高迁移率族蛋白B1对小鼠调节性T细胞免疫功能的影响及机制研究
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摘要
目的:高迁移率族蛋白B1(HMGB1)作为一种晚期炎症介质,介导了脓毒症和其他系统性炎症的致死性。本实验拟通过观察体外刺激小鼠调节性T细胞相关指标的表达变化规律,进而阐明HMGB1对该细胞免疫功能的影响并对其机制进行初步探讨。旨在为进一步体内实验及感染后期严重脓毒症的预防和治疗提供新思路。
方法:断颈处死小鼠无菌取脾脏,分离单个核细胞。①采用免疫磁珠法分离获取正常BALB/c小鼠脾脏CD4~+T,CD4~+CD25~-T细胞及CD4~+CD25~Treg,鉴定细胞纯度。②分别以植物凝集素(PHA)、刀豆素A(Con A)及固相包被抗-CD3这三种不同的刺激剂诱导活化Treg,观察T淋巴细胞毒性相关抗原4(cytotoxic Tlymphocyte-associated antigen 4,CTLA-4)及叉头翼状螺旋转录因子(forkhead/wingedhelix transcription factor,Foxp3)表达的时间-效应关系。③将Treg依HMGB1(100ng/ml)刺激时间不同设为24 h组、48 h组、72 h组观察HMGB1刺激与CTLA-4及Foxp3表达的时间-效应关系。将Treg依HMGB1浓度不同设为0ng/ml组(对照组)、10ng/ml组、100ng/ml组、1000ng/ml组,72h后用流式细胞仪分析CTLA-4、Foxp3表达情况及对IL-10分泌的影响(剂量-效应关系)。④分别提取CD4~+CD25~+Treg及CD4~+CD25~-T细胞,设单纯CD4~+CD25~-对照组,另依CD25~+:CD25~-比例分设1:1组、1:5组、1:10组、1:20组,通过MTT比色试验检测CD4~+CD25~+Treg对CD4~+CD25~-T细胞抑制的细胞比例关系。⑤HMGB1刺激Treg 72h。刺激后细胞依CD25~+:CD25~-比例设1:1及1:5组。各组分设CD25~-组、未刺激Treg组及HMGB1-Treg组。通过MTT比色试验分析HMGB1刺激对Treg细胞抑制功能的影响。⑥SYBR GREEN法测定HMGB1刺激与Foxp3基因表达的时间、剂量-效应关系。⑦分别留取细胞培养上清,ELISA法测定不同细胞因子的变化情况。
结果:1.小鼠CD4~+CD25~+Treg纯度分析:多次细胞分选实验证实,正常小鼠脾脏单个核细胞经过MACS两次分选后,CD4~+CD25~+T细胞纯度可达到91.74%～98.14%,其中CD25细胞低于3%;CD4~+CD25~-T细胞纯度达88.73%～93.85%,其中CD25~+细胞少于1%。所获得的CD4~+CD25~+T细胞经台盼蓝检测活性大于97%。2.PHA对于CD4~+CD25~+Treg细胞无明显活化作用,CTLA-4及Foxp3表达与对照组比较平均荧光强度没有明显差异(P＞0.05)。而Con A刺激Treg CTLA-4的表达上调呈一过性,作用持续时间不超过48 h,且对于Foxp3的表达也无明显的影响。抗-CD3则能够较好地活化Treg,表现为CTLA-4及Foxp3表达在24～72 h均明显增强(P＜0.05或P＜0.01),其中24、48 h表达上调更为明显(P＜0.01),并可延续至刺激后72 h。3.HMGB1刺激Treg,CTLA-4表达在24～72 h均有所下降(P＜0.05或P＜0.01),其中以作用48、72h表达下调尤为明显(P＜0.01);而不同剂量HMGB1(10ng/ml、100ng/ml、1000ng/ml)刺激均可诱导CTLA-4表达下降(P＜0.05或P＜0.01),其中HMGB1浓度在1000ng/ml时其表达减弱最明显。Foxp3表达与CTLA-4呈现出相同的趋势。细胞培养上清中IL-10水平呈现与HMGB1的剂量依赖关系,即HMGB1刺激浓度越高IL-10水平下降越明显。4.CD4~+CD25~-T细胞在活化后表现出增殖反应,但随Treg比例增加,CD4~+CD25~-T细胞增殖反应抑制。当细胞比例达到1:1时表现为对其抑制效应达到90%左右。当加入HMGB1(1000ng/ml)刺激的Treg时,CD4~+CD25~-T细胞增殖受抑程度减轻。这一现象在细胞比例为1:1及1:5组均表现出相同的趋势。5.经HMGB1刺激后的Treg Foxp3 mRNA表达分别于24～72h明显下调(P＜0.05或P＜0.01),其中以作用48、72h后表达下降尤为显著(P＜0.01);给予HMGB1刺激72 h后,10ng/ml、100ng/ml、1000ng/ml的HMGB1刺激均可诱导Foxp3表达减弱(P＜0.0或P＜0.01),其中HMGB1的浓度在1000 ng/ml时Foxp3表达下调最明显。6.与正常对照组比较,不同时间及剂量HMGB1体外刺激Treg,其细胞培养上清中IL-2水平均无统计学差异(P＞0.05)。而细胞培养上清中IL-10水平随HMGB1刺激时间延长及浓度增高而下降明显(P＜0.05或P＜0.01)。将CD4~+CD25~-T细胞中加入Treg共培养后,CD4~+CD25~-T细胞上清中IL-2、IFN-γ水平明显下降,而当加入HMGB1刺激的Treg后,随HMGB1刺激浓度增加,二者生成受抑制的程度明显逆转(P＜0.05或P＜0.01)。与对照组相比,Treg组IL-4/IL-10生成明显增加,而HMGB1-Treg组IL-4/IL-10水平下降并有统计学差异(P＜0.05或P＜0.01),且在HMGB1浓度为10ng/ml与100ng/ml时下降更为明显(P＜0.01)。
结论:1.两步法免疫磁珠分离CD4~+CD25~+Treg细胞,所得细胞纯度高,细胞活力无影响,完全可以满足进一步实验的要求。2.在多种细胞刺激剂中,抗-CD3可以较好地活化Treg,为进一步实验提供了可能。3.HMGB1可能通过下调细胞表面抑制性分子的表达及抑制性细胞因子的分泌两条途径下调Treg的功能,而Foxp3基因及蛋白表达的一致性说明HMGB1是通过抑制关键基因Foxp3表达机制进而影响细胞免疫功能。4.HMGB1体外刺激不能改变Treg免疫无反应性,Treg介导了Th1向Th2的漂移,但HMGB1弱化了Treg诱导T淋巴细胞增殖、IL-2生成及功能性极化过程。
Objective:High mobility group box 1 protein(HMGB1) as a late-acting cytokine mediates lethality of sepsis and systemic inflammation.The present study was performed to determine the effect of HMGB 1 on regulatory T cells(Tregs) of spleen in mice,and to clarify the potential mechanism of immunosuppression related to stimulation with HMGB1, aiming at a possible method for preventing the development of sepsis and multiple organ dysfunction syndrome following serious injure or inflammation.
