Enhanced FasL expression by HCV core induces the production of CXCR3 chemokines and liver damage

Hepatitis C virus (HCV) infection is associated with a high rate of viral persistence and the development of chronic liver disease. Even though hepatocytes serve as a major reservoir for HCV infection, the virus can also infect PBMCs. The expression of HCV core protein in T cells can alter cell activation and is associated with liver inflammation. However, the molecular and cellular basis for the role of HCV core-expressing T cells in liver inflammation is not understood. Here, we use DO11.10 mice that express the HCV core protein in the OVA specific TCR on CD4+ T lymphocytes. In vivo antigenic stimulation triggers a marked influx of core-expressing antigen-specific CD4+ T cells into the liver of core(+)TCR mice but not their core(-)TCR littermates. This influx was accompanied by hepatic damage and elevations in serum ALT levels.; Adoptive transfer of 111In-labeled CD4+ lymphocytes demonstrate that the core(+)TCR lymphocytes traffic primarily to the liver. Phenotypic analysis of the liver-infiltrating T cells revealed a highly activated phenotype with IHL from core(+)TCR mice demonstrating increased levels of FasL. Adoptive transfer of liver infiltrating core-expressing CD4 + T cells directly demonstrated the capacity of these activated T cells to induce liver inflammation. Importantly, anti-FasL antibody treatment of the mice abrogated the liver inflammation, suggesting that activated T cells expressing elevated levels of FasL may be involved in the bystander killing of hepatocyte, as well as the induction of chronic liver inflammation.; To understand the mechanism(s) of FasL-mediated liver inflammation, we examined the effect of FasL expressing CD4+ T cells on the initiation of hepatic damage through analysis of chemokine and chemokine receptor expression. Strikingly, liver inflammation in core(+)TCR mice was accompanied by a dramatic increase in IP-10 and Mig production. The intrahepatic lymphocytes were primarily CXCR3-positive and anti-CXCR3 antibody treatment abrogates migration of CXCR3+ lymphocytes into the liver and hepatic damage. Importantly, the blockade of Fas/FasL interaction reduces the expression of IP-10 and Mig and cellular infiltration into the liver. These findings suggest that activated CD4+ T cells with elevated FasL expression are involved in promoting liver inflammation and hepatic damage through the induction of chemokines.