimmune encephalomyelitis in H-2b mice: fine specificity and T cell receptor V beta expressionof encephalitogenic T cells. Eur J Immunol25:1951-1959.
2Jones MV, Nguyen TT, Deboy CA, Griffin JW, Whartenby KA, et al.(2008) Behavioral and pathological outcomes inMOG35-55experimental autoimmune encephalomyelitis. J Neuroimmunol199:83-93.
3Brostoff SW, Mason DW (1984) Experimental allergic encephalomyelitis: successful treatment in vivo with amonoclonal antibody that recognizes T helper cells. J Immunol133:1938-1942.
4Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol23:683-747.
1Hafler DA (2004) Multiple sclerosis. J Clin Invest113:788-794.
2Gocke AR, Cravens PD, Ben LH, Hussain RZ, Northrop SC, et al.(2007) T-bet regulates the fate of Th1and Th17lymphocytes in autoimmunity. J Immunol178:1341-1348.
3Heremans H, Dillen C, Groenen M, Martens E, Billiau A (1996) Chronic relapsing experimental autoimmuneencephalomyelitis (CREAE) in mice: enhancement by monoclonal antibodies against interferon-gamma. Eur J Immunol
426:2393-2398.Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, et al.(2003) Interleukin-23rather than interleukin-12is the criticalcytokine for autoimmune inflammation of the brain. Nature421:744-748.
5Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, et al.(2005) IL-23drives a pathogenic T cellpopulation that induces autoimmune inflammation. J Exp Med201:233-240.
6Eugster HP, Frei K, Kopf M, Lassmann H, Fontana A (1998) IL-6-deficient mice resist myelin oligodendrocyteglycoprotein-induced autoimmune encephalomyelitis. Eur J Immunol28:2178-2187.
7Park H, Li Z, Yang XO, Chang SH, Nurieva R, et al.(2005) A distinct lineage of CD4T cells regulates tissueinflammation by producing interleukin17. Nat Immunol6:1133-1141.
Du C, Liu C, Kang J, Zhao G, Ye Z, et al.(2009) MicroRNA miR-326regulates TH-17differentiation and is associatedwith the pathogenesis of multiple sclerosis. Nat Immunol10:1252-1259.
9Mycko MP, Cichalewska M, Machlanska A, Cwiklinska H, Mariasiewicz M, et al.(2012) MicroRNA-301a regulationof a T-helper17immune response controls autoimmune demyelination. Proc Natl Acad Sci U S A109: E1248-1257.
10O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al.(2010) MicroRNA-155promotes autoimmuneinflammation by enhancing inflammatory T cell development. Immunity33:607-619.
11Laatsch RH (1962) Glycerol phosphate dehydrogenase activity of developing rat central nervous system. J Neurochem192:487-492.
Chora AA, Fontoura P, Cunha A, Pais TF, Cardoso S, et al.(2007) Heme oxygenase-1and carbon monoxide suppressautoimmune neuroinflammation. J Clin Invest117:438-447.
1So AY, Garcia-Flores Y, Minisandram A, Martin A, Taganov K, et al.(2012) Regulation of APC development,immune response, and autoimmunity by Bach1/HO-1pathway in mice. Blood120:2428-2437.
1Kusters, J.G., van Vliet, A.H.&Kuipers, E.J.(2006) Pathogenesis of Helicobacter pylori infection. Clin Microbiol Rev19,449-490.
2Pappo, J., et al.(1999) Helicobacter pylori infection in immunized mice lacking major histocompatibility complexclass I and class II functions. Infect Immun67,337-341
3Dong, C.(2008) TH17cells in development: an updated view of their molecular identity and genetic programming. NatRev Immunol8,337-348.
4Shi, Y., et al.(2010) Helicobacter pylori-induced Th17responses modulate Th1cell responses, benefit bacterial growth,
5and contribute to pathology in mice. J Immunol184,5121-5129.Andersen, L.P.(2007) Colonization and infection by Helicobacter pylori in humans. Helicobacter12Suppl2,12-15.
6Tan, S.&Berg, D.E.(2004) Motility of urease-deficient derivatives of Helicobacter pylori. J Bacteriol186,885-888.
1Andrutis, K.A., et al.(1995) Inability of an isogenic urease-negative mutant stain of Helicobacter mustelae to colonizethe ferret stomach. Infect Immun63,3722-3725.
2Harris, P.R., Mobley, H.L., Perez-Perez, G.I., Blaser, M.J.&Smith, P.D.(1996) Helicobacter pylori urease is a potentstimulus of mononuclear phagocyte activation and inflammatory cytokine production. Gastroenterology111,419-425.
DeLyria, E.S., Redline, R.W.&Blanchard, T.G.(2009) Vaccination of mice against H pylori induces a strong Th-17response and immunity that is neutrophil dependent. Gastroenterology136,247-256.
1Lu, D.S., et al.(2003)[Recombinant Helicobacter pylori urease B subunit and its biological properties]. Di Yi Jun YiDa Xue Xue Bao23,549-552.
1Oppmann, B., et al.(2000) Novel p19protein engages IL-12p40to form a cytokine, IL-23, with biological activitiessimilar as well as distinct from IL-12. Immunity13,715-725.
2Kryczek, I., et al.(2007) Cutting edge: opposite effects of IL-1and IL-2on the regulation of IL-17+T cell pool IL-1subverts IL-2-mediated suppression. J Immunol179,1423-1426.
3Ivanov, II, et al.(2006) The orphan nuclear receptor RORgammat directs the differentiation program ofproinflammatory IL-17+T helper cells. Cell126,1121-1133.
Zhou, L., et al.(2007) IL-6programs T(H)-17cell differentiation by promoting sequential engagement of the IL-21andIL-23pathways. Nat Immunol8,967-974.
1Ambros V (2004) The functions of animal microRNAs. Nature431:350-355.
2Cai X, Hagedorn CH, Cullen BR (2004) Human microRNAs are processed from capped, polyadenylated transcriptsthat can also function as mRNAs. RNA10:1957-1966.
3Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004) Processing of primary microRNAs by theMicroprocessor complex. Nature432:231-235.
4Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U (2004) Nuclear export of microRNA precursors. Science303:95-98.
5Haasch D, Chen YW, Reilly RM, Chiou XG, Koterski S, et al.(2002) T cell activation induces a noncoding RNAtranscript sensitive to inhibition by immunosuppressant drugs and encoded by the proto-oncogene, BIC. Cell Immunol217:78-86.
1Kutty RK, Nagineni CN, Samuel W, Vijayasarathy C, Hooks JJ, et al.(2010) Inflammatory cytokines regulatemicroRNA-155expression in human retinal pigment epithelial cells by activating JAK/STAT pathway. Biochem BiophysRes Commun402:390-395.
