T cell dysfunction by hepatitis C virus core protein involves PD-1/PDL-1 signaling
T cell dysfunction by hepatitis C virus core protein involves PD-1/PDL-1 signaling
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DOI：
10.1089/vim.2006.0096
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发表时间：
2007-06-01
期刊：
影响因子：
2.2
通讯作者：
Moorman, Jonathan
中科院分区：
文献类型：
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作者：
Yao, Zhi Q.;King, Ellis;Moorman, Jonathan
有报道表明，由PD-1（程序性死亡-1）和PDL-1（程序性死亡配体-1）介导的负性T细胞共刺激途径与T细胞衰竭和持续病毒感染有关。人类持续性丙型肝炎病毒（HCV）感染也以T淋巴细胞功能受损为特征，但PD-1和PDL-1途径在HCV感染中的作用尚不清楚。在这里，我们报告了从慢性hcv感染患者中分离的T细胞与健康供者相比，表达的PD-1水平明显更高。此外，暴露于HCV核心（一种免疫抑制的核衣壳蛋白）的健康供体T细胞上，PD-1和PDL-1的表达上调；PD-1的上调是通过HCV核心与补体受体gC1qR的相互作用介导的。重要的是，被HCV核心失调的T细胞功能，包括T细胞活化、增殖和凋亡，可以通过阻断PD-1和PDL-1接合来恢复。我们的研究结果表明，HCV核心可以上调与病毒持久性相关的关键负T细胞信号通路，并在持续感染个体的T细胞上高度表达。人类PD-1和PDL-1通路的上调代表了一种新的可能是常见的机制，病毒通过这种机制篡夺宿主的机制来促进持久性。
Reports have shown that a negative T cell costimulatory pathway mediated by PD-1 ( programmed death-1) and PDL-1 ( programmed death ligand-1) is associated with T cell exhaustion and persistent viral infection. Persistent hepatitis C virus (HCV) infection in humans is also characterized by impaired T lymphocyte function, but the role of the PD-1 and PDL-1 pathway in HCV infection is unknown. Here we report that T cells isolated from chronically HCV-infected patients express significantly higher levels of PD-1 when compared with healthy donors. In addition, PD-1 and PDL-1 expression is upregulated on healthy donor T cells exposed to HCV core, a nucleocapsid protein that is immunosuppressive; upregulation of PD-1 is mediated through interaction of HCV core with the complement receptor, gC1qR. Importantly, T cell functions that are dysregulated by HCV core, including T cell activation, proliferation, and apoptosis, can be restored by blocking PD-1 and PDL-1 engagement. Our results indicate that HCV core can upregulate a key negative T cell signaling pathway associated with viral persistence and highly expressed on the T cells of persistently infected individuals. This upregulation of the PD-1 and PDL-1 pathway in humans represents a novel and perhaps common mechanism by which a virus usurps host machinery to facilitate persistence.