Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Department of Dermatology, Venereology, and Allergology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Sci Rep. 2017 Aug 10;7(1):7785. doi: 10.1038/s41598-017-08578-7.
CD4+ helper T cells and cytotoxic CD8+ T cells are key players for adaptive immune responses against acute infections with retroviruses. Similar to textbook knowledge the most important function of CD4+ T cells during an acute retrovirus infection seems to be their helper function for other immune cells. Whereas there was no direct anti-viral activity of CD4+ T cells during acute Friend Virus (FV) infection, they were absolutely required for the control of chronic infection. During chronic FV infection a population of activated FV-specific CD4+ T cells did not express cytotoxic molecules, but Fas Ligand that can induce Fas-induced apoptosis in target cells. Using an MHC II-restricted in vivo CTL assay we demonstrated that FV-specific CD4+ T cells indeed mediated cytotoxic effects against FV epitope peptide loaded targets. CD4 + CTL killing was also detected in FV-infected granzyme B knockout mice confirming that the exocytosis pathway was not involved. However, killing could be blocked by antibodies against FasL, which identified the Fas/FasL pathway as critical cytotoxic mechanism during chronic FV infection. Interestingly, targeting the co-stimulatory receptor CD137 with an agonistic antibody enhanced CD4+ T cell cytotoxicity. This immunotherapy may be an interesting new approach for the treatment of chronic viral infections.
CD4+辅助性 T 细胞和细胞毒性 CD8+T 细胞是针对逆转录病毒急性感染产生适应性免疫反应的关键因素。与教科书知识类似，在急性逆转录病毒感染期间，CD4+T 细胞最重要的功能似乎是为其他免疫细胞提供辅助功能。虽然在急性 Friend 病毒（FV）感染期间，CD4+T 细胞没有直接的抗病毒活性，但它们对于控制慢性感染是绝对必需的。在慢性 FV 感染中，一群激活的 FV 特异性 CD4+T 细胞不表达细胞毒性分子，但表达 Fas 配体，它可以诱导靶细胞的 Fas 诱导凋亡。使用 MHC II 限制性体内 CTL 测定，我们证明了 FV 特异性 CD4+T 细胞确实对负载 FV 表位肽的靶细胞具有细胞毒性作用。在 FV 感染的颗粒酶 B 敲除小鼠中也检测到 CD4+CTL 杀伤，证实了该途径不涉及胞吐作用。然而，通过针对 FasL 的抗体可以阻断杀伤，这表明 Fas/FasL 途径是慢性 FV 感染期间的关键细胞毒性机制。有趣的是，用激动性抗体靶向共刺激受体 CD137 增强了 CD4+T 细胞的细胞毒性。这种免疫疗法可能是治疗慢性病毒感染的一种新的有趣方法。