2O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D (2007) MicroRNA-155is induced during themacrophage inflammatory response. Proc Natl Acad Sci U S A104:1604-1609.
3Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer6:857-866.
4Martinez-Nunez RT, Louafi F, Sanchez-Elsner T (2011) The interleukin13(IL-13) pathway in human macrophages ismodulated by microRNA-155via direct targeting of interleukin13receptor alpha1(IL13Ralpha1). J Biol Chem286:1786-1794.
5Worm J, Stenvang J, Petri A, Frederiksen KS, Obad S, et al.(2009) Silencing of microRNA-155in mice during acuteinflammatory response leads to derepression of c/ebp Beta and down-regulation of G-CSF. Nucleic Acids Res37:5784-5792.
Louafi F, Martinez-Nunez RT, Sanchez-Elsner T (2010) MicroRNA-155targets SMAD2and modulates the responseof macrophages to transforming growth factor-{beta}. J Biol Chem285:41328-41336.
1Nazari-Jahantigh M, Wei Y, Noels H, Akhtar S, Zhou Z, et al.(2012) MicroRNA-155promotes atherosclerosis byrepressing Bcl6in macrophages. J Clin Invest122:4190-4202.
2Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, et al.(2007) Requirement of bic/microRNA-155for normalimmune function. Science316:608-611.
Dunand-Sauthier I, Santiago-Raber ML, Capponi L, Vejnar CE, Schaad O, et al.(2011) Silencing of c-Fos expressionby microRNA-155is critical for dendritic cell maturation and function. Blood117:4490-4500.
4Ceppi M, Pereira PM, Dunand-Sauthier I, Barras E, Reith W, et al.(2009) MicroRNA-155modulates the interleukin-1signaling pathway in activated human monocyte-derived dendritic cells. Proc Natl Acad Sci U S A106:2735-2740.
5Chen T, Yan H, Li Z, Jing T, Zhu W, et al.(2011) MicroRNA-155regulates lipid uptake, adhesion/chemokine markersecretion and SCG2expression in oxLDL-stimulated dendritic cells/macrophages. Int J Cardiol147:446-447.
6Ramiro AR, Jankovic M, Eisenreich T, Difilippantonio S, Chen-Kiang S, et al.(2004) AID is required for c-myc/IgHchromosome translocations in vivo. Cell118:431-438.
Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, et al.(2007) microRNA-155regulates the generation ofimmunoglobulin class-switched plasma cells. Immunity27:847-859.
1Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, et al.(2007) Regulation of the germinal center response bymicroRNA-155. Science316:604-608.
2Tili E, Croce CM, Michaille JJ (2009) miR-155: on the crosstalk between inflammation and cancer. Int Rev Immunol28:264-284.
3Pedersen IM, Otero D, Kao E, Miletic AV, Hother C, et al.(2009) Onco-miR-155targets SHIP1to promoteTNFalpha-dependent growth of B cell lymphomas. EMBO Mol Med1:288-295.
4Eis PS, Tam W, Sun L, Chadburn A, Li Z, et al.(2005) Accumulation of miR-155and BIC RNA in human B celllymphomas. Proc Natl Acad Sci U S A102:3627-3632.
O'Connell RM, Chaudhuri AA, Rao DS, Baltimore D (2009) Inositol phosphatase SHIP1is a primary target ofmiR-155. Proc Natl Acad Sci U S A106:7113-7118.
6Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, et al.(2007) Regulation of the germinal center response bymicroRNA-155. Science316:604-608.
7Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL (2010) Micro-RNA-155inhibits IFN-gammasignaling in CD4+T cells. Eur J Immunol40:225-231.
8Dudda JC, Salaun B, Ji Y, Palmer DC, Monnot GC, et al.(2013) MicroRNA-155is required for effector CD8+T cellresponses to virus infection and cancer. Immunity38:742-753.
Oertli M, Engler DB, Kohler E, Koch M, Meyer TF, et al.(2011) MicroRNA-155is essential for the T cell-mediatedcontrol of Helicobacter pylori infection and for the induction of chronic Gastritis and Colitis. J Immunol187:3578-3586.
1O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al.(2010) MicroRNA-155promotes autoimmune
2inflammation by enhancing inflammatory T cell development. Immunity33:607-619.Gracias DT, Stelekati E, Hope JL, Boesteanu AC, Doering TA, et al.(2013) The microRNA miR-155controls CD8(+)T cell responses by regulating interferon signaling. Nat Immunol14:593-602.
3Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, et al.(2009) Cutting edge: the Foxp3target miR-155contributes to the development of regulatory T cells. J Immunol182:2578-2582.
4Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, et al.(2009) Foxp3-dependent microRNA155confers competitivefitness to regulatory T cells by targeting SOCS1protein. Immunity30:80-91.
5Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, et al.(2009) Cutting edge: the Foxp3target miR-155contributes to the development of regulatory T cells. J Immunol182:2578-2582.
Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, et al.(2009) Cutting edge: the Foxp3target miR-155contributes to the development of regulatory T cells. J Immunol182:2578-2582.
[1] Wherry EJ (2011) T cell exhaustion. Nat Immunol12:492-499.
[2] Blackburn SD, Wherry EJ (2007) IL-10, T cell exhaustion and viral persistence.Trends Microbiol15:143-146.
[3] Francisco LM, Sage PT, Sharpe AH (2010) The PD-1pathway in tolerance andautoimmunity. Immunol Rev236:219-242.
[4] Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T (1994) Structure andchromosomal localization of the human PD-1gene (PDCD1). Genomics23:704-706.
[5] Ishida Y, Agata Y, Shibahara K, Honjo T (1992) Induced expression of PD-1, a novelmember of the immunoglobulin gene superfamily, upon programmed cell death.EMBO J11:3887-3895.
[6] Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, et al.(2006) Restoringfunction in exhausted CD8T cells during chronic viral infection. Nature439:682-687.
[7] Curran MA, Montalvo W, Yagita H, Allison JP (2010) PD-1and CTLA-4combination blockade expands infiltrating T cells and reduces regulatory T andmyeloid cells within B16melanoma tumors. Proc Natl Acad Sci U S A107:4275-4280.
[8] Noval Rivas M, Weatherly K, Hazzan M, Vokaer B, Dremier S, et al.(2009)Reviving function in CD4+T cells adapted to persistent systemic antigen. J Immunol183:4284-4291.
[9] Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, et al.(2010) TargetingTim-3and PD-1pathways to reverse T cell exhaustion and restore anti-tumorimmunity. J Exp Med207:2187-2194.
[10] Ambros V (2004) The functions of animal microRNAs. Nature431:350-355.
[11] Muljo SA, Ansel KM, Kanellopoulou C, Livingston DM, Rao A, et al.(2005)Aberrant T cell differentiation in the absence of Dicer. J Exp Med202:261-269.