Methods:①CD4~+CD25~+Tregs and CD4~+CD25~-T cells were isolated from the spleens of male BABL/c mice by magnetic beads.The purity of these cells were detected.②CD4~+CD25~+Tregs were seeded on 96-well(1×10~5 cells /well) cell culture plates supplemented with PHA(20μg/ml),Con A(5mg/ml) or coated with anti-CD3(1μg/ml). After stimulated with different stimulus for various length of time,the expressions of cytotoxic T lymphocyte-associated antigen 4(CTLA-4) and forkhead/winged helix transcription factor 3(Foxp3) molecules of Tregs were determined.The time-dependent responses between different stimulus and CTLA-4 as well as Foxp3 were analyzed by means of flow cytometry.③CD4~+CD25~+Tregs were seeded on 96-well(1×10~5 cells/well) cell culture plates coated with anti-CD3(1μg/ml) and soluble anti-CD28(1μg/ml),and the cells were stimulated with HMGB1 for various length of time or in different concentrations.After being stimulated,the expressions of CTLA-4 and Foxp3 molecules of Tregs were determined.The time-dependent and dose-dependent responses between HMGB1 and CTLA-4 and Foxp3 were analyzed by means of flow cytometry,the IL-10 secretion collected in the cell suspension was determined by means of ELISA.④CD4~+CD25~+Treg and CD4~+CD25~-T cells were isolated separately.When cultured with Treg in ratio of 1:1,1:5,1:10,and 1:20,respectively,the proliferation of CD4~+CD25~-T cells was analyzed by MTT test.⑤After being stimulated for 72 h in concentration of 1000ng/ml HMGB1,Tregs were cultured with CD4~+CD25~-T.cells together in the cell-ratio of 1:1 and 1:5.Proliferation of CD4~+CD25~-T was analyzed by MTT test.⑥CD4~+CD25~+Tregs were seeded and stimulated with HMGB1 for various length of time or in different concentrations on 96-well(1×10~5 cells /well) cell culture plates coated with anti-CD3(1μg/ml) and soluble anti-CD28(1μg/ml).After being stimulated,the time-dependent and dose- dependent responses between HMGB1 and Foxp3 mRNA were analyzed by means of quantatative PCR of SYBR GREEN.⑦By collecting the cells suspension,the different kinds of cytokines were examined by means of ELISA,including IL-2,IL-10,IL-4 and interferon(IFN)-γ.
Results:1.The purity of CD4~+CD25~+Tregs and CD4~+CD25~-T cells were 91.74%～98.14%and 88.73%～93.85%respectively after isolated twice by magnetic beads, and the activity of Treg exceeded 97%.2.After stimulation with PHA,the CTLA-4 expressions on surface of mice splenic Tregs and intranuclear Foxp3 molecules were unchanged(P＞0.05).In Con A-treated group,the expression of CTLA-4 was significantly enhanced at 24 h(P＜0.01),while the CTLA-4 expression returned to the control range at 48 h and 72 h.The expression of Foxp3 was not markedly different between ConA-treated group and controls.When treated with plate-bound anti-CD3,both CTLA-4 and Foxp3 expressions were significantly up-regulated at 24 h to 72 h(P＜0.05 or P＜0.01),especially at 24 h and 48 h(P＜0.01).3.After stimulation with HMGB1,the CTLA-4 expressions on surface of mice splenic Tregs and intranuclear Foxp3 molecules and Foxp3mRNA were markedly decreased at 24 h to 72 h(P＜0.05 or P＜0.01),and the expression levels of CTLA-4 and Foxp3 and Foxp3mRNA were lowest at 72 h(P＜0.01).When Tregs were cultured in the presence of 10ng/ml,100ng/ml,and 1000ng/ml HMGB1 for 72 h, expressions of the CTLA-4 and Foxp3 molecules and Foxp3mRNA were significantly down-regulated(P＜0.05 or P＜0.01),and values of them were lowest in 1000ng/ml HMGB1-treated group(P＜0.01).4.The suppressive activity of proliferation of CD4~+CD25~-T cells was exceeded 90%when the proportion of Tregs to CD25T cells was 1:1,meanwhile,the suppressive activity of Tregs was markedly decreased when stimulated with HMGB1.5.The secretion of IL-2 of Tregs stimulated by HMGB1 was not markedly changed(P＞0.05),while a dose-dependent decrease between IL-10 and HMGB1 was obviously(P＜0.05 or P＜0.01).When CD4~+CD25~-T cells were cultured with stimulated Tregs,in comparsion with unstimulated-Treg group,the levels of IL-2 and IFN-γwere elevated following the increased concentration of HMGB1(P＜0.05 or P＜0.01).Meanwhile the secretion of IL-4 and IL-10 were significantly decreased when cultured with stimulated Tregs(P＜0.05 or P＜0.01).
Conclusion:1.The CD4~+CD25~+Tregs isolated by magnetic beads were pure and suitable for the subsequent experiments.2.Among different stimulus,anti-CD3 appears to be an effective immunoregulatory signal that influences the activation of mice splenic Tregs.3.HMGB1 stimulation can result in significantly down-regulatory expressions of suppressive molecules CTLA-4 and Foxp3 as well as cytokine IL-10 of splenic Tregs in mice,by inhibiting the Foxp3mRNA expression.4.HMGB1 cannot break down the anergy of Tregs in vitro,but can significantly down-regulate the immunosuppression of mice splenic Tregs,thereby influences the proliferation of effector T cells,secretion of IL-2 and cells- polarization.
