Increased Fas ligand expression of CD4+ T cells by HCV core induces T cell-dependent hepatic inflammation.

Hepatitis C virus (HCV) infection is associated with a high rate of viral persistence and the development of chronic liver disease. The expression of HCV core protein in T cells has previously been reported to alter T cell activation and has been linked to the development of liver inflammation. However, the molecular and cellular basis for the role of HCV core-expressing T cells in liver inflammation is not understood. Here, using double-transgenic mice of CD2/HCV-core transgenic mice and ovalbumin (OVA)-specific T cell receptor transgenic mice, we demonstrated that in vivo antigenic stimulation (OVA peptide administration) triggers a marked influx of core-expressing, antigen-specific, transgenic CD4+ T cells into the liver of these mice. Phenotypic analysis of the liver-infiltrating T cells revealed high expression levels of CD44 and Fas ligand (FasL). Adoptive transfer of liver-infiltrating, core-expressing CD4+ T cells into severe combined immunodeficiency mice directly demonstrated the capacity of these activated T cells to induce liver inflammation. It is important that anti-FasL antibody treatment of the mice at the time of cell transfer abrogated the liver inflammation induced by core-expressing CD4+ T cells. These findings suggest that activated T lymphocytes expressing elevated levels of FasL may be involved in the bystander killing of hepatocyte, as well as the induction of chronic liver inflammation, by promoting recruitment of proinflammatory cells to the liver.

Hepatitis C virus core protein leads to immune suppression and liver damage in a transgenic murine model.

Hepatitis C virus (HCV) is remarkably efficient in establishing persistent infection, possibly mediated by an impaired immune response to HCV infection. There is compelling evidence that HCV can infect immune cells, such as macrophages, B cells, and T cells. It has been previously reported that HCV core, the first protein expressed during the early phase of viral infection, contains the immunomodulatory function of suppressing host immune responses. This altered function of immune cells caused by HCV infection may explain the ineffective immune response to HCV. To further characterize the immunomodulatory role of HCV core in vivo, we generated transgenic (TG) mice by directing the expression of core protein to T lymphocytes by using the CD2 promoter. T-lymphocyte responses, including the production of gamma interferon and interleukin-2, were significantly diminished in these mice compared to their non-TG littermates. The inhibition of T-lymphocyte responsiveness may be due to the increased susceptibility of peripheral T lymphocytes to Fas-mediated apoptosis. Surprisingly, significant lymphocyte infiltration was observed in the portal tracts of livers isolated from core TG mice, associated with increasing serum alanine aminotransferase levels. Moreover, no intrahepatic lymphocytes or liver damage was found in non-TG littermates and core TG mice bred to Fas-deficient lpr mice. These results suggest that HCV core drives liver injury by increasing Fas-mediated apoptosis and liver infiltration of peripheral T cells.