Programmed Death-1 Affects Suppressor of Cytokine Signaling-1 Expression in T Cells During Hepatitis C Infection
Programmed Death-1 Affects Suppressor of Cytokine Signaling-1 Expression in T Cells During Hepatitis C Infection
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DOI：
10.1089/vim.2010.0010
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发表时间：
2010-10-01
期刊：
影响因子：
2.2
通讯作者：
Moorman, Jonathan P.
中科院分区：
文献类型：
--
作者：
Frazier, Ashley D.;Zhang, Chun L.;Moorman, Jonathan P.
慢性丙型肝炎病毒 (HCV) 感染与 T 细胞耗竭相关，而 T 细胞耗竭是通过 PD-1 负调节途径上调介导的。 PD-1 表达由 HCV 核心蛋白诱导，该蛋白还诱导 SOCS-1 上调，SOCS-1 是控制 Jak/STAT 通路调节细胞因子表达的关键调节剂。为了确定这两条负调控途径在 T 细胞信号传导过程中是否存在关联，通过在 HCV 核心蛋白存在下用抗 CD3/CD28 刺激的 T 细胞阻断 PD-1 途径来检查 SOCS-1 表达。在存在或不存在HCV核心蛋白的情况下，用抗PD-1或抗PDL-1抗体处理从健康受试者或HCV感染个体中分离的T细胞，并通过RT-PCR或免疫印迹检测SOCS-1基因表达，同时通过流式细胞术分析测定T细胞功能。在暴露于 HCV 核心蛋白的健康 T 细胞中，PD-1 和 SOCS-1 基因表达均上调，而阻断 PD-1 通路则下调这些细胞中 SOCS-1 基因的表达。此外，与健康受试者相比，从慢性HCV感染受试者中分离的T细胞表现出PD-1和SOCS-1表达增加，并且从HCV感染受试者中分离的T细胞中的SOCS-1表达也通过阻断PD-1信号传导而受到抑制；这反过来又增强了 STAT-1 的磷酸化，并改善了 HCV 感染情况下观察到的受损 T 细胞增殖。这些数据表明，PD-1和SOCS-1在HCV感染期间T细胞信号传导失调中存在关联，并且它们的相互作用可能协同抑制T细胞信号传导途径，从而导致慢性病毒感染期间T细胞耗竭。
Chronic hepatitis C virus (HCV) infection is associated with T-cell exhaustion that is mediated through upregulation of the PD-1 negative regulatory pathway. PD-1 expression is induced by HCV core protein, which also induces upregulation of SOCS-1, a key modulator that controls the Jak/STAT pathway regulating cytokine expression. To determine whether these two negative regulatory pathways are linked during T-cell signaling, SOCS-1 expression was examined by blocking the PD-1 pathway in T cells stimulated with anti-CD3/CD28 in the presence of HCV core protein. T cells isolated from healthy subjects or HCV-infected individuals were treated with anti-PD-1 or anti-PDL-1 antibodies in the presence or absence of HCV core protein, and SOCS-1 gene expression was detected by RT-PCR or immunoblotting, while T-cell functions were assayed by flow cytometric analyses. Both PD-1 and SOCS-1 gene expression were upregulated in healthy T cells exposed to HCV core protein, and blocking the PD-1 pathway downregulated SOCS-1 gene expression in these cells. Additionally, T cells isolated from chronically HCV-infected subjects exhibited increased PD-1 and SOCS-1 expression compared to healthy subjects, and SOCS-1 expression in T cells isolated from HCV-infected subjects was also inhibited by blocking PD-1 signaling; this in turn enhanced the phosphorylation of STAT-1, and improved the impaired T-cell proliferation observed in the setting of HCV infection. These data demonstrate that PD-1 and SOCS-1 are linked in dysregulating T-cell signaling during HCV infection, and their cross-talk may coordinately inhibit T-cell signaling pathways that lead to T-cell exhaustion during chronic viral infection.