[12] Cobb BS, Nesterova TB, Thompson E, Hertweck A, O'Connor E, et al.(2005) T celllineage choice and differentiation in the absence of the RNase III enzyme Dicer. JExp Med201:1367-1373.
[13] Guo S, Lu J, Schlanger R, Zhang H, Wang JY, et al.(2010) MicroRNA miR-125acontrols hematopoietic stem cell number. Proc Natl Acad Sci U S A107:14229-14234.
[14] Koralov SB, Muljo SA, Galler GR, Krek A, Chakraborty T, et al.(2008) Dicerablation affects antibody diversity and cell survival in the B lymphocyte lineage. Cell132:860-874.
[15] Liston A, Lu LF, O'Carroll D, Tarakhovsky A, Rudensky AY (2008) Dicer-dependentmicroRNA pathway safeguards regulatory T cell function. J Exp Med205:1993-2004.
[16] Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, et al.(2009)Cutting edge: the Foxp3target miR-155contributes to the development of regulatoryT cells. J Immunol182:2578-2582.
[17] Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, et al.(2009) Foxp3-dependentmicroRNA155confers competitive fitness to regulatory T cells by targeting SOCS1protein. Immunity30:80-91.
[18] O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al.(2010)MicroRNA-155promotes autoimmune inflammation by enhancing inflammatory Tcell development. Immunity33:607-619.
[19] Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, et al.(2007) Regulation of thegerminal center response by microRNA-155. Science316:604-608.
[20] Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL (2010)Micro-RNA-155inhibits IFN-gamma signaling in CD4+T cells. Eur J Immunol40:225-231.
[21] Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, et al.(2007)microRNA-155regulates the generation of immunoglobulin class-switched plasmacells. Immunity27:847-859.
[22] Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, et al.(1998) Viralimmune evasion due to persistence of activated T cells without effector function. JExp Med188:2205-2213.
[23] Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R (2003) Viralpersistence alters CD8T-cell immunodominance and tissue distribution and results indistinct stages of functional impairment. J Virol77:4911-4927.
[24] Moskophidis D, Lechner F, Pircher H, Zinkernagel RM (1993) Virus persistence inacutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effectorT cells. Nature362:758-761.
[25] Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, et al.(2006) HIVnonprogressors preferentially maintain highly functional HIV-specific CD8+T cells.Blood107:4781-4789.
[26] Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, et al.(2000) Analysis ofsuccessful immune responses in persons infected with hepatitis C virus. J Exp Med191:1499-1512.
[27] Nishimura H, Agata Y, Kawasaki A, Sato M, Imamura S, et al.(1996)Developmentally regulated expression of the PD-1protein on the surface ofdouble-negative (CD4-CD8-) thymocytes. Int Immunol8:773-780.
[28] Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1and its ligands in toleranceand immunity. Annu Rev Immunol26:677-704.
[29] Polanczyk MJ, Hopke C, Vandenbark AA, Offner H (2006) Estrogen-mediatedimmunomodulation involves reduced activation of effector T cells, potentiation ofTreg cells, and enhanced expression of the PD-1costimulatory pathway. J NeurosciRes84:370-378.
[30] Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, et al.(1996) Expression ofthe PD-1antigen on the surface of stimulated mouse T and B lymphocytes. IntImmunol8:765-772.
[31] Freeman GJ, Wherry EJ, Ahmed R, Sharpe AH (2006) Reinvigorating exhaustedHIV-specific T cells via PD-1-PD-1ligand blockade. J Exp Med203:2223-2227.
[32] Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, et al.(2008) The commongamma-chain cytokines IL-2, IL-7, IL-15, and IL-21induce the expression ofprogrammed death-1and its ligands. J Immunol181:6738-6746.
[33] Oestreich KJ, Yoon H, Ahmed R, Boss JM (2008) NFATc1regulates PD-1expression upon T cell activation. J Immunol181:4832-4839.
[34] Cho HY, Lee SW, Seo SK, Choi IW, Choi I (2008) Interferon-sensitive responseelement (ISRE) is mainly responsible for IFN-alpha-induced upregulation ofprogrammed death-1(PD-1) in macrophages. Biochim Biophys Acta1779:811-819.
[35] Yao S, Wang S, Zhu Y, Luo L, Zhu G, et al.(2009) PD-1on dendritic cells impedesinnate immunity against bacterial infection. Blood113:5811-5818.
[36] Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, et al.(2000) Engagement ofthe PD-1immunoinhibitory receptor by a novel B7family member leads to negativeregulation of lymphocyte activation. J Exp Med192:1027-1034.
[37] Blank C, Mackensen A (2007) Contribution of the PD-L1/PD-1pathway to T-cellexhaustion: an update on implications for chronic infections and tumor evasion.Cancer Immunol Immunother56:739-745.
[38] Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, et al.(2004) PD-1inhibitsT-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome anddownstream signaling to PKCtheta. FEBS Lett574:37-41.
[39] Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, et al.(2005)CTLA-4and PD-1receptors inhibit T-cell activation by distinct mechanisms. MolCell Biol25:9543-9553.
[40] Bennett F, Luxenberg D, Ling V, Wang IM, Marquette K, et al.(2003) Programdeath-1engagement upon TCR activation has distinct effects on costimulation andcytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28,IL-7, and IL-15responses. J Immunol170:711-718.
[41] Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, et al.(2006)Upregulation of PD-1expression on HIV-specific CD8+T cells leads to reversibleimmune dysfunction. Nat Med12:1198-1202.
[42] Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, et al.(2004) PD-L1/B7H-1inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenicCD8+T cells. Cancer Res64:1140-1145.
[43] Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, et al.(2002) Involvement of PD-L1on tumor cells in the escape from host immune system and tumor immunotherapy byPD-L1blockade. Proc Natl Acad Sci U S A99:12293-12297.
[44] Cai X, Hagedorn CH, Cullen BR (2004) Human microRNAs are processed fromcapped, polyadenylated transcripts that can also function as mRNAs. RNA10:1957-1966.
[45] Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004) Processing ofprimary microRNAs by the Microprocessor complex. Nature432:231-235.
[46] Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U (2004) Nuclear export ofmicroRNA precursors. Science303:95-98.
[47] Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4encodes small RNAs with antisense complementarity to lin-14. Cell75:843-854.
[48] Belver L, Papavasiliou FN, Ramiro AR (2011) MicroRNA control of lymphocytedifferentiation and function. Curr Opin Immunol23:368-373.
[49] Bronevetsky Y, Villarino AV, Eisley CJ, Barbeau R, Barczak AJ, et al.(2013) T cellactivation induces proteasomal degradation of Argonaute and rapid remodeling of themicroRNA repertoire. J Exp Med210:417-432.
