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 γ/δ form of the T-cell receptor for antigen (TCRγδ). In this study, we investigated whether liver biopsy specimens obtained from individuals with viral (HCV and/or HBV) or nonviral hepatitis contained TCRγδ⁺ 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 TCRγδ⁺ 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 TCRγδ⁺ T cells. Liver TCRγδ⁺ 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-γ), tumor necrosis factor α (TNF-α), and interleukin 8 (IL-8) following activation by anti-CD3. Surprisingly, none of these liver TCRγδ⁺ 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-γ and TNF-α production by liver TCRγδ⁺ T cells. These results suggest that TCRγδ⁺ T cells may play a role in the liver pathology of HCV infections.