方法:断颈处死小鼠无菌取脾脏,分离单个核细胞。①采用免疫磁珠法分离获取正常BALB/c小鼠脾脏CD4~+T,CD4~+CD25~-T细胞及CD4~+CD25~Treg,鉴定细胞纯度。②分别以植物凝集素(PHA)、刀豆素A(Con A)及固相包被抗-CD3这三种不同的刺激剂诱导活化Treg,观察T淋巴细胞毒性相关抗原4(cytotoxic Tlymphocyte-associated antigen 4,CTLA-4)及叉头翼状螺旋转录因子(forkhead/wingedhelix transcription factor,Foxp3)表达的时间-效应关系。③将Treg依HMGB1(100ng/ml)刺激时间不同设为24 h组、48 h组、72 h组观察HMGB1刺激与CTLA-4及Foxp3表达的时间-效应关系。将Treg依HMGB1浓度不同设为0ng/ml组(对照组)、10ng/ml组、100ng/ml组、1000ng/ml组,72h后用流式细胞仪分析CTLA-4、Foxp3表达情况及对IL-10分泌的影响(剂量-效应关系)。④分别提取CD4~+CD25~+Treg及CD4~+CD25~-T细胞,设单纯CD4~+CD25~-对照组,另依CD25~+:CD25~-比例分设1:1组、1:5组、1:10组、1:20组,通过MTT比色试验检测CD4~+CD25~+Treg对CD4~+CD25~-T细胞抑制的细胞比例关系。⑤HMGB1刺激Treg 72h。刺激后细胞依CD25~+:CD25~-比例设1:1及1:5组。各组分设CD25~-组、未刺激Treg组及HMGB1-Treg组。通过MTT比色试验分析HMGB1刺激对Treg细胞抑制功能的影响。⑥SYBR GREEN法测定HMGB1刺激与Foxp3基因表达的时间、剂量-效应关系。⑦分别留取细胞培养上清,ELISA法测定不同细胞因子的变化情况。
结果:1.小鼠CD4~+CD25~+Treg纯度分析:多次细胞分选实验证实,正常小鼠脾脏单个核细胞经过MACS两次分选后,CD4~+CD25~+T细胞纯度可达到91.74%～98.14%,其中CD25细胞低于3%;CD4~+CD25~-T细胞纯度达88.73%～93.85%,其中CD25~+细胞少于1%。所获得的CD4~+CD25~+T细胞经台盼蓝检测活性大于97%。2.PHA对于CD4~+CD25~+Treg细胞无明显活化作用,CTLA-4及Foxp3表达与对照组比较平均荧光强度没有明显差异(P＞0.05)。而Con A刺激Treg CTLA-4的表达上调呈一过性,作用持续时间不超过48 h,且对于Foxp3的表达也无明显的影响。抗-CD3则能够较好地活化Treg,表现为CTLA-4及Foxp3表达在24～72 h均明显增强(P＜0.05或P＜0.01),其中24、48 h表达上调更为明显(P＜0.01),并可延续至刺激后72 h。3.HMGB1刺激Treg,CTLA-4表达在24～72 h均有所下降(P＜0.05或P＜0.01),其中以作用48、72h表达下调尤为明显(P＜0.01);而不同剂量HMGB1(10ng/ml、100ng/ml、1000ng/ml)刺激均可诱导CTLA-4表达下降(P＜0.05或P＜0.01),其中HMGB1浓度在1000ng/ml时其表达减弱最明显。Foxp3表达与CTLA-4呈现出相同的趋势。细胞培养上清中IL-10水平呈现与HMGB1的剂量依赖关系,即HMGB1刺激浓度越高IL-10水平下降越明显。4.CD4~+CD25~-T细胞在活化后表现出增殖反应,但随Treg比例增加,CD4~+CD25~-T细胞增殖反应抑制。当细胞比例达到1:1时表现为对其抑制效应达到90%左右。当加入HMGB1(1000ng/ml)刺激的Treg时,CD4~+CD25~-T细胞增殖受抑程度减轻。这一现象在细胞比例为1:1及1:5组均表现出相同的趋势。5.经HMGB1刺激后的Treg Foxp3 mRNA表达分别于24～72h明显下调(P＜0.05或P＜0.01),其中以作用48、72h后表达下降尤为显著(P＜0.01);给予HMGB1刺激72 h后,10ng/ml、100ng/ml、1000ng/ml的HMGB1刺激均可诱导Foxp3表达减弱(P＜0.0或P＜0.01),其中HMGB1的浓度在1000 ng/ml时Foxp3表达下调最明显。6.与正常对照组比较,不同时间及剂量HMGB1体外刺激Treg,其细胞培养上清中IL-2水平均无统计学差异(P＞0.05)。而细胞培养上清中IL-10水平随HMGB1刺激时间延长及浓度增高而下降明显(P＜0.05或P＜0.01)。将CD4~+CD25~-T细胞中加入Treg共培养后,CD4~+CD25~-T细胞上清中IL-2、IFN-γ水平明显下降,而当加入HMGB1刺激的Treg后,随HMGB1刺激浓度增加,二者生成受抑制的程度明显逆转(P＜0.05或P＜0.01)。与对照组相比,Treg组IL-4/IL-10生成明显增加,而HMGB1-Treg组IL-4/IL-10水平下降并有统计学差异(P＜0.05或P＜0.01),且在HMGB1浓度为10ng/ml与100ng/ml时下降更为明显(P＜0.01)。
结论:1.两步法免疫磁珠分离CD4~+CD25~+Treg细胞,所得细胞纯度高,细胞活力无影响,完全可以满足进一步实验的要求。2.在多种细胞刺激剂中,抗-CD3可以较好地活化Treg,为进一步实验提供了可能。3.HMGB1可能通过下调细胞表面抑制性分子的表达及抑制性细胞因子的分泌两条途径下调Treg的功能,而Foxp3基因及蛋白表达的一致性说明HMGB1是通过抑制关键基因Foxp3表达机制进而影响细胞免疫功能。4.HMGB1体外刺激不能改变Treg免疫无反应性,Treg介导了Th1向Th2的漂移,但HMGB1弱化了Treg诱导T淋巴细胞增殖、IL-2生成及功能性极化过程。
Objective:High mobility group box 1 protein(HMGB1) as a late-acting cytokine mediates lethality of sepsis and systemic inflammation.The present study was performed to determine the effect of HMGB 1 on regulatory T cells(Tregs) of spleen in mice,and to clarify the potential mechanism of immunosuppression related to stimulation with HMGB1, aiming at a possible method for preventing the development of sepsis and multiple organ dysfunction syndrome following serious injure or inflammation.
Methods:①CD4~+CD25~+Tregs and CD4~+CD25~-T cells were isolated from the spleens of male BABL/c mice by magnetic beads.The purity of these cells were detected.②CD4~+CD25~+Tregs were seeded on 96-well(1×10~5 cells /well) cell culture plates supplemented with PHA(20μg/ml),Con A(5mg/ml) or coated with anti-CD3(1μg/ml). After stimulated with different stimulus for various length of time,the expressions of cytotoxic T lymphocyte-associated antigen 4(CTLA-4) and forkhead/winged helix transcription factor 3(Foxp3) molecules of Tregs were determined.The time-dependent responses between different stimulus and CTLA-4 as well as Foxp3 were analyzed by means of flow cytometry.③CD4~+CD25~+Tregs were seeded on 96-well(1×10~5 cells/well) cell culture plates coated with anti-CD3(1μg/ml) and soluble anti-CD28(1μg/ml),and the cells were stimulated with HMGB1 for various length of time or in different concentrations.After being stimulated,the expressions of CTLA-4 and Foxp3 molecules of Tregs were determined.The time-dependent and dose-dependent responses between HMGB1 and CTLA-4 and Foxp3 were analyzed by means of flow cytometry,the IL-10 secretion collected in the cell suspension was determined by means of ELISA.④CD4~+CD25~+Treg and CD4~+CD25~-T cells were isolated separately.When cultured with Treg in ratio of 1:1,1:5,1:10,and 1:20,respectively,the proliferation of CD4~+CD25~-T cells was analyzed by MTT test.⑤After being stimulated for 72 h in concentration of 1000ng/ml HMGB1,Tregs were cultured with CD4~+CD25~-T.cells together in the cell-ratio of 1:1 and 1:5.Proliferation of CD4~+CD25~-T was analyzed by MTT test.⑥CD4~+CD25~+Tregs were seeded and stimulated with HMGB1 for various length of time or in different concentrations on 96-well(1×10~5 cells /well) cell culture plates coated with anti-CD3(1μg/ml) and soluble anti-CD28(1μg/ml).After being stimulated,the time-dependent and dose- dependent responses between HMGB1 and Foxp3 mRNA were analyzed by means of quantatative PCR of SYBR GREEN.⑦By collecting the cells suspension,the different kinds of cytokines were examined by means of ELISA,including IL-2,IL-10,IL-4 and interferon(IFN)-γ.
