Phenotype and fate of liver-resident CD8 T cells during acute and chronic hepacivirus infection

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-gamma, TNF-alpha, and IL2, 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-gamma 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. Approximately 60-80% of humans fail to clear the hepatitis C virus infection, and the mechanism of HCV persistence and immune evasion remains elusive. T cells play an essential role in the control and clearance of HCV infection in humans and chimpanzees. Recently, we developed lab mouse and rat models for rodent HCV-like virus (RHV). Further development of these new rodent models is highly significant due to the lack of relevant animal models to study HCV immunity and pathogenesis. Here, we developed and used mouse MHC class I and class II tetramers to characterize the RHV-specific effector and memory T cells during acute and chronic RHV infection in immunocompetent lab mice. The control and clearance of primary and secondary RHV infection were associated with the expansion of liver-resident T cells expressing cytotoxic markers and antiviral cytokines. Chronic infection resulted in the exhaustion of T cells and the development of severe liver diseases. We defined the fundamental characteristics and unique transcriptome signature of liver-resident RHV-specific CD8 T cells during acute and chronic hepacivirus infection. Thus, our data and the newly developed mouse MHC class I and class II tetramers will allow the RHV mouse model to identify the liver-specific responses that shape the nature of liver-resident T cells and the divergent outcomes of hepacivirus infection and pathogenesis.