调控BCL-6信号干预Tfh细胞分化:治疗炎症性肠病新策略
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摘要
自滤泡辅助性T细胞(follicular helper T cells,Tfh细胞)发现以来,大量证据表明与炎症性肠病的发病有关.Tfh细胞及其亚群分泌不同细胞因子皆可在炎症性肠病的发病过程中扮演重要角色,为靶向治疗炎症性肠病提供重要思路.BCL-6信号作为Tfh细胞分化途径上的关键性转录因子,可调控Tfh细胞的增殖、分化.在BCL-6信号缺乏时无法产生Tfh细胞,且BCL-6信号也可通过正性调控、负性调控以及表观遗传学等多种途径有效调控Tfh细胞的分化.在BCL-6信号调控异常时可导致Tfh的分化异常导致炎症性肠病的发生.因此可以通过干预BCL-6信号来调控Tfh细胞分化来作为治疗炎症性肠病新的有效靶点.
Since the discovery of follicular helper T(Tfh) cells, there has been a great deal of evidence that this cell type is involved in the pathogenesis of inflammatory bowel disease. Different cytokines secreted by different subtypes of Tfh cells play an important role in the pathogenesis of inflammatory bowel disease, and thus provide an important approach for the targeted treatment of this disease. As a key transcription factor in Tfh cell differentiation, BCL-6 signaling can regulate the proliferation and differentiation of Tfh cells. In the absence of BCL-6 signaling, Tfh cells cannot be produced. BCL-6 signaling can also effectively regulate Tfh cell differentiation through positive regulation, negative regulation, and epigenetics. Abnormal regulation of BCL-6 signaling can induce abnormal differentiation of Tfh and lead to the occurrence of inflammatory bowel disease. Therefore, Tfh cell differentiation can be regulated by intervention of BCL-6 signaling, which may be used as a new strategy for the treatment of inflammatory bowel disease.
Since the discovery of follicular helper T(Tfh) cells, there has been a great deal of evidence that this cell type is involved in the pathogenesis of inflammatory bowel disease. Different cytokines secreted by different subtypes of Tfh cells play an important role in the pathogenesis of inflammatory bowel disease, and thus provide an important approach for the targeted treatment of this disease. As a key transcription factor in Tfh cell differentiation, BCL-6 signaling can regulate the proliferation and differentiation of Tfh cells. In the absence of BCL-6 signaling, Tfh cells cannot be produced. BCL-6 signaling can also effectively regulate Tfh cell differentiation through positive regulation, negative regulation, and epigenetics. Abnormal regulation of BCL-6 signaling can induce abnormal differentiation of Tfh and lead to the occurrence of inflammatory bowel disease. Therefore, Tfh cell differentiation can be regulated by intervention of BCL-6 signaling, which may be used as a new strategy for the treatment of inflammatory bowel disease.
引文
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2 Breitfeld D,Ohl L,Kremmer E,Ellwart J,Sallusto F,Lipp M,F?rster R.Follicular B helper T cells express CXC chemokine receptor 5,localize to B cell follicles,and support immunoglobulin production.J Exp Med 2000;192:1545-1552[PMID:11104797DOI:10.1084/jem.192.11.1545]
3 Scherm MG,Ott VB,Daniel C.Follicular Helper T Cells in Autoimmunity.Curr Diab Rep 2016;16:75[PMID:27324759DOI:10.1007/s11892-016-0770-2]
4 Vinuesa CG,Linterman MA,Yu D,Mac Lennan IC.Follicular Helper T Cells.Annu Rev Immunol 2016;34:335-368[PMID:26907215 DOI:10.1146/annurev-immunol-041015-055605]
5 Leddon SA,Richards KA,Treanor JJ,Sant AJ.Abundance and specificity of influenza reactive circulating memory follicular helper and non-follicular helper CD4 T cells in healthy adults.Immunology2015;146:157-162[PMID:26094691 DOI:10.1111/imm.12491]