Results:1.The purity of CD4~+CD25~+Tregs and CD4~+CD25~-T cells were 91.74%～98.14%and 88.73%～93.85%respectively after isolated twice by magnetic beads, and the activity of Treg exceeded 97%.2.After stimulation with PHA,the CTLA-4 expressions on surface of mice splenic Tregs and intranuclear Foxp3 molecules were unchanged(P＞0.05).In Con A-treated group,the expression of CTLA-4 was significantly enhanced at 24 h(P＜0.01),while the CTLA-4 expression returned to the control range at 48 h and 72 h.The expression of Foxp3 was not markedly different between ConA-treated group and controls.When treated with plate-bound anti-CD3,both CTLA-4 and Foxp3 expressions were significantly up-regulated at 24 h to 72 h(P＜0.05 or P＜0.01),especially at 24 h and 48 h(P＜0.01).3.After stimulation with HMGB1,the CTLA-4 expressions on surface of mice splenic Tregs and intranuclear Foxp3 molecules and Foxp3mRNA were markedly decreased at 24 h to 72 h(P＜0.05 or P＜0.01),and the expression levels of CTLA-4 and Foxp3 and Foxp3mRNA were lowest at 72 h(P＜0.01).When Tregs were cultured in the presence of 10ng/ml,100ng/ml,and 1000ng/ml HMGB1 for 72 h, expressions of the CTLA-4 and Foxp3 molecules and Foxp3mRNA were significantly down-regulated(P＜0.05 or P＜0.01),and values of them were lowest in 1000ng/ml HMGB1-treated group(P＜0.01).4.The suppressive activity of proliferation of CD4~+CD25~-T cells was exceeded 90%when the proportion of Tregs to CD25T cells was 1:1,meanwhile,the suppressive activity of Tregs was markedly decreased when stimulated with HMGB1.5.The secretion of IL-2 of Tregs stimulated by HMGB1 was not markedly changed(P＞0.05),while a dose-dependent decrease between IL-10 and HMGB1 was obviously(P＜0.05 or P＜0.01).When CD4~+CD25~-T cells were cultured with stimulated Tregs,in comparsion with unstimulated-Treg group,the levels of IL-2 and IFN-γwere elevated following the increased concentration of HMGB1(P＜0.05 or P＜0.01).Meanwhile the secretion of IL-4 and IL-10 were significantly decreased when cultured with stimulated Tregs(P＜0.05 or P＜0.01).
Conclusion:1.The CD4~+CD25~+Tregs isolated by magnetic beads were pure and suitable for the subsequent experiments.2.Among different stimulus,anti-CD3 appears to be an effective immunoregulatory signal that influences the activation of mice splenic Tregs.3.HMGB1 stimulation can result in significantly down-regulatory expressions of suppressive molecules CTLA-4 and Foxp3 as well as cytokine IL-10 of splenic Tregs in mice,by inhibiting the Foxp3mRNA expression.4.HMGB1 cannot break down the anergy of Tregs in vitro,but can significantly down-regulate the immunosuppression of mice splenic Tregs,thereby influences the proliferation of effector T cells,secretion of IL-2 and cells- polarization.
引文
1. Zheng SG, Meng LZ, Wang JH, et al. Transfer of regulatory T cells generated ex vivo modifies graft rejection through induction of tolerogenic CD4~+CD25~+ cells in the recipient. Int Immunol, 2006, 18(2):279-289.
2. Ronchetti S, Zollo O, Bruscoli S, et al. Frontline: GITR, a member of the TNF receptor superfamily, is co-stimulatory to mouse T lymphocyte subpopulations. Eur J Immunol, 2004, 34(3):613-622.
3. Zoltan F. Development and function of CD25~+CD4~+ regulatory T cells. Curr Opin Immunol, 2004,16(2):203-208.
4. Zheng SG, Wang JH, Stohl W, et al. TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4~+CD25~+ regulatory cells. J Immunol, 2006,176(6):3321-3329.
5. Shevach EM. CD4~+CD25~+ suppressive T cells: more questions than answers. Nat Rev Immunol, 2002, 2(6):389-400.
6. Fehervari Z, Sakaguchi S. Development and function of CD25~+CD4~+regulatory T cells. Curr Opin Immunol, 2004, 16(2):203-208.
7. Jonulei H, Schmitt E. The Regulatory T cell Family: distinct subsets and their interrelations. J Immunol, 2003, 171(12):6323-6327.
8. Read S, Greenwald R, Izcue A, et al. Blockade of CTLA-4 on CD4~+CD25~+ regulatory T cells abrogates their function in vivo. J Immunol, 2006,177(7): 4376-4383.
9. Fontenot JD, Rudensky A. A well adapted regulatory contrivance: regulatory T cell development and the Forkhead family transcription factor Foxp3. Nat Immunol, 2005, 6(4):331-337.
10. Chatenoud L. CD3-specific antibody-induced active tolerance: from bench to bedside. Nat Rev Immunol, 2003, 3(2): 123-132.
11. Le Gall F, Reusch U, Moldenbauer G, et al. Immunosuppression properties of anti-CD3 single-chain Fv and diabody. J Immunol Methods, 2004, 285(1): 111-127.
12. June CH, Blazar BR. Clinical application of expanded CD4~+25~+ cells. Semin Immunol, 2006, 18(2):78-88.
13. D'Ambrosio D. Regulatory T cells: how do they find their space in the immunological arena? Semin Cancer Biol, 2006, 16(2):91-97.
1.Monneret G,Debard AL,Venet F,et al.Marked elevation of human circulating CD4CD25 regulatory T cells in sepsis-induced immunoparalysis.Crit Care Med,2003,31(7):2068-2071.
2.Heuer JG,Zhang T,Zhao J,et al.Adoptive transfer of in vitro-stimulated CD4+CD25+regulatory T cells increases bacterial clearance and improves survival in polymicrobial sepsis.J Immunol,2005,174(11):7141-7146.
3.Yagi H,Nomura T,Nakamura M,et al.Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells.Int Immunol,2004,16(11):1643-1656.
4.张立天,姚咏明,陆家齐,等.高迁移率族蛋白-1在脓毒症所致多器官功能损伤中的作用.中华外科杂志,2003,41(4):303-306.
5.王忠堂,姚咏明,盛志勇,等.休克期切痂对烫伤大鼠肝、肺组织高迁移率族蛋白B1表达及促炎/抗炎平衡的影响.中华外科杂志,2004,42(14):839-844.
6.Sakaguchi S,Sakaguchi N,Shimizu J,et al.Immunologic tolerance maintained by CD4+CD25+ regulatory T cells:their common role in controlling autoimmunity,tumor immunity and transplantation tolerance.Immunol Rev,2001,182:18-32.
7.Ronchetti S,Zollo O,Bruscoli S,et al.Frontline:GITR,a member of the TNF receptor superfamily,is co-stimulatory to mouse T lymphocyte subpopula-tions.Eur J Immunol,2004,34(3):613-622.
8.张莹,姚咏明.调节性T细胞与脓毒症关系的研究进展.中国危重病急救医学,2006,18(11):695-697.
9.Read S,Greenwald R,Izcue A,et al.Blockade of CTLA-4 on CD4~+CD25~+ regulatory T cells abrogates their function in vivo.J Immunol,2006,177(7):4376-4383.
