Immune correlates of hepatitis C virus (HCV) clearance and control remain poorly defined due to the lack of an informative animal model. We recently described acute and chronic rodent HCV-like virus (RHV) infections in lab mice. Here, we developed MHC class I and class II tetramers to characterize the serial changes in RHV-specific CD8 and CD4 T cells during acute and chronic infection in C57BL/6J mice. RHV infection induced rapid expansion of T cells targeting viral structural and nonstructural proteins. After virus clearance, the virus-specific T cells transitioned from effectors to long-lived liver-resident memory T cells (TRM). The effector and memory CD8 and CD4 T cells primarily produced Th1 cytokines, IFN-γ, TNF-α, and IL-2, upon ex vivo antigen stimulation, and their phenotype and transcriptome differed significantly between the liver and spleen. Rapid clearance of RHV reinfection coincided with the proliferation of virus-specific CD8 TRM cells in the liver. Chronic RHV infection was associated with the exhaustion of CD8 T cells (Tex) and the development of severe liver diseases. Interestingly, the virus-specific CD8 Tex cells continued proliferation in the liver despite the persistent high-titer viremia and retained partial antiviral functions, as evident from their ability to degranulate and produce IFN-γ upon ex vivo antigen stimulation. Thus, RHV infection in mice provides a unique model to study the function and fate of liver-resident T cells during acute and chronic hepatotropic infection.

中文翻译：

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急性和慢性肝炎病毒感染期间肝脏驻留 CD8 T 细胞的表型和命运。

由于缺乏信息丰富的动物模型，丙型肝炎病毒（HCV）清除和控制的免疫相关性仍不清楚。我们最近描述了实验室小鼠的急性和慢性啮齿类 HCV 样病毒 (RHV) 感染。在这里，我们开发了 MHC I 类和 II 类四聚体来表征 C57BL/6J 小鼠急性和慢性感染期间 RHV 特异性 CD8 和 CD4 T 细胞的系列变化。RHV 感染诱导针对病毒结构和非结构蛋白的 T 细胞快速扩增。病毒清除后，病毒特异性 T 细胞从效应细胞转变为长寿命肝脏驻留记忆 T 细胞 (TRM)。在离体抗原刺激下，效应和记忆CD8和CD4 T细胞主要产生Th1细胞因子、IFN-γ、TNF-α和IL-2，并且它们的表型和转录组在肝脏和脾脏之间存在显着差异。RHV 再感染的快速清除与肝脏中病毒特异性 CD8 TRM 细胞的增殖同时发生。慢性 RHV 感染与 CD8 T 细胞 (Tex) 的耗竭和严重肝脏疾病的发展有关。有趣的是，尽管存在持续的高滴度病毒血症，病毒特异性 CD8 Tex 细胞仍在肝脏中持续增殖，并保留了部分抗病毒功能，这从它们在离体抗原刺激后脱颗粒和产生 IFN-γ 的能力中可以明显看出。因此，小鼠 RHV 感染提供了一个独特的模型来研究急性和慢性亲肝感染期间肝脏驻留 T 细胞的功能和命运。