Tim-3 pathway controls regulatory and effector T cell balance during hepatitis C virus infection.
Tim-3 pathway controls regulatory and effector T cell balance during hepatitis C virus infection.
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Tim-3 通路控制丙型肝炎病毒感染期间的调节性和效应 T 细胞平衡
DOI：
10.4049/jimmunol.1200162
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发表时间：
2012-07-15
期刊：
影响因子：
--
通讯作者：
Yao ZQ
中科院分区：
文献类型：
--
作者：
Moorman JP;Wang JM;Zhang Y;Ji XJ;Ma CJ;Wu XY;Jia ZS;Wang KS;Yao ZQ
丙型肝炎病毒（HCV）在破坏人体免疫以建立慢性感染方面是显著的。抑制信号通路（如T细胞Ig和粘蛋白结构域蛋白-3 [Tim-3]）的上调和调节性T细胞（Tregs）的积累在抑制抗病毒效应T细胞（Teff）反应中起关键作用，而Teff是病毒清除所必需的。尽管Tim-3通路已被证明负调控Teffs，但其在调节Foxp3+ Tregs中的作用尚未得到充分探讨。在这项研究中，我们研究了Tim-3通路是否以及如何改变慢性HCV感染患者Foxp3+ Treg的发育和功能。我们发现，与健康人相比，Tim-3不仅在产生il -2的CD4+CD25+Foxp3−Teffs上上调，而且在CD4+CD25+Foxp3+ Tregs上也上调，后者在慢性hcv感染者外周血中积累。Tim-3在Foxp3+ Tregs上的表达与增殖标志物Ki67在Tregs上的表达呈正相关，而与il -2生成Teffs的增殖呈负相关。此外，Foxp3+ Tregs对TCR激活诱导的细胞凋亡更具抗性，而Foxp3−Teffs对TCR激活诱导的细胞凋亡更敏感，这可以通过阻断Tim-3信号通路来逆转。与其在T细胞增殖和凋亡中的作用一致，阻断Tim-3对CD4+CD25+ T细胞的作用，通过改善STAT-5信号传导，促进Teffs比Tregs更显著地扩增，从而纠正了HCV感染诱导的Foxp3+ Tregs/Foxp3−Teffs失衡。综上所述，Tim-3通路似乎通过改变HCV感染期间的细胞增殖和凋亡来控制Treg和Teff平衡。
Hepatitis C virus (HCV) is remarkable at disrupting human immunity to establish chronic infection. Upregulation of inhibitory signaling pathways (such as T cell Ig and mucin domain protein-3 [Tim-3]) and accumulation of regulatory T cells (Tregs) play pivotal roles in suppressing antiviral effector T cell (Teff) responses that are essential for viral clearance. Although the Tim-3 pathway has been shown to negatively regulate Teffs, its role in regulating Foxp3+ Tregs is poorly explored. In this study, we investigated whether and how the Tim-3 pathway alters Foxp3+ Treg development and function in patients with chronic HCV infection. We found that Tim-3 was upregulated, not only on IL-2–producing CD4+CD25+Foxp3− Teffs, but also on CD4+CD25+Foxp3+ Tregs, which accumulate in the peripheral blood of chronically HCV-infected individuals when compared with healthy subjects. Tim-3 expression on Foxp3+ Tregs positively correlated with expression of the proliferation marker Ki67 on Tregs, but it was inversely associated with proliferation of IL-2–producing Teffs. Moreover, Foxp3+ Tregs were found to be more resistant to, and Foxp3− Teffs more sensitive to, TCR activation-induced cell apoptosis, which was reversible by blocking Tim-3 signaling. Consistent with its role in T cell proliferation and apoptosis, blockade of Tim-3 on CD4+CD25+ T cells promoted expansion of Teffs more substantially than Tregs through improving STAT-5 signaling, thus correcting the imbalance of Foxp3+ Tregs/Foxp3− Teffs that was induced by HCV infection. Taken together, the Tim-3 pathway appears to control Treg and Teff balance through altering cell proliferation and apoptosis during HCV infection.
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影响因子：
5.4
作者：
Anderson, Ana C.;Lord, Graham M.;Dardalhon, Valerie;Lee, David H.;Sabatos-Peyton, Catherine A.;Glimcher, Laurie H.;Kuchroo, Vijay K.
通讯作者：
Kuchroo, Vijay K.
影响因子：
5.5
作者：
Moorman, Jonathan P.;Zhang, Chun L.;Ni, Lei;Ma, Cheng J.;Zhang, Ying;Wu, Xiao Y.;Thayer, Penny;Islam, Tareq M.;Borthwick, Thomas;Yao, Zhi Q.
通讯作者：
Yao, Zhi Q.
影响因子：
4
作者：
Guo, Min;Mao, Xiaobo;Zeng, Qiutang
通讯作者：
Zeng, Qiutang
影响因子：
4.4
作者：
Cruise, Michael W.;Lukens, John R.;Hahn, Young S.
通讯作者：
Hahn, Young S.
影响因子：
3.1
作者：
Kramer, Erik Seth;Hofmann, Charlotte;Sterling, Richard K.
通讯作者：
Sterling, Richard K.