10.Fontenot JD,Rudensky A.A well adapted regulatory contrivance:regulatory T cell development and the Forkhead family transcription factor Foxp3.Nat Immunol,2005,6(4):331-337.
11.Wang H,Bloom O,Zhang M,et al.HMGB1 as a late mediator of endotoxin lethality in mice.Science,1999,285:248-251.
12.Fiuza C,Bustin M,Talwar S,et al.Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells.Blood,2003,101(7):2652-2660.
13.徐姗,姚咏明,董宁等.高迁移率族蛋白B1对大鼠脾脏树突状细胞表面共刺激分子表达的影响.中华创伤杂志,2006,22(8):579-583.
14.MacConmara MP,Maung AA,Fujimi S,et al.Increased CD4~+CD25~+ T regulatory cell activity in trauma patients depresses protective Th1 immunity.Ann Surg,2006,244(4):514-523.
15.Zhao DM,Thornton AM,DiPaolo RJ,et al.Activated CD4~+CD25~+ T cells selectively kill B lymphocytes.Blood,2006,107(10):3925-3932.
16.Caramalho I,Lopes-Carvalho T,Ostler D,et al.Regulatory T cells selectively express Toll-like receptors and activated by lipopolysaccharide.J Exp Med,2003,197:403-411.
17.Valencia X,Stephens G,Goldbach-Mansky R,et al.TNF downmodulates the function of human CD4~+CD25hi T-regulatory cells.Blood,2006,108(1):253-261.
18.Liu H,Komai-Koma M,Xu D,et al.Toll-like receptor 2 signaling modulates the functions of CD4~+CD25~+ regulatory T cells.Proc Natl Acad Sci U S A,2006,103(18):7048-7053.
1.Choileain NN,MacConmara M,Zang Y,et al.Enhanced regulatory T cell activity is an element of the host response to injury.J Immunol,2006,176(1):225-236.
2.Miyara M,Sakaguchi S.Natural regulatory T cells:mechanisms of suppression.Trends Mol Med,2007,13(3):108-116.
3.MacConmara MP,Maung AA,Fujimi S,et al.Increased CD4~+CD25~+T regulatory cell activity in trauma patients depresses protective Th1 immunity.Ann Surg,2006,244(4):514-523.
4.姚咏明.高迁移率族蛋白B1作用的新认识.中国危重病急救医学,2005,17(6):321-323.
5.刘辉,姚咏明,于燕,等.信号转导及转录激活子1和3抑制剂对高迁移率族蛋白B1诱导鼠巨噬细胞合成肿瘤坏死因子α的影响.中华外科杂志,2006,44(3):193-197.
6.Bharat A,Fields RC,Trulock EP,et al.Induction of IL-10 suppressors in lung transplant patients by CD4~+25~+ regulatory T cells through CTLA-4 signaling.J Immunol,2006,177(8):5631-5638.
7.Coffer PJ,Burgering BM.Forkheadbox transcription factors and their role in the immune system.Nat Rev Immunol,2004,4(11):889-899.
8.Zhang XS,Ding Y,Peng RQ,et al.The changes of CD4~+CD25~+/CD4~+ proportion in spleen of tumor-bearing BALB/c mice.J Transl Med,2005,3(1):5-10.
9.polarics Z,Siddiqi M,Siegel JH,et al.Depressed interleukin-12-producing activity by monocytes correlates with adverse clinical course and a shift toward Th2-type lymphocyte pattern in severely injured male trauma patients.Crit Care Med,2003,31(6):1722-1729.
10.Ayala A,Chung CS,Song GY,et al.IL-10 mediation of activation-induced TH1 cell apoptosis and lymphoid dysfunction in polymicrobial sepsis.Cytokine,2001,14(1):37-48.
11.Ono S,Ueno C,Aosasa S,et al.Severe sepsis induces deficient interferon-gamma and interleukin-12 production,but interleukin-12 therapy improves survival in peritonitis. Am J Surg, 2001, 182(5):491-497.
12. Quinn KM, McHugh RS, Rich FJ, et al. Inactivation of CD4+ CD25+ regulatory T cells during early mycobacterial infection increases cytokine production but does not affect pathogen load. Immunol Cell Biol, 2006, 84(5):467-474.
13. Venet F, Lepape A, Debard AL, et al. The Th2 response as monitored by CRTH2 or CCR3 expression is severely decreased during septic shock. Clin Immunol, 2004, 113(3):278-284.
14. Heuer JG, Zhang T, Zhao J, et al. Adoptive transfer of in vitro-stimulated CD4~+CD25~+ regulatory T cells increases bacterial clearance and improves survival in polymicrobial sepsis. J Immunol, 2005, 174(11):7141-7146.
15. Choileain NN, Redmond HP. Regulatory T-cells and autoimmunity. J Surg Res, 2006, 130(1):124-135.
1. Akira Suto, Hiroshi, Nakajima, et al. CD4+CD25+ T cell development is regulated by at least 2 distinct mechanisms. Blood, 2002, 99(7):555-560.
2. Chatila TA. Role of regulatory T cells in human diseases. J Allergy Clin Immunol, 2005, 116(5):949-959.
3. Sakaguchi S, Sakaguchi N, Shimizu J, et al. Immunologic tolerance maintained by CD4+CD25+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity and transplantation tolerance. Immunol Rev, 2001,182:18-32.
4. Bozza S, Perruccio K, Montagnoli C,et al. A dendritic cell vaccine agaist invasive aspergillosis in allogeneic hematopoietic transplantation. Blood, 2004, 102(10):3807-3814.
5. Taams LS, Smith J, Rustin MH, et al. Human anergic/suppressive CD4+ CD25+ T cells: a highly differentiated and apoptosis-prone population. Eur J Immunol, 2001, 31(4):1122-1131.
6. Stassen M, Schmitt E, Jonuleit H. Human CD4+CD25+ regulatory T cells and infectious tolerance. Transplantation, 2004, 77(1 Suppl):S23-25.
7. Sakaguchi S. Regulatory T cells mediating compromises between host and parasite. Nat Immunol, 2003, 4(1): 10-11.
8. Shevach EM.CD4+CD25+ suppressive T cells: more questions than answers. Nat Rev Immunol, 2002, 2(6):389-400.
9. Kingsley CI, Karim M, Bushell AR, et al. CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4 and IL-10-dependent immuno-regulation of alloresponses. J Immunol, 2002, 168(3): 1080-1086.
10. Zhang X, Izikson L, Liu L, et al. Activation of CD25+CD4+ regulatory T cells by an oral antigen administration. J Immunol, 2001, 167(8):4245-4253.
11. Waldmann H. Reprogramming the immune system. Immunol Rev, 2002, 185:227-235.
12. Barthlott T, Kassiotis G, Stockinger B. T cell regulation as aside effect of homeostasis and competition. J Exp Med, 2003, 197(4):451-460.
13. Belkaid Y. Rouse BT. Natural regulatory T cells in infectious disease. Nat Immunol, 2005, 6(4):353-360.
14. Walker C, Sawicka E, et al. Immuno therapy with mycobacteria. Curr Opin Allergy Clin Immunol, 2003, 3(6):481-486.
15. Von Boehmer H. Mechamisms of suppression by suppressor T cell. Nat Immunol,2005, 6(4):338-344.
16. Liu H, Hu B, Xu D, et al.CD4+CD25+ regulatory T cells cure murine colitis:the role of IL-10,TGF-beta,and CTLA-4. J Immunol, 2003, 171(10):5012-5017.