[50] Zhou X, Jeker LT, Fife BT, Zhu S, Anderson MS, et al.(2008) Selective miRNAdisruption in T reg cells leads to uncontrolled autoimmunity. J Exp Med205:1983-1991.
[51] Li QJ, Chau J, Ebert PJ, Sylvester G, Min H, et al.(2007) miR-181a is an intrinsicmodulator of T cell sensitivity and selection. Cell129:147-161.
[52] Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, et al.(2010) Function ofmiR-146a in controlling Treg cell-mediated regulation of Th1responses. Cell142:914-929.
[53] Stittrich AB, Haftmann C, Sgouroudis E, Kuhl AA, Hegazy AN, et al.(2010) ThemicroRNA miR-182is induced by IL-2and promotes clonal expansion of activatedhelper T lymphocytes. Nat Immunol11:1057-1062.
[54] Mattes J, Collison A, Plank M, Phipps S, Foster PS (2009) Antagonism ofmicroRNA-126suppresses the effector function of TH2cells and the development ofallergic airways disease. Proc Natl Acad Sci U S A106:18704-18709.
[55] Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, et al.(2007) Requirementof bic/microRNA-155for normal immune function. Science316:608-611.
[56] Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms ofpost-transcriptional regulation by microRNAs: are the answers in sight? Nat RevGenet9:102-114.
[57] Jiang S, Li C, Olive V, Lykken E, Feng F, et al.(2011) Molecular dissection of themiR-17-92cluster's critical dual roles in promoting Th1responses and preventinginducible Treg differentiation. Blood118:5487-5497.
[58] Ma F, Xu S, Liu X, Zhang Q, Xu X, et al.(2011) The microRNA miR-29controlsinnate and adaptive immune responses to intracellular bacterial infection by targetinginterferon-gamma. Nat Immunol12:861-869.
[59] Takahashi R, Nishimoto S, Muto G, Sekiya T, Tamiya T, et al.(2011) SOCS1isessential for regulatory T cell functions by preventing loss of Foxp3expression aswell as IFN-{gamma} and IL-17A production. J Exp Med208:2055-2067.
[60] Dudda JC, Salaun B, Ji Y, Palmer DC, Monnot GC, et al.(2013) MicroRNA-155isrequired for effector CD8+T cell responses to virus infection and cancer. Immunity38:742-753.
[61] Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, et al.(2007) A mammalianmicroRNA expression atlas based on small RNA library sequencing. Cell129:1401-1414.
[62] Eis PS, Tam W, Sun L, Chadburn A, Li Z, et al.(2005) Accumulation of miR-155andBIC RNA in human B cell lymphomas. Proc Natl Acad Sci U S A102:3627-3632.
[63] O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D (2007)MicroRNA-155is induced during the macrophage inflammatory response. Proc NatlAcad Sci U S A104:1604-1609.
[64] Kutty RK, Nagineni CN, Samuel W, Vijayasarathy C, Hooks JJ, et al.(2010)Inflammatory cytokines regulate microRNA-155expression in human retinal pigmentepithelial cells by activating JAK/STAT pathway. Biochem Biophys Res Commun402:390-395.
[65] Haasch D, Chen YW, Reilly RM, Chiou XG, Koterski S, et al.(2002) T cellactivation induces a noncoding RNA transcript sensitive to inhibition byimmunosuppressant drugs and encoded by the proto-oncogene, BIC. Cell Immunol217:78-86.
[66] Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat RevCancer6:857-866.
[67] Metzler M, Wilda M, Busch K, Viehmann S, Borkhardt A (2004) High expression ofprecursor microRNA-155/BIC RNA in children with Burkitt lymphoma. GenesChromosomes Cancer39:167-169.
[68] van den Berg A, Kroesen BJ, Kooistra K, de Jong D, Briggs J, et al.(2003) Highexpression of B-cell receptor inducible gene BIC in all subtypes of Hodgkinlymphoma. Genes Chromosomes Cancer37:20-28.
[69] O'Connell RM, Rao DS, Chaudhuri AA, Boldin MP, Taganov KD, et al.(2008)Sustained expression of microRNA-155in hematopoietic stem cells causes amyeloproliferative disorder. J Exp Med205:585-594.
[70] Bluml S, Bonelli M, Niederreiter B, Puchner A, Mayr G, et al.(2011) Essential roleof microRNA-155in the pathogenesis of autoimmune arthritis in mice. ArthritisRheum63:1281-1288.
[71] Oertli M, Engler DB, Kohler E, Koch M, Meyer TF, et al.(2011) MicroRNA-155isessential for the T cell-mediated control of Helicobacter pylori infection and for theinduction of chronic Gastritis and Colitis. J Immunol187:3578-3586.
[72] Clare S, John V, Walker AW, Hill JL, Abreu-Goodger C, et al.(2013) Enhancedsusceptibility to Citrobacter rodentium infection in microRNA-155-deficient mice.Infect Immun81:723-732.
[73] Ramiro AR, Jankovic M, Eisenreich T, Difilippantonio S, Chen-Kiang S, et al.(2004)AID is required for c-myc/IgH chromosome translocations in vivo. Cell118:431-438.
[74] Cobb BS, Hertweck A, Smith J, O'Connor E, Graf D, et al.(2006) A role for Dicer inimmune regulation. J Exp Med203:2519-2527.
[75] Niimoto T, Nakasa T, Ishikawa M, Okuhara A, Izumi B, et al.(2010)MicroRNA-146a expresses in interleukin-17producing T cells in rheumatoid arthritispatients. BMC Musculoskelet Disord11:209.
[76] Yoshimura A, Naka T, Kubo M (2007) SOCS proteins, cytokine signalling andimmune regulation. Nat Rev Immunol7:454-465.
[77] Yao R, Ma YL, Liang W, Li HH, Ma ZJ, et al.(2012) MicroRNA-155modulatesTreg and Th17cells differentiation and Th17cell function by targeting SOCS1. PLoSOne7: e46082.
[78] Dunand-Sauthier I, Santiago-Raber ML, Capponi L, Vejnar CE, Schaad O, et al.(2011) Silencing of c-Fos expression by microRNA-155is critical for dendritic cellmaturation and function. Blood117:4490-4500.
[79] O'Connell RM, Chaudhuri AA, Rao DS, Baltimore D (2009) Inositol phosphataseSHIP1is a primary target of miR-155. Proc Natl Acad Sci U S A106:7113-7118.
[80] Tenhunen R, Marver HS, Schmid R (1968) The enzymatic conversion of heme tobilirubin by microsomal heme oxygenase. Proc Natl Acad Sci U S A61:748-755.
[81] Jozkowicz A, Was H, Dulak J (2007) Heme oxygenase-1in tumors: is it a false friend?Antioxid Redox Signal9:2099-2117.
