Characterization of liver T-cell receptor γδ+ T cells obtained from individuals chronically infected with hepatitis C virus (HCV):: Evidence for these T cells playing a role in the liver pathology associated with HCV infections

The pathogenic mechanisms involved in viral hepatitis are not completely understood. Evidence suggests that the pathology associated with hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are a result of the immune response in the liver to these viruses, The livers of patients with viral hepatitis have been shown to contain elevated numbers of T cells expressing the gamma/delta form of the T-cell receptor for antigen (TCR gamma delta). In this study, we investigated whether liver biopsy specimens obtained from individuals with viral (HCV and/or HBV) or nonviral hepatitis contained TCR gamma delta (+) T cells that could be expanded in vitro by cytokines. A high percentage of liver biopsy specimens obtained from HCV- and/or HBV-infected individuals contained high numbers of TCR gamma delta (+) T cells. In contrast, T-cell lines generated from liver biopsy tissues obtained from individuals with nonviral hepatitis or from normal controls had no preferential expansion of TCR gamma delta (+) T cells. Liver TCR gamma delta (+) T-cell lines from HCV-infected individuals had high levels of non-major histocompatibility complex (MHC)-restricted cytotoxic activity against different targets including primary hepatocytes and produced interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin 8 (IL-8) following activation by anti-CD3. Surprisingly, none of these liver TCR gamma delta (+) T-cell Lines could recognize any of the structural or nonstructural proteins of HCV and had no cytotoxic activity against cells infected with recombinant vaccinia viruses expressing different HCV proteins. However, the crosslinking of CD81, which has been shown to bind HCV particles and E2, resulted in significant levels of IFN-gamma and TNF-alpha production by liver TCR gamma delta (+) T cells. These results suggest that TCR gamma delta (+) T cells may play a role in the liver pathology of HCV infections.