17. Mills KH. Regulatory T cells: friend or foe in immunity to infection? Nat Rev Immunol, 2004, 4(11):841-855.
18. Allez M, Mayer L. Regulatory T Cells Peace Keepers in the Gut. Inflamm Bowel Dis, 2004, 10(5):666-676.
19. McGuirk P, McCann C, Mills KH, et al. Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by bordetella pertussis. J Exp Med, 2002, 195(2):221-231.
20. Raghavan S, Holmgren J. CD4+CD25+ suppressor T cells regulate pathogen induced inflammation and disease. Immunol Med Microbiol, 2005, 44(2): 121-127.
21. Xu D,Liu H,Komai KM.CD4+CD25+ regulatory T cells suppress differentiation and functions of Th1 and Th2 cells, leishmania major infection, and colitis in mice. J Immunol, 2003, 170(1):394-399.
22. Capron A, Dombrowicz D, Capron M. Helminth infections and allergic diseases: from the Th2 paradigm to regulatory networks. Clin Rev Allergy Immunol, 2004, 26(1):25-34.
23. Belkaid Y, Ciriaco A.CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature, 2002, 420(6915):502-507.
24. Suvas S, Kumaraguru U, Pack CD, et al. CD4+CD25+ T cell regulate virus-specific primary and memory CD8+ T cells response. J Exp Med, 2003, 198(6):889-901.
25. Mario U.Mondelli and Vincenzo Barnaba. Viral and host immune regulatory mechanisms in hepatitis C Virus infection. Eur Jour Gastroenterology & Hepatology, 2006, 118(4):327-331.
26. Aandahl EM, Michaelsson J, Moretto WJ, et al. Human CD4+CD25+regulatory T cell control T cell response to human immunodeficiency virus and cytomegalovirus antigens. J Virus, 2004, 78(5):2454-2459.
27. Antachopoulos C, Roilides E. Cytokines and fungal infections. Br J Haematol, 2005, 129(5):583-596.
28. Stephens GL, McHugh RS, Whitters MJ, et al. Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+T cell. J Immunol, 2004, 173(8):5008-5020.
29. Maizels RM. Infections and allergy-helminths, hygiene and host immune regulation. Curr Opin Immunol, 2005, 17(6):656-661.
30. Walker C, Sawicka E, Rook GA. Immunotherapy with mycobacteria. Curr Opin Allergy. Clin Immunol, 2003, (6):481-486.
31. Hori S, Sakaguchi S. Foxp3:a critical regulator of the development and function of regulatory T cells. Microbes Infect, 2004, 6(8):745-751.
32. Shi HN, Walker A.T helper cell subclasses and clinical disease states. Curr Opin Gastro, 2002, 18:711-716.
33. Monneret G, Debard AL, Venet F, et al. Marked elevation of human circulating CD4CD25 regulatory T cells in sepsis-induced immunoparalysis. Crit Care Med, 2003, 31(7): 2068-2071.
34. Venet F, Pachot A, Debard AL, et al. Increased percentage of CD4+CD25+ regulatory T cells during septic shock is due to the decrease of CD4+CD25- lymphocytes. Crit Care Med, 2004, 32(11):2329-2331.
35. Heuer JG, Zhang T, Zhao J, et al. Adoptive transfer of in vitro-stimulated CD4+CD25+ regulatory T cells increases bacterial clearance and improves survival in polymicrobial sepsis. J Immunol, 2005,174(11):7141-7146.
36. Jones-Carson J, Fantuzzi G, Siegmund B, et al. Suppressor alphabeta T lymphocytes control innate resistance to endotoxic shock. J Infect Dis, 2005, 192(6): 1039-1046.
37. Venet F, Lepape A, Debard AL, et al. The Th2 response as monitored by CRTH2 or CCR3 expression is severely decreased during septic shock. Clin Immunol, 2004, 113(3):278-284.
38. Monneret G, Debard AL, Venet F, et al. Marked elevation of human circulating CD4+CD25+ regulatory T cells in sepsis-induced immunoparalysis. Crit Care Med, 2003, 31(7):2068-2071.
39. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. NEngl J Med, 2003, 348(2):138-150.
40. Smit JJ, Folkerts G, Nijkamp FR Mycobacteria, genes and the hygiene hypothesis. Curr Opin Allergy Clin Immunol, 2004, 4(1):57-62.
41. Wolf M, et al. Control of T cell hyperactivation in IL-2-deficient mice by CD4+CD25- and CD4+CD25+ T cell: evidence for two distinct regulatory mechanisms. Eur J Immunol, 2001, 31(6): 1637-1645.
42. Kuipers H, Lambrecht BN. The interplay of dendritic cells, Th2 cells and regulatory T cells in asthma. Curr Opin Immunol, 2004, 16(6):702-708.
43. Belz G, Smith C, Bharadwaj M, Rice A, Jackson D. DCs as targets for vaccine design. Cytotherapy. 2004, 6(2):88-98.
44. Roncarolo MG, Levings MK, Traversari C. Differentiation of T regulatory cells by immature dendritic cells. J Exp Med, 2001, 193(2):F5-9.
2. Ronchetti S, Zollo O, Bruscoli S, et al. Frontline: GITR, a member of the TNF receptor superfamily, is co-stimulatory to mouse T lymphocyte subpopulations. Eur J Immunol, 2004, 34(3):613-622.
3. Zoltan F. Development and function of CD25~+CD4~+ regulatory T cells. Curr Opin Immunol, 2004,16(2):203-208.
4. Zheng SG, Wang JH, Stohl W, et al. TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4~+CD25~+ regulatory cells. J Immunol, 2006,176(6):3321-3329.
5. Shevach EM. CD4~+CD25~+ suppressive T cells: more questions than answers. Nat Rev Immunol, 2002, 2(6):389-400.
6. Fehervari Z, Sakaguchi S. Development and function of CD25~+CD4~+regulatory T cells. Curr Opin Immunol, 2004, 16(2):203-208.
7. Jonulei H, Schmitt E. The Regulatory T cell Family: distinct subsets and their interrelations. J Immunol, 2003, 171(12):6323-6327.
8. Read S, Greenwald R, Izcue A, et al. Blockade of CTLA-4 on CD4~+CD25~+ regulatory T cells abrogates their function in vivo. J Immunol, 2006,177(7): 4376-4383.
9. Fontenot JD, Rudensky A. A well adapted regulatory contrivance: regulatory T cell development and the Forkhead family transcription factor Foxp3. Nat Immunol, 2005, 6(4):331-337.
10. Chatenoud L. CD3-specific antibody-induced active tolerance: from bench to bedside. Nat Rev Immunol, 2003, 3(2): 123-132.
11. Le Gall F, Reusch U, Moldenbauer G, et al. Immunosuppression properties of anti-CD3 single-chain Fv and diabody. J Immunol Methods, 2004, 285(1): 111-127.
12. June CH, Blazar BR. Clinical application of expanded CD4~+25~+ cells. Semin Immunol, 2006, 18(2):78-88.
13. D'Ambrosio D. Regulatory T cells: how do they find their space in the immunological arena? Semin Cancer Biol, 2006, 16(2):91-97.