[82] Panchenko MV, Farber HW, Korn JH (2000) Induction of heme oxygenase-1byhypoxia and free radicals in human dermal fibroblasts. Am J Physiol Cell Physiol278:C92-C101.
[83] Christou H, Bailey N, Kluger MS, Mitsialis SA, Kourembanas S (2005) Extracellularacidosis induces heme oxygenase-1expression in vascular smooth muscle cells. Am JPhysiol Heart Circ Physiol288: H2647-2652.
[84] Ferreira A, Balla J, Jeney V, Balla G, Soares MP (2008) A central role for free hemein the pathogenesis of severe malaria: the missing link? J Mol Med (Berl)86:1097-1111.
[85] Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, et al.(1992) Ferritin: acytoprotective antioxidant strategem of endothelium. J Biol Chem267:18148-18153.
[86] Poss KD, Tonegawa S (1997) Reduced stress defense in heme oxygenase1-deficientcells. Proc Natl Acad Sci U S A94:10925-10930.
[87] Yet SF, Layne MD, Liu X, Chen YH, Ith B, et al.(2003) Absence of hemeoxygenase-1exacerbates atherosclerotic lesion formation and vascular remodeling.FASEB J17:1759-1761.
[88] Zenke-Kawasaki Y, Dohi Y, Katoh Y, Ikura T, Ikura M, et al.(2007) Heme inducesubiquitination and degradation of the transcription factor Bach1. Mol Cell Biol27:6962-6971.
[89] Hira S, Tomita T, Matsui T, Igarashi K, Ikeda-Saito M (2007) Bach1, aheme-dependent transcription factor, reveals presence of multiple heme binding siteswith distinct coordination structure. IUBMB Life59:542-551.
[90] Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, et al.(1999) Nrf2, aCap'n'Collar transcription factor, regulates induction of the heme oxygenase-1gene. JBiol Chem274:26071-26078.
[91] Wilks A (2002) Heme oxygenase: evolution, structure, and mechanism. AntioxidRedox Signal4:603-614.
[92] Brouard S, Otterbein LE, Anrather J, Tobiasch E, Bach FH, et al.(2000) Carbonmonoxide generated by heme oxygenase1suppresses endothelial cell apoptosis. JExp Med192:1015-1026.
[93] Gozzelino R, Jeney V, Soares MP (2010) Mechanisms of cell protection by hemeoxygenase-1. Annu Rev Pharmacol Toxicol50:323-354.
[94] Zuckerbraun BS, Chin BY, Bilban M, d'Avila JC, Rao J, et al.(2007) Carbonmonoxide signals via inhibition of cytochrome c oxidase and generation ofmitochondrial reactive oxygen species. FASEB J21:1099-1106.
[95] Bilban M, Bach FH, Otterbein SL, Ifedigbo E, d'Avila JC, et al.(2006) Carbonmonoxide orchestrates a protective response through PPARgamma. Immunity24:601-610.
[96] Nakao A, Kimizuka K, Stolz DB, Neto JS, Kaizu T, et al.(2003) Carbon monoxideinhalation protects rat intestinal grafts from ischemia/reperfusion injury. Am J Pathol163:1587-1598.
[97] Chin BY, Jiang G, Wegiel B, Wang HJ, Macdonald T, et al.(2007)Hypoxia-inducible factor1alpha stabilization by carbon monoxide results incytoprotective preconditioning. Proc Natl Acad Sci U S A104:5109-5114.
[98] Brouard S, Berberat PO, Tobiasch E, Seldon MP, Bach FH, et al.(2002) Hemeoxygenase-1-derived carbon monoxide requires the activation of transcription factorNF-kappa B to protect endothelial cells from tumor necrosis factor-alpha-mediatedapoptosis. J Biol Chem277:17950-17961.
[99] Ferris CD, Jaffrey SR, Sawa A, Takahashi M, Brady SD, et al.(1999) Haemoxygenase-1prevents cell death by regulating cellular iron. Nat Cell Biol1:152-157.
[100] Baker HM, Anderson BF, Baker EN (2003) Dealing with iron: common structuralprinciples in proteins that transport iron and heme. Proc Natl Acad Sci U S A100:3579-3583.
[101] Cozzi A, Levi S, Corsi B, Santambrogio P, Campanella A, et al.(2003) Role of ironand ferritin in TNFalpha-induced apoptosis in HeLa cells. FEBS Lett537:187-192.
[102] Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, et al.(2004) Ferritin heavy chainupregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressingreactive oxygen species. Cell119:529-542.
[103] Maghzal GJ, Leck MC, Collinson E, Li C, Stocker R (2009) Limited role for thebilirubin-biliverdin redox amplification cycle in the cellular antioxidant protection bybiliverdin reductase. J Biol Chem284:29251-29259.
[104] Reiter TA, Pang B, Dedon P, Demple B (2006) Resistance to nitric oxide-inducednecrosis in heme oxygenase-1overexpressing pulmonary epithelial cells associatedwith decreased lipid peroxidation. J Biol Chem281:36603-36612.
[105] Fondevila C, Shen XD, Tsuchiyashi S, Yamashita K, Csizmadia E, et al.(2004)Biliverdin therapy protects rat livers from ischemia and reperfusion injury.Hepatology40:1333-1341.
[106] Wang H, Lee SS, Dell'Agnello C, Tchipashvili V, d'Avila JC, et al.(2006) Bilirubincan induce tolerance to islet allografts. Endocrinology147:762-768.
[107] Overhaus M, Moore BA, Barbato JE, Behrendt FF, Doering JG, et al.(2006)Biliverdin protects against polymicrobial sepsis by modulating inflammatorymediators. Am J Physiol Gastrointest Liver Physiol290: G695-703.
[108] Hu CM, Lin HH, Chiang MT, Chang PF, Chau LY (2007) Systemic expression ofheme oxygenase-1ameliorates type1diabetes in NOD mice. Diabetes56:1240-1247.
[109] Chora AA, Fontoura P, Cunha A, Pais TF, Cardoso S, et al.(2007) Hemeoxygenase-1and carbon monoxide suppress autoimmune neuroinflammation. J ClinInvest117:438-447.
[110] Lehmann E, El-Tantawy WH, Ocker M, Bartenschlager R, Lohmann V, et al.(2010)The heme oxygenase1product biliverdin interferes with hepatitis C virus replicationby increasing antiviral interferon response. Hepatology51:398-404.
[111] Protzer U, Seyfried S, Quasdorff M, Sass G, Svorcova M, et al.(2007) Antiviralactivity and hepatoprotection by heme oxygenase-1in hepatitis B virus infection.Gastroenterology133:1156-1165.
[112] Silva-Gomes S, Appelberg R, Larsen R, Soares MP, Gomes MS (2013) Hemecatabolism by heme oxygenase-1confers host resistance to Mycobacterium infection.Infect Immun81:2536-2545.
