Hepatitis C virus specific CD4+ T cell phenotype and function in different infection outcomes
Hepatitis C virus specific CD4+ T cell phenotype and function in different infection outcomes
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DOI：
10.1172/jci126277
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发表时间：
2020-02-03
影响因子：
15.9
通讯作者：
Lauer, Georg M.
中科院分区：
文献类型：
--
作者：
Chen, Diana Y.;Wolski, David;Lauer, Georg M.
CD 4（+）T细胞衰竭是慢性丙型肝炎病毒（HCV）感染的标志。然而，HCV持续感染中病毒特异性CD 4（+）T细胞受损和丧失的机制仍不清楚。在此，我们纵向检测了不同感染结局的急性感染期间HCV特异性CD 4（+）T细胞。我们发现，HCV特异性CD 4（+）T细胞的特征是与CD 8（+）T细胞相比，T细胞抑制性受体的表达范围更窄，PD-1和CTLA-4的初始高表达水平与所有患者的增殖负调控相关，无论结果如何。此外，HCV特异性CD 4（+）T细胞在早期消退和持续感染期间的表型相似，并分泌相似水平的细胞因子。然而，在病毒控制下，CD 4（+）T细胞迅速下调抑制性受体，并分化为长寿的记忆细胞。相反，持续的病毒血症继续驱动T细胞活化和PD-1和CTLA-4表达，并阻断T细胞分化，直到细胞迅速从循环中消失。我们的数据支持抑制性受体介导的CD 4（+）T细胞调节在早期HCV感染中的重要生理作用，无论结果如何，持续的HCV病毒血症导致PD-1和CTLA-4的持续上调。
CD4(+) T cell failure is a hallmark of chronic hepatitis C virus (HCV) infection. However, the mechanisms underlying the impairment and loss of virus-specific CD4(+) T cells in persisting HCV infection remain unclear. Here we examined HCV-specific CD4(+) T cells longitudinally during acute infection with different infection outcomes. We found that HCV-specific CD4(+) T cells are characterized by expression of a narrower range of T cell inhibitory receptors compared with CD8(+) T cells, with initially high expression levels of PD-1 and CTLA-4 that were associated with negative regulation of proliferation in all patients, irrespective of outcome. In addition, HCV-specific CD4(+) T cells were phenotypically similar during early resolving and persistent infection and secreted similar levels of cytokines. However, upon viral control, CD4(+) T cells quickly downregulated inhibitory receptors and differentiated into long-lived memory cells. In contrast, persisting viremia continued to drive T cell activation and PD-1 and CTLA-4 expression, and blocked T cell differentiation, until the cells quickly disappeared from the circulation. Our data support an important and physiological role for inhibitory receptor-mediated regulation of CD4(+) T cells in early HCV infection, irrespective of outcome, with persistent HCV viremia leading to sustained upregulation of PD-1 and CTLA-4.