1.Monneret G,Debard AL,Venet F,et al.Marked elevation of human circulating CD4CD25 regulatory T cells in sepsis-induced immunoparalysis.Crit Care Med,2003,31(7):2068-2071.
2.Heuer JG,Zhang T,Zhao J,et al.Adoptive transfer of in vitro-stimulated CD4+CD25+regulatory T cells increases bacterial clearance and improves survival in polymicrobial sepsis.J Immunol,2005,174(11):7141-7146.
3.Yagi H,Nomura T,Nakamura M,et al.Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells.Int Immunol,2004,16(11):1643-1656.
4.张立天,姚咏明,陆家齐,等.高迁移率族蛋白-1在脓毒症所致多器官功能损伤中的作用.中华外科杂志,2003,41(4):303-306.
5.王忠堂,姚咏明,盛志勇,等.休克期切痂对烫伤大鼠肝、肺组织高迁移率族蛋白B1表达及促炎/抗炎平衡的影响.中华外科杂志,2004,42(14):839-844.
6.Sakaguchi S,Sakaguchi N,Shimizu J,et al.Immunologic tolerance maintained by CD4+CD25+ regulatory T cells:their common role in controlling autoimmunity,tumor immunity and transplantation tolerance.Immunol Rev,2001,182:18-32.
7.Ronchetti S,Zollo O,Bruscoli S,et al.Frontline:GITR,a member of the TNF receptor superfamily,is co-stimulatory to mouse T lymphocyte subpopula-tions.Eur J Immunol,2004,34(3):613-622.
8.张莹,姚咏明.调节性T细胞与脓毒症关系的研究进展.中国危重病急救医学,2006,18(11):695-697.
9.Read S,Greenwald R,Izcue A,et al.Blockade of CTLA-4 on CD4~+CD25~+ regulatory T cells abrogates their function in vivo.J Immunol,2006,177(7):4376-4383.
10.Fontenot JD,Rudensky A.A well adapted regulatory contrivance:regulatory T cell development and the Forkhead family transcription factor Foxp3.Nat Immunol,2005,6(4):331-337.
11.Wang H,Bloom O,Zhang M,et al.HMGB1 as a late mediator of endotoxin lethality in mice.Science,1999,285:248-251.
12.Fiuza C,Bustin M,Talwar S,et al.Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells.Blood,2003,101(7):2652-2660.
13.徐姗,姚咏明,董宁等.高迁移率族蛋白B1对大鼠脾脏树突状细胞表面共刺激分子表达的影响.中华创伤杂志,2006,22(8):579-583.
14.MacConmara MP,Maung AA,Fujimi S,et al.Increased CD4~+CD25~+ T regulatory cell activity in trauma patients depresses protective Th1 immunity.Ann Surg,2006,244(4):514-523.
15.Zhao DM,Thornton AM,DiPaolo RJ,et al.Activated CD4~+CD25~+ T cells selectively kill B lymphocytes.Blood,2006,107(10):3925-3932.
16.Caramalho I,Lopes-Carvalho T,Ostler D,et al.Regulatory T cells selectively express Toll-like receptors and activated by lipopolysaccharide.J Exp Med,2003,197:403-411.
17.Valencia X,Stephens G,Goldbach-Mansky R,et al.TNF downmodulates the function of human CD4~+CD25hi T-regulatory cells.Blood,2006,108(1):253-261.
18.Liu H,Komai-Koma M,Xu D,et al.Toll-like receptor 2 signaling modulates the functions of CD4~+CD25~+ regulatory T cells.Proc Natl Acad Sci U S A,2006,103(18):7048-7053.
1.Choileain NN,MacConmara M,Zang Y,et al.Enhanced regulatory T cell activity is an element of the host response to injury.J Immunol,2006,176(1):225-236.
2.Miyara M,Sakaguchi S.Natural regulatory T cells:mechanisms of suppression.Trends Mol Med,2007,13(3):108-116.
3.MacConmara MP,Maung AA,Fujimi S,et al.Increased CD4~+CD25~+T regulatory cell activity in trauma patients depresses protective Th1 immunity.Ann Surg,2006,244(4):514-523.
4.姚咏明.高迁移率族蛋白B1作用的新认识.中国危重病急救医学,2005,17(6):321-323.
5.刘辉,姚咏明,于燕,等.信号转导及转录激活子1和3抑制剂对高迁移率族蛋白B1诱导鼠巨噬细胞合成肿瘤坏死因子α的影响.中华外科杂志,2006,44(3):193-197.
6.Bharat A,Fields RC,Trulock EP,et al.Induction of IL-10 suppressors in lung transplant patients by CD4~+25~+ regulatory T cells through CTLA-4 signaling.J Immunol,2006,177(8):5631-5638.
7.Coffer PJ,Burgering BM.Forkheadbox transcription factors and their role in the immune system.Nat Rev Immunol,2004,4(11):889-899.
8.Zhang XS,Ding Y,Peng RQ,et al.The changes of CD4~+CD25~+/CD4~+ proportion in spleen of tumor-bearing BALB/c mice.J Transl Med,2005,3(1):5-10.
9.polarics Z,Siddiqi M,Siegel JH,et al.Depressed interleukin-12-producing activity by monocytes correlates with adverse clinical course and a shift toward Th2-type lymphocyte pattern in severely injured male trauma patients.Crit Care Med,2003,31(6):1722-1729.
10.Ayala A,Chung CS,Song GY,et al.IL-10 mediation of activation-induced TH1 cell apoptosis and lymphoid dysfunction in polymicrobial sepsis.Cytokine,2001,14(1):37-48.
11.Ono S,Ueno C,Aosasa S,et al.Severe sepsis induces deficient interferon-gamma and interleukin-12 production,but interleukin-12 therapy improves survival in peritonitis. Am J Surg, 2001, 182(5):491-497.
12. Quinn KM, McHugh RS, Rich FJ, et al. Inactivation of CD4+ CD25+ regulatory T cells during early mycobacterial infection increases cytokine production but does not affect pathogen load. Immunol Cell Biol, 2006, 84(5):467-474.
13. Venet F, Lepape A, Debard AL, et al. The Th2 response as monitored by CRTH2 or CCR3 expression is severely decreased during septic shock. Clin Immunol, 2004, 113(3):278-284.
14. Heuer JG, Zhang T, Zhao J, et al. Adoptive transfer of in vitro-stimulated CD4~+CD25~+ regulatory T cells increases bacterial clearance and improves survival in polymicrobial sepsis. J Immunol, 2005, 174(11):7141-7146.
15. Choileain NN, Redmond HP. Regulatory T-cells and autoimmunity. J Surg Res, 2006, 130(1):124-135.
1. Akira Suto, Hiroshi, Nakajima, et al. CD4+CD25+ T cell development is regulated by at least 2 distinct mechanisms. Blood, 2002, 99(7):555-560.
2. Chatila TA. Role of regulatory T cells in human diseases. J Allergy Clin Immunol, 2005, 116(5):949-959.
3. Sakaguchi S, Sakaguchi N, Shimizu J, et al. Immunologic tolerance maintained by CD4+CD25+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity and transplantation tolerance. Immunol Rev, 2001,182:18-32.