[113] Pamplona A, Ferreira A, Balla J, Jeney V, Balla G, et al.(2007) Heme oxygenase-1and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. NatMed13:703-710.
[114] Doi K, Akaike T, Fujii S, Tanaka S, Ikebe N, et al.(1999) Induction of haemoxygenase-1nitric oxide and ischaemia in experimental solid tumours andimplications for tumour growth. Br J Cancer80:1945-1954.
[115] Deininger MH, Meyermann R, Trautmann K, Duffner F, Grote EH, et al.(2000)Heme oxygenase (HO)-1expressing macrophages/microglial cells accumulate duringoligodendroglioma progression. Brain Res882:1-8.
[116] Torisu-Itakura H, Furue M, Kuwano M, Ono M (2000) Co-expression of thymidinephosphorylase and heme oxygenase-1in macrophages in human malignant verticalgrowth melanomas. Jpn J Cancer Res91:906-910.
[117] Maines MD, Abrahamsson PA (1996) Expression of heme oxygenase-1(HSP32) inhuman prostate: normal, hyperplastic, and tumor tissue distribution. Urology47:727-733.
[118] Tsuji MH, Yanagawa T, Iwasa S, Tabuchi K, Onizawa K, et al.(1999) Hemeoxygenase-1expression in oral squamous cell carcinoma as involved in lymph nodemetastasis. Cancer Lett138:53-59.
[119] Berberat PO, Dambrauskas Z, Gulbinas A, Giese T, Giese N, et al.(2005) Inhibitionof heme oxygenase-1increases responsiveness of pancreatic cancer cells to anticancertreatment. Clin Cancer Res11:3790-3798.
[120] Pae HO, Oh GS, Choi BM, Chae SC, Kim YM, et al.(2004) Carbon monoxideproduced by heme oxygenase-1suppresses T cell proliferation via inhibition of IL-2production. J Immunol172:4744-4751.
[121] Burt TD, Seu L, Mold JE, Kappas A, McCune JM (2010) Naive human T cells areactivated and proliferate in response to the heme oxygenase-1inhibitor tinmesoporphyrin. J Immunol185:5279-5288.
[122] Soares MP, Bach FH (2009) Heme oxygenase-1: from biology to therapeutic potential.Trends Mol Med15:50-58.
[123] Exner M, Minar E, Wagner O, Schillinger M (2004) The role of heme oxygenase-1promoter polymorphisms in human disease. Free Radic Biol Med37:1097-1104.
[124] Hengartner MO, Horvitz HR (1994) Programmed cell death in Caenorhabditis elegans.Curr Opin Genet Dev4:581-586.
[125] Soares MP, Lin Y, Anrather J, Csizmadia E, Takigami K, et al.(1998) Expression ofheme oxygenase-1can determine cardiac xenograft survival. Nat Med4:1073-1077.
[126] Tartaglia LA, Rothe M, Hu YF, Goeddel DV (1993) Tumor necrosis factor's cytotoxicactivity is signaled by the p55TNF receptor. Cell73:213-216.
[127] Soares MP, Seldon MP, Gregoire IP, Vassilevskaia T, Berberat PO, et al.(2004)Heme oxygenase-1modulates the expression of adhesion molecules associated withendothelial cell activation. J Immunol172:3553-3563.
[128] Mahoney DJ, Cheung HH, Mrad RL, Plenchette S, Simard C, et al.(2008) BothcIAP1and cIAP2regulate TNFalpha-mediated NF-kappaB activation. Proc Natl AcadSci U S A105:11778-11783.
[129] Micheau O, Tschopp J (2003) Induction of TNF receptor I-mediated apoptosis viatwo sequential signaling complexes. Cell114:181-190.
[130] Perkins ND (2007) Integrating cell-signalling pathways with NF-kappaB and IKKfunction. Nat Rev Mol Cell Biol8:49-62.
[131] Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U (1995) Control of Ikappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science267:1485-1488.
[132] Chen Z, Hagler J, Palombella VJ, Melandri F, Scherer D, et al.(1995) Signal-inducedsite-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasomepathway. Genes Dev9:1586-1597.
[133] Henkel T, Machleidt T, Alkalay I, Kronke M, Ben-Neriah Y, et al.(1993) Rapidproteolysis of I kappa B-alpha is necessary for activation of transcription factorNF-kappa B. Nature365:182-185.
[134] Seldon MP, Silva G, Pejanovic N, Larsen R, Gregoire IP, et al.(2007) Hemeoxygenase-1inhibits the expression of adhesion molecules associated withendothelial cell activation via inhibition of NF-kappaB RelA phosphorylation atserine276. J Immunol179:7840-7851.
[135] Fiers W, Beyaert R, Declercq W, Vandenabeele P (1999) More than one way to die:apoptosis, necrosis and reactive oxygen damage. Oncogene18:7719-7730.
[136] Wada T, Penninger JM (2004) Mitogen-activated protein kinases in apoptosisregulation. Oncogene23:2838-2849.
[137] Silva G, Cunha A, Gregoire IP, Seldon MP, Soares MP (2006) The antiapoptoticeffect of heme oxygenase-1in endothelial cells involves the degradation of p38alphaMAPK isoform. J Immunol177:1894-1903.
[138] Arruda MA, Rossi AG, de Freitas MS, Barja-Fidalgo C, Graca-Souza AV (2004)Heme inhibits human neutrophil apoptosis: involvement of phosphoinositide3-kinase,MAPK, and NF-kappaB. J Immunol173:2023-2030.
[139] Zhang X, Shan P, Alam J, Fu XY, Lee PJ (2005) Carbon monoxide differentiallymodulates STAT1and STAT3and inhibits apoptosis via a phosphatidylinositol3-kinase/Akt and p38kinase-dependent STAT3pathway during anoxia-reoxygenationinjury. J Biol Chem280:8714-8721.
[140] Brunt KR, Fenrich KK, Kiani G, Tse MY, Pang SC, et al.(2006) Protection of humanvascular smooth muscle cells from H2O2-induced apoptosis through functionalcodependence between HO-1and AKT. Arterioscler Thromb Vasc Biol26:2027-2034.
[141] Salinas M, Wang J, Rosa de Sagarra M, Martin D, Rojo AI, et al.(2004) Proteinkinase Akt/PKB phosphorylates heme oxygenase-1in vitro and in vivo. FEBS Lett578:90-94.
[142] Tang YL, Tang Y, Zhang YC, Qian K, Shen L, et al.(2004) Protection from ischemicheart injury by a vigilant heme oxygenase-1plasmid system. Hypertension43:746-751.
[143] Katori M, Buelow R, Ke B, Ma J, Coito AJ, et al.(2002) Heme oxygenase-1overexpression protects rat hearts from cold ischemia/reperfusion injury via anantiapoptotic pathway. Transplantation73:287-292.