6 Tubo NJ,Pagán AJ,Taylor JJ,Nelson RW,Linehan JL,Ertelt JM,Huseby ES,Way SS,Jenkins MK.Single naive CD4+T cells from a diverse repertoire produce different effector cell types during infection.Cell 2013;153:785-796[PMID:23663778 DOI:10.1016/j.cell.2013.04.007]
7 Choi YS,Yang JA,Yusuf I,Johnston RJ,Greenbaum J,Peters B,Crotty S.Bcl6 expressing follicular helper CD4 T cells are fate committed early and have the capacity to form memory.JImmunol 2013;190:4014-4026[PMID:23487426 DOI:10.4049/jimmunol.1202963]
8 Ise W.Development and function of follicular helper T cells.Biosci Biotechnol Biochem 2016;80:1-6[PMID:26120879 DOI:10.1080/09168451.2015.1056512]
9王丽芳,张宇,邓晖.滤泡辅助性T细胞的多发调控研究进展.中国免疫学杂志2016;32:1400-1404
10 Costantino AB,Acosta CDV,Onetti L,Mussano E,Cadile II,Ferrero PV.Follicular helper T cells in peripheral blood of patients with rheumatoid arthritis.Reumatol Clin 2017;13:338-343[PMID:27595364 DOI:10.1016/j.reuma.2016.07.003]
11 Zhang CJ,Gong Y,Zhu W,Qi Y,Yang CS,Fu Y,Chang G,Li Y,Shi S,Wood K,Ladha S,Shi FD,Liu Q,Yan Y.Augmentation of Circulating Follicular Helper T Cells and Their Impact on Autoreactive B Cells in Myasthenia Gravis.J Immunol 2016;197:2610-2617[PMID:27543617 DOI:10.4049/jimmunol.1500725]
12 Shin D,Kim DS,Kim SH,Je JH,Kim HJ,Young Kim D,Kim SM,Lee MG.Decreased PD-1 positive blood follicular helper T cells in patients with psoriasis.Arch Dermatol Res 2016;308:593-599[PMID:27501809 DOI:10.1007/s00403-016-1679-y]
13 Wang Z,Wang Z,Diao Y,Qian X,Zhu N,Dong W.Circulating follicular helper T cells in Crohn’s disease(CD)and CD-associated colorectal cancer.Tumour Biol 2014;35:9355-9359[PMID:24943684 DOI:10.1007/s13277-014-2208-2]
14 Thomas T,Chandan J S.Multidisciplinary management:Inflammatory bowel disease.Br Dent J 2017;222:4-5[PMID:28084386 DOI:10.1038/sj.bdj.2017.9]
15何岚,孙兵.滤泡辅助性T细胞分化和功能的研究进展.生命科学2016;28:146-153
16段春巧,杨雯雯,雷玲彦,郭惠芳,张明峰,高丽霞,孙超.Bcl-6/Blimp-1/IL-21在原发性干燥综合征中的致病作用.中国免疫学杂志2015;31:384-388,392
17 Remenyi B,Carapetis J,Wyber R,Taubert K,Mayosi BM;World Heart Federation.Position statement of the World Heart Federation on the prevention and control of rheumatic heart disease.Nat Rev Cardiol 2013;10:284-292[PMID:23546444 DOI:10.1038/nrcardio.2013.34]
18 Toor D,Vohra H.Immune responsiveness during disease progression from acute rheumatic fever to chronic rheumatic heart disease.Microbes Infect 2012;14:1111-1117[PMID:22796386 DOI:10.1016/j.micinf.2012.07.003]
19 Guilherme L,Ferreira FM,K?hler KF,Postol E,Kalil J.A vaccine against Streptococcus pyogenes:the potential to prevent rheumatic fever and rheumatic heart disease.Am J Cardiovasc Drugs 2013;13:1-4[PMID:23355360 DOI:10.1007/s40256-013-0005-8]
20 Choi YS,Eto D,Yang JA,Lao C,Crotty S.Cutting edge:STAT1is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation.J Immunol 2013;190:3049-3053[PMID:23447690 DOI:10.4049/jimmunol.1203032]
21 Choi YS,Yang JA,Crotty S.Dynamic regulation of Bcl6 in follicular helper CD4 T(Tfh)cells.Curr Opin Immunol 2013;25:366-372[PMID:23688737 DOI:10.1016/j.coi.2013.04.003]
22 Choi YS,Kageyama R,Eto D,Escobar TC,Johnston RJ,Monticelli L,Lao C,Crotty S.ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6.Immunity 2011;34:932-946[PMID:21636296DOI:10.1016/j.immuni.2011.03.023]
