Hepatitis C virus attenuates interferon-induced major histocompatibility complex class I expression and decreases CD8+ T cell effector functions.
Hepatitis C virus attenuates interferon-induced major histocompatibility complex class I expression and decreases CD8+ T cell effector functions.
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DOI：
10.1053/j.gastro.2014.01.054
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发表时间：
2014-05
期刊：
影响因子：
29.4
通讯作者：
Shin EC
中科院分区：
文献类型：
--
作者：
Kang W;Sung PS;Park SH;Yoon S;Chang DY;Kim S;Han KH;Kim JK;Rehermann B;Chwae YJ;Shin EC
MHC I类限制性CD 8 + T细胞是清除丙型肝炎病毒（HCV）感染所必需的。I型和II型干扰素（IFN）上调I类MHC表达。然而，关于HCV感染对IFN诱导的MHC I类表达的影响知之甚少。我们使用的HCV细胞培养系统（HCV 2）与基因型2a日本暴发性肝炎-1株，研究IFN诱导的MHC I类分子的表达及其调控机制。通过流式细胞术、代谢标记、免疫沉淀和免疫印迹分析来分析HCV感染的Huh-7.5细胞。用表达小发夹（sh）RNA的慢病毒敲低蛋白激酶R（PKR）。在共培养研究中，使用HCV特异性CD 8 + T细胞证明了HCV对MHC I类调节的功能作用。虽然MHC I类分子的基线水平不受HCV感染的影响，但IFN诱导的MHC I类分子的表达在HCV感染的细胞中显著减弱。这与HCV RNA的复制有关，而与病毒蛋白无关。HCV感染减少IFN诱导的MHC I类蛋白的合成，并诱导PKR和eIF 2 α的磷酸化。干扰素诱导的MHC I类分子表达通过shRNA介导的HCV感染细胞PKR敲低而恢复。HCV特异性CD 8 + T细胞和表达HLA-A2的HCV感染细胞的共培养表明，HCV感染降低了HCV特异性CD 8 + T细胞的效应子功能;这些功能通过shRNA介导的PKR敲低而恢复。IFN诱导的MHC I类的表达在HCV感染的细胞中通过PKR的活化而减弱，PKR的活化降低了HCV特异性CD 8 + T细胞的效应子功能。这似乎是HCV规避抗病毒适应性免疫应答的重要机制。
MHC class I-restricted CD8+ T cells are required for clearance of hepatitis C virus (HCV) infection. MHC class I expression is upregulated by type I and II interferons (IFNs). However, little is known about the effects of HCV infection on IFN-induced expression of MHC class I. We used the HCV cell culture system (HCVcc) with the genotype 2a Japanese Fulminant Hepatitis-1 strain to investigate IFN-induced expression of MHC class I and its regulatory mechanisms. HCVcc-infected Huh-7.5 cells were analyzed by flow cytometry, metabolic labeling, immunoprecipitation, and immunoblotting analyses. Protein kinase R (PKR) was knocked-down with lentiviruses that express small hairpin (sh)RNAs. The functional effects of MHC class I regulation by HCV were demonstrated in co-culture studies, using HCV-specific CD8+ T cells. Although the baseline level of MHC class I was not affected by HCV infection, IFN-induced expression of MHC class I was notably attenuated in HCV-infected cells. This was associated with replicating HCV RNA, not with viral protein. HCV infection reduced IFN-induced synthesis of MHC class I protein and induced phosphorylation of PKR and eIF2α. IFN-induced MHC class I expression was restored by shRNA-mediated knockdown of PKR in HCV-infected cells. Co-culture of HCV-specific CD8+ T cells and HCV-infected cells that expressed HLA-A2 demonstrated that HCV infection reduced the effector functions of HCV-specific CD8+ T cells; these functions were restored by shRNA-mediated knockdown of PKR. IFN-induced expression of MHC class I is attenuated in HCV-infected cells by activation of PKR, which reduces the effector functions of HCV-specific CD8+ T cells. This appears to be an important mechanism by which HCV circumvents antiviral adaptive immune responses.
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