Immune Activation Induces Telomeric DNA Damage and Promotes Short-Lived Effector T Cell Differentiation in Chronic HCV Infection.
Immune Activation Induces Telomeric DNA Damage and Promotes Short-Lived Effector T Cell Differentiation in Chronic HCV Infection.
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DOI：
10.1002/hep.32008
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Yao ZQ
中科院分区：
文献类型：
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作者：
Nguyen LN;Nguyen LNT;Zhao J;Schank M;Dang X;Cao D;Khanal S;Thakuri BKC;Zhang J;Lu Z;Wu XY;El Gazzar M;Ning S;Wang L;Moorman JP;Yao ZQ
丙型肝炎病毒(丙型肝炎病毒)是一种慢性感染率高、T细胞功能障碍的病毒。虽然众所周知，慢性抗原刺激是T细胞功能受损的驱动力，但在丙型肝炎病毒感染过程中，免疫激活导致T细胞功能障碍的确切机制仍不清楚。在这里，我们证明了来自慢性丙型肝炎患者的循环CD_4+T细胞呈现免疫激活状态，细胞激活标志物HLADR、GLUT1、颗粒酶B和短命效应标志物CD127KLRG1+的过度表达证明了这一点。相比之下，慢性丙型肝炎患者的CD4+T细胞中干细胞样转录因子TCF1和端粒重复序列结合因子2(TRF2)的表达明显低于健康人(HS)。机制研究表明，丙型肝炎患者的CD4+T细胞在T细胞受体(TCR)刺激下表现出PI3K/Akt/mTOR信号过度激活，促进促炎效应细胞分化、端粒DNA损伤和细胞凋亡。抑制Akt信号在T细胞激活过程中保护了前体记忆细胞群，并防止了炎性效应细胞的扩张、DNA损伤和凋亡性死亡。此外，TRF2的敲除降低了HS-T细胞的干性，并引发了端粒DNA损伤和细胞凋亡，而TRF2的过表达则阻止了端粒DNA的损伤。这些结果提示，通过抑制Akt信号调节免疫激活，通过增强TRF2表达保护端粒，可能为微调慢性丙型肝炎持续免疫激活和炎症状态下的获得性免疫反应开辟新的治疗策略。
Hepatitis C virus (HCV) leads to a high rate of chronic infection and T cell dysfunction. While it is well-known that chronic antigenic stimulation is a driving force for impaired T cell functions, the precise mechanisms underlying immune activation-induced T cell dysfunctions during HCV infection remain elusive. Here, we demonstrated that circulating CD4+ T cells from chronically HCV-infected patients exhibit an immune activation status, as evidenced by the overexpression of cell activation markers HLA-DR, GLUT1, Granzyme B, and the short-lived effector marker CD127− KLRG1+. In contrast, the expression of stem cell-like transcription factor TCF1 and telomeric repeat-binding factor 2 (TRF2) are significantly reduced in CD4+ T cells from chronically HCV-infected patients compared to healthy subjects (HS). Mechanistic studies revealed that CD4+ T cells from HCV subjects exhibit PI3K/Akt/mTOR signaling hyperactivation upon T cell receptor (TCR) stimulation, promoting pro-inflammatory effector cell differentiation, telomeric DNA damage, and cellular apoptosis. Inhibition of Akt signaling during T cell activation preserved the precursor memory cell population and prevented inflammatory effector cell expansion, DNA damage, and apoptotic death. Moreover, knockdown of TRF2 reduced HS-T cell stemness and triggered telomeric DNA damage and cellular apoptosis, whereas overexpression of TRF2 in HCV-CD4 T cells prevented telomeric DNA damage. These results suggest that modulation of immune activation via inhibiting Akt signaling and protecting telomeres via enhancing TRF2 expression may open new therapeutic strategies to fine-tune the adaptive immune responses in the setting of persistent immune activation and inflammation during chronic HCV infection.
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影响因子：
5.4
作者：
Negro，Francesco
通讯作者：
Negro，Francesco
影响因子：
15.9
作者：
Chen, Diana Y.;Wolski, David;Lauer, Georg M.
通讯作者：
Lauer, Georg M.
影响因子：
8.8
作者：
Kim, Chulwoo;Hu, Bin;Goronzy, Jorg J.
通讯作者：
Goronzy, Jorg J.
影响因子：
64.8
作者：
Okamoto, Keiji;Bartocci, Cristina;Ouzounov, Iliana;Diedrich, Jolene K.;Yates, John R., III;Denchi, Eros Lazzerini
通讯作者：
Denchi, Eros Lazzerini
DOI：
10.1038/nri3198
发表时间：
2012-04-20
期刊：
Nature reviews. Immunology
影响因子：
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作者：
通讯作者：
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