23 Yuan MJ,Wang T.Advances of the interleukin-21 signaling pathway in immunity and angiogenesis.Biomed Rep 2016;5:3-6[PMID:27330746 DOI:10.3892/br.2016.665]
24 Ma CS,Suryani S,Avery DT,Chan A,Nanan R,Santner-Nanan B,Deenick EK,Tangye SG.Early commitment of na?ve human CD4(+)T cells to the T follicular helper(T(FH))cell lineage is induced by IL-12.Immunol Cell Biol 2009;87:590-600[PMID:19721453 DOI:10.1038/icb.2009.64]
25 Yu S,Jia L,Zhang Y,Zhong J,Yang B,Wu C.IL-12 induced the generation of IL-21-and IFN-γ-co-expressing poly-functional CD4+T cells from human naive CD4+T cells.Cell Cycle 2015;14:3362-3372[PMID:26566861 DOI:10.1080/15384101.2015.1093703]
26 Schmitt N,Liu Y,Bentebibel SE,Munagala I,Bourdery L,Venuprasad K,Banchereau J,Ueno H.The cytokine TGF-βco-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells.Nat Immunol 2014;15:856-865[PMID:25064073 DOI:10.1038/ni.2947]
27 Linterman MA,Pierson W,Lee SK,Kallies A,Kawamoto S,Rayner TF,Srivastava M,Divekar DP,Beaton L,Hogan JJ,Fagarasan S,Liston A,Smith KG,Vinuesa CG.Foxp3+follicular regulatory T cells control the germinal center response.Nat Med 2011;17:975-982[PMID:21785433 DOI:10.1038/nm.2425]
28 Chung Y,Tanaka S,Chu F,Nurieva RI,Martinez GJ,Rawal S,Wang YH,Lim H,Reynolds JM,Zhou XH,Fan HM,Liu ZM,Neelapu SS,Dong C.Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions.Nat Med2011;17:983-988[PMID:21785430 DOI:10.1038/nm.2426]
29 Crotty S,Johnston RJ,Schoenberger SP.Effectors and memories:Bcl-6 and Blimp-1 in T and B lymphocyte differentiation.Nat Immunol 2010;11:114-120[PMID:20084069 DOI:10.1038/ni.1837]
30 Crotty S.T follicular helper cell differentiation,function,and roles in disease.Immunity 2014;41:529-542[PMID:25367570DOI:10.1016/j.immuni.2014.10]
31 Johnston RJ,Poholek AC,Di Toro D,Yusuf I,Eto D,Barnett B,Dent AL,Craft J,Crotty S.Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation.Science 2009;325:1006-1010[PMID:19608860DOI:10.1126/science.1175870]
32 Johnston RJ,Choi YS,Diamond JA,Yang JA,Crotty S.STAT5is a potent negative regulator of TFH cell differentiation.JExp Med 2012;209:243-250[PMID:22271576 DOI:10.1084/jem.20111174]
33 Vogel KU,Edelmann SL,Jeltsch KM,Bertossi A,Heger K,Heinz GA,Z?ller J,Warth SC,Hoefig KP,Lohs C,Neff F,Kremmer E,Schick J,Repsilber D,Geerlof A,Blum H,Wurst W,Heikenw?lder M,Schmidt-Supprian M,Heissmeyer V.Roquin paralogs 1 and 2 redundantly repress the Icos and Ox40 costimulator m RNAs and control follicular helper T cell differentiation.Immunity 2013;38:655-668[PMID:23583643DOI:10.1016/j.immuni.2012.12.004]
34 Nurieva RI,Podd A,Chen Y,Alekseev AM,Yu M,Qi X,Huang H,Wen R,Wang J,Li HS,Watowich SS,Qi H,Dong C,Wang D.STAT5 protein negatively regulates T follicular helper(Tfh)cell generation and function.J Biol Chem 2012;287:11234-11239[PMID:22318729 DOI:10.1074/jbc.M111.324046]
35 Wang H,Geng J,Wen X,Bi E,Kossenkov AV,Wolf AI,Tas J,Choi YS,Takata H,Day TJ,Chang LY,Sprout SL,Becker EK,Willen J,Tian L,Wang X,Xiao C,Jiang P,Crotty S,Victora GD,Showe LC,Tucker HO,Erikson J,Hu H.The transcription factor Foxp1 is a critical negative regulator of the differentiation of follicular helper T cells.Nat Immunol 2014;15:667-675[PMID:24859450 DOI:10.1038/ni.2890]
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