[144] McDaid J, Yamashita K, Chora A, Ollinger R, Strom TB, et al.(2005) Hemeoxygenase-1modulates the allo-immune response by promoting activation-inducedcell death of T cells. FASEB J19:458-460.
[145] Urban JL, Kumar V, Kono DH, Gomez C, Horvath SJ, et al.(1988) Restricted use ofT cell receptor V genes in murine autoimmune encephalomyelitis raises possibilitiesfor antibody therapy. Cell54:577-592.
[146] Laatsch RH (1962) Glycerol phosphate dehydrogenase activity of developing ratcentral nervous system. J Neurochem9:487-492.
[147] Mendel I, Kerlero de Rosbo N, Ben-Nun A (1995) A myelin oligodendrocyteglycoprotein peptide induces typical chronic experimental autoimmuneencephalomyelitis in H-2b mice: fine specificity and T cell receptor V beta expressionof encephalitogenic T cells. Eur J Immunol25:1951-1959.
[148] Tuohy VK, Lu Z, Sobel RA, Laursen RA, Lees MB (1989) Identification of anencephalitogenic determinant of myelin proteolipid protein for SJL mice. J Immunol142:1523-1527.
[149] Jones MV, Nguyen TT, Deboy CA, Griffin JW, Whartenby KA, et al.(2008)Behavioral and pathological outcomes in MOG35-55experimental autoimmuneencephalomyelitis. J Neuroimmunol199:83-93.
[150] Brostoff SW, Mason DW (1984) Experimental allergic encephalomyelitis: successfultreatment in vivo with a monoclonal antibody that recognizes T helper cells. JImmunol133:1938-1942.
[151] Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol23:683-747.
[152] Hafler DA (2004) Multiple sclerosis. J Clin Invest113:788-794.
[153] Yura M, Takahashi I, Serada M, Koshio T, Nakagami K, et al.(2001) Role ofMOG-stimulated Th1type "light up"(GFP+) CD4+T cells for the development ofexperimental autoimmune encephalomyelitis (EAE). J Autoimmun17:17-25.
[154] Gocke AR, Cravens PD, Ben LH, Hussain RZ, Northrop SC, et al.(2007) T-betregulates the fate of Th1and Th17lymphocytes in autoimmunity. J Immunol178:1341-1348.
[155] Lublin FD, Knobler RL, Kalman B, Goldhaber M, Marini J, et al.(1993) Monoclonalanti-gamma interferon antibodies enhance experimental allergic encephalomyelitis.Autoimmunity16:267-274.
[156] Heremans H, Dillen C, Groenen M, Martens E, Billiau A (1996) Chronic relapsingexperimental autoimmune encephalomyelitis (CREAE) in mice: enhancement bymonoclonal antibodies against interferon-gamma. Eur J Immunol26:2393-2398.
[157] Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, et al.(2003) Interleukin-23ratherthan interleukin-12is the critical cytokine for autoimmune inflammation of the brain.Nature421:744-748.
[158] Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, et al.(2005) IL-23drives a pathogenic T cell population that induces autoimmune inflammation. J ExpMed201:233-240.
[159] Eugster HP, Frei K, Kopf M, Lassmann H, Fontana A (1998) IL-6-deficient miceresist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis.Eur J Immunol28:2178-2187.
[160] Park H, Li Z, Yang XO, Chang SH, Nurieva R, et al.(2005) A distinct lineage of CD4T cells regulates tissue inflammation by producing interleukin17. Nat Immunol6:1133-1141.
[161] Hu Y, Ota N, Peng I, Refino CJ, Danilenko DM, et al.(2010) IL-17RC is required forIL-17A-and IL-17F-dependent signaling and the pathogenesis of experimentalautoimmune encephalomyelitis. J Immunol184:4307-4316.
[162] Du C, Liu C, Kang J, Zhao G, Ye Z, et al.(2009) MicroRNA miR-326regulatesTH-17differentiation and is associated with the pathogenesis of multiple sclerosis.Nat Immunol10:1252-1259.
[163] Mycko MP, Cichalewska M, Machlanska A, Cwiklinska H, Mariasiewicz M, et al.(2012) MicroRNA-301a regulation of a T-helper17immune response controlsautoimmune demyelination. Proc Natl Acad Sci U S A109: E1248-1257.
[164] Murugaiyan G, Beynon V, Mittal A, Joller N, Weiner HL (2011) SilencingmicroRNA-155ameliorates experimental autoimmune encephalomyelitis. J Immunol187:2213-2221.
[165] So AY, Garcia-Flores Y, Minisandram A, Martin A, Taganov K, et al.(2012)Regulation of APC development, immune response, and autoimmunity byBach1/HO-1pathway in mice. Blood120:2428-2437.
[166] Kusters, J.G., van Vliet, A.H.&Kuipers, E.J.(2006) Pathogenesis of Helicobacterpylori infection. Clin Microbiol Rev19,449-490.
[167] Pappo, J., et al.(1999) Helicobacter pylori infection in immunized mice lacking majorhistocompatibility complex class I and class II functions. Infect Immun67,337-341.
[168] Dong, C.(2008) TH17cells in development: an updated view of their molecularidentity and genetic programming. Nat Rev Immunol8,337-348.
[169] Shi, Y., et al.(2010) Helicobacter pylori-induced Th17responses modulate Th1cellresponses, benefit bacterial growth, and contribute to pathology in mice. J Immunol184,5121-5129.
[170] Caruso, R., et al.(2008) IL-23-mediated regulation of IL-17production inHelicobacter pylori-infected gastric mucosa. Eur J Immunol38,470-478.
[171] Andersen, L.P.(2007) Colonization and infection by Helicobacter pylori in humans.Helicobacter12Suppl2,12-15.
[172] Tan, S.&Berg, D.E.(2004) Motility of urease-deficient derivatives of Helicobacterpylori. J Bacteriol186,885-888.
[173] Andrutis, K.A., et al.(1995) Inability of an isogenic urease-negative mutant stain ofHelicobacter mustelae to colonize the ferret stomach. Infect Immun63,3722-3725.
[174] Harris, P.R., Mobley, H.L., Perez-Perez, G.I., Blaser, M.J.&Smith, P.D.(1996)Helicobacter pylori urease is a potent stimulus of mononuclear phagocyte activationand inflammatory cytokine production. Gastroenterology111,419-425.
[175] DeLyria, E.S., Redline, R.W.&Blanchard, T.G.(2009) Vaccination of mice againstH pylori induces a strong Th-17response and immunity that is neutrophil dependent.Gastroenterology136,247-256.
[176] Lu, D.S., et al.(2003)[Recombinant Helicobacter pylori urease B subunit and itsbiological properties]. Di Yi Jun Yi Da Xue Xue Bao23,549-552.