4. Bozza S, Perruccio K, Montagnoli C,et al. A dendritic cell vaccine agaist invasive aspergillosis in allogeneic hematopoietic transplantation. Blood, 2004, 102(10):3807-3814.
5. Taams LS, Smith J, Rustin MH, et al. Human anergic/suppressive CD4+ CD25+ T cells: a highly differentiated and apoptosis-prone population. Eur J Immunol, 2001, 31(4):1122-1131.
6. Stassen M, Schmitt E, Jonuleit H. Human CD4+CD25+ regulatory T cells and infectious tolerance. Transplantation, 2004, 77(1 Suppl):S23-25.
7. Sakaguchi S. Regulatory T cells mediating compromises between host and parasite. Nat Immunol, 2003, 4(1): 10-11.
8. Shevach EM.CD4+CD25+ suppressive T cells: more questions than answers. Nat Rev Immunol, 2002, 2(6):389-400.
9. Kingsley CI, Karim M, Bushell AR, et al. CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4 and IL-10-dependent immuno-regulation of alloresponses. J Immunol, 2002, 168(3): 1080-1086.
10. Zhang X, Izikson L, Liu L, et al. Activation of CD25+CD4+ regulatory T cells by an oral antigen administration. J Immunol, 2001, 167(8):4245-4253.
11. Waldmann H. Reprogramming the immune system. Immunol Rev, 2002, 185:227-235.
12. Barthlott T, Kassiotis G, Stockinger B. T cell regulation as aside effect of homeostasis and competition. J Exp Med, 2003, 197(4):451-460.
13. Belkaid Y. Rouse BT. Natural regulatory T cells in infectious disease. Nat Immunol, 2005, 6(4):353-360.
14. Walker C, Sawicka E, et al. Immuno therapy with mycobacteria. Curr Opin Allergy Clin Immunol, 2003, 3(6):481-486.
15. Von Boehmer H. Mechamisms of suppression by suppressor T cell. Nat Immunol,2005, 6(4):338-344.
16. Liu H, Hu B, Xu D, et al.CD4+CD25+ regulatory T cells cure murine colitis:the role of IL-10,TGF-beta,and CTLA-4. J Immunol, 2003, 171(10):5012-5017.
17. Mills KH. Regulatory T cells: friend or foe in immunity to infection? Nat Rev Immunol, 2004, 4(11):841-855.
18. Allez M, Mayer L. Regulatory T Cells Peace Keepers in the Gut. Inflamm Bowel Dis, 2004, 10(5):666-676.
19. McGuirk P, McCann C, Mills KH, et al. Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by bordetella pertussis. J Exp Med, 2002, 195(2):221-231.
20. Raghavan S, Holmgren J. CD4+CD25+ suppressor T cells regulate pathogen induced inflammation and disease. Immunol Med Microbiol, 2005, 44(2): 121-127.
21. Xu D,Liu H,Komai KM.CD4+CD25+ regulatory T cells suppress differentiation and functions of Th1 and Th2 cells, leishmania major infection, and colitis in mice. J Immunol, 2003, 170(1):394-399.
22. Capron A, Dombrowicz D, Capron M. Helminth infections and allergic diseases: from the Th2 paradigm to regulatory networks. Clin Rev Allergy Immunol, 2004, 26(1):25-34.
23. Belkaid Y, Ciriaco A.CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature, 2002, 420(6915):502-507.
24. Suvas S, Kumaraguru U, Pack CD, et al. CD4+CD25+ T cell regulate virus-specific primary and memory CD8+ T cells response. J Exp Med, 2003, 198(6):889-901.
25. Mario U.Mondelli and Vincenzo Barnaba. Viral and host immune regulatory mechanisms in hepatitis C Virus infection. Eur Jour Gastroenterology & Hepatology, 2006, 118(4):327-331.
26. Aandahl EM, Michaelsson J, Moretto WJ, et al. Human CD4+CD25+regulatory T cell control T cell response to human immunodeficiency virus and cytomegalovirus antigens. J Virus, 2004, 78(5):2454-2459.
27. Antachopoulos C, Roilides E. Cytokines and fungal infections. Br J Haematol, 2005, 129(5):583-596.
28. Stephens GL, McHugh RS, Whitters MJ, et al. Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+T cell. J Immunol, 2004, 173(8):5008-5020.
29. Maizels RM. Infections and allergy-helminths, hygiene and host immune regulation. Curr Opin Immunol, 2005, 17(6):656-661.
30. Walker C, Sawicka E, Rook GA. Immunotherapy with mycobacteria. Curr Opin Allergy. Clin Immunol, 2003, (6):481-486.
31. Hori S, Sakaguchi S. Foxp3:a critical regulator of the development and function of regulatory T cells. Microbes Infect, 2004, 6(8):745-751.
32. Shi HN, Walker A.T helper cell subclasses and clinical disease states. Curr Opin Gastro, 2002, 18:711-716.
33. Monneret G, Debard AL, Venet F, et al. Marked elevation of human circulating CD4CD25 regulatory T cells in sepsis-induced immunoparalysis. Crit Care Med, 2003, 31(7): 2068-2071.
34. Venet F, Pachot A, Debard AL, et al. Increased percentage of CD4+CD25+ regulatory T cells during septic shock is due to the decrease of CD4+CD25- lymphocytes. Crit Care Med, 2004, 32(11):2329-2331.
35. Heuer JG, Zhang T, Zhao J, et al. Adoptive transfer of in vitro-stimulated CD4+CD25+ regulatory T cells increases bacterial clearance and improves survival in polymicrobial sepsis. J Immunol, 2005,174(11):7141-7146.
36. Jones-Carson J, Fantuzzi G, Siegmund B, et al. Suppressor alphabeta T lymphocytes control innate resistance to endotoxic shock. J Infect Dis, 2005, 192(6): 1039-1046.
37. Venet F, Lepape A, Debard AL, et al. The Th2 response as monitored by CRTH2 or CCR3 expression is severely decreased during septic shock. Clin Immunol, 2004, 113(3):278-284.
38. Monneret G, Debard AL, Venet F, et al. Marked elevation of human circulating CD4+CD25+ regulatory T cells in sepsis-induced immunoparalysis. Crit Care Med, 2003, 31(7):2068-2071.
39. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. NEngl J Med, 2003, 348(2):138-150.
40. Smit JJ, Folkerts G, Nijkamp FR Mycobacteria, genes and the hygiene hypothesis. Curr Opin Allergy Clin Immunol, 2004, 4(1):57-62.
41. Wolf M, et al. Control of T cell hyperactivation in IL-2-deficient mice by CD4+CD25- and CD4+CD25+ T cell: evidence for two distinct regulatory mechanisms. Eur J Immunol, 2001, 31(6): 1637-1645.
42. Kuipers H, Lambrecht BN. The interplay of dendritic cells, Th2 cells and regulatory T cells in asthma. Curr Opin Immunol, 2004, 16(6):702-708.
43. Belz G, Smith C, Bharadwaj M, Rice A, Jackson D. DCs as targets for vaccine design. Cytotherapy. 2004, 6(2):88-98.
44. Roncarolo MG, Levings MK, Traversari C. Differentiation of T regulatory cells by immature dendritic cells. J Exp Med, 2001, 193(2):F5-9.
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