[177] Oppmann, B., et al.(2000) Novel p19protein engages IL-12p40to form a cytokine,IL-23, with biological activities similar as well as distinct from IL-12. Immunity13,715-725.
[178] Kryczek, I., et al.(2007) Cutting edge: opposite effects of IL-1and IL-2on theregulation of IL-17+T cell pool IL-1subverts IL-2-mediated suppression. J Immunol179,1423-1426.
[179] Ivanov, II, et al.(2006) The orphan nuclear receptor RORgammat directs thedifferentiation program of proinflammatory IL-17+T helper cells. Cell126,1121-1133.
[180] Korn, T., et al.(2007) IL-21initiates an alternative pathway to induceproinflammatory T(H)17cells. Nature448,484-487.
[181] Zhou, L., et al.(2007) IL-6programs T(H)-17cell differentiation by promotingsequential engagement of the IL-21and IL-23pathways. Nat Immunol8,967-974.
[1] Ambros V (2004) The functions of animal microRNAs. Nature431:350-355.
[2] Cai X, Hagedorn CH, Cullen BR (2004) Human microRNAs are processed fromcapped, polyadenylated transcripts that can also function as mRNAs. RNA10:1957-1966.
[3] Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004) Processing ofprimary microRNAs by the Microprocessor complex. Nature432:231-235.
[4] Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U (2004) Nuclear export ofmicroRNA precursors. Science303:95-98.
[5] Haasch D, Chen YW, Reilly RM, Chiou XG, Koterski S, et al.(2002) T cellactivation induces a noncoding RNA transcript sensitive to inhibition byimmunosuppressant drugs and encoded by the proto-oncogene, BIC. Cell Immunol217:78-86.
[6] Kutty RK, Nagineni CN, Samuel W, Vijayasarathy C, Hooks JJ, et al.(2010)Inflammatory cytokines regulate microRNA-155expression in human retinal pigmentepithelial cells by activating JAK/STAT pathway. Biochem Biophys Res Commun402:390-395.
[7] O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D (2007)MicroRNA-155is induced during the macrophage inflammatory response. Proc NatlAcad Sci U S A104:1604-1609.
[8] Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat RevCancer6:857-866.
[9] Martinez-Nunez RT, Louafi F, Sanchez-Elsner T (2011) The interleukin13(IL-13)pathway in human macrophages is modulated by microRNA-155via direct targetingof interleukin13receptor alpha1(IL13Ralpha1). J Biol Chem286:1786-1794.
[10] Worm J, Stenvang J, Petri A, Frederiksen KS, Obad S, et al.(2009) Silencing ofmicroRNA-155in mice during acute inflammatory response leads to derepression ofc/ebp Beta and down-regulation of G-CSF. Nucleic Acids Res37:5784-5792.
[11] Louafi F, Martinez-Nunez RT, Sanchez-Elsner T (2010) MicroRNA-155targetsSMAD2and modulates the response of macrophages to transforming growthfactor-{beta}. J Biol Chem285:41328-41336.
[12] Nazari-Jahantigh M, Wei Y, Noels H, Akhtar S, Zhou Z, et al.(2012) MicroRNA-155promotes atherosclerosis by repressing Bcl6in macrophages. J Clin Invest122:4190-4202.
[13] Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, et al.(2007) Requirementof bic/microRNA-155for normal immune function. Science316:608-611.
[14] Dunand-Sauthier I, Santiago-Raber ML, Capponi L, Vejnar CE, Schaad O, et al.(2011) Silencing of c-Fos expression by microRNA-155is critical for dendritic cellmaturation and function. Blood117:4490-4500.
[15] Ceppi M, Pereira PM, Dunand-Sauthier I, Barras E, Reith W, et al.(2009)MicroRNA-155modulates the interleukin-1signaling pathway in activated humanmonocyte-derived dendritic cells. Proc Natl Acad Sci U S A106:2735-2740.
[16] Chen T, Yan H, Li Z, Jing T, Zhu W, et al.(2011) MicroRNA-155regulates lipiduptake, adhesion/chemokine marker secretion and SCG2expression inoxLDL-stimulated dendritic cells/macrophages. Int J Cardiol147:446-447.
[17] Ramiro AR, Jankovic M, Eisenreich T, Difilippantonio S, Chen-Kiang S, et al.(2004)AID is required for c-myc/IgH chromosome translocations in vivo. Cell118:431-438.
[18] Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, et al.(2007)microRNA-155regulates the generation of immunoglobulin class-switched plasmacells. Immunity27:847-859.
[19] Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, et al.(2007) Regulation of thegerminal center response by microRNA-155. Science316:604-608.
[20] Tili E, Croce CM, Michaille JJ (2009) miR-155: on the crosstalk betweeninflammation and cancer. Int Rev Immunol28:264-284.
[21] Pedersen IM, Otero D, Kao E, Miletic AV, Hother C, et al.(2009) Onco-miR-155targets SHIP1to promote TNFalpha-dependent growth of B cell lymphomas. EMBOMol Med1:288-295.
[22] Eis PS, Tam W, Sun L, Chadburn A, Li Z, et al.(2005) Accumulation of miR-155andBIC RNA in human B cell lymphomas. Proc Natl Acad Sci U S A102:3627-3632.
[23] O'Connell RM, Chaudhuri AA, Rao DS, Baltimore D (2009) Inositol phosphataseSHIP1is a primary target of miR-155. Proc Natl Acad Sci U S A106:7113-7118.
[24] Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL (2010)Micro-RNA-155inhibits IFN-gamma signaling in CD4+T cells. Eur J Immunol40:225-231.
[25] Dudda JC, Salaun B, Ji Y, Palmer DC, Monnot GC, et al.(2013) MicroRNA-155isrequired for effector CD8+T cell responses to virus infection and cancer. Immunity38:742-753.
[26] Oertli M, Engler DB, Kohler E, Koch M, Meyer TF, et al.(2011) MicroRNA-155isessential for the T cell-mediated control of Helicobacter pylori infection and for theinduction of chronic Gastritis and Colitis. J Immunol187:3578-3586.
[27] O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al.(2010)MicroRNA-155promotes autoimmune inflammation by enhancing inflammatory Tcell development. Immunity33:607-619.
[28] Gracias DT, Stelekati E, Hope JL, Boesteanu AC, Doering TA, et al.(2013) ThemicroRNA miR-155controls CD8(+) T cell responses by regulating interferonsignaling. Nat Immunol14:593-602.
[29] Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, et al.(2009)Cutting edge: the Foxp3target miR-155contributes to the development of regulatoryT cells. J Immunol182:2578-2582.
[30] Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, et al.(2009) Foxp3-dependentmicroRNA155confers competitive fitness to regulatory T cells by targeting SOCS1protein. Immunity30:80-91.