CD4+ T Cell Immunosuppression by HCV+ Hepatocytes

Hepatitis C Virus (HCV) is remarkably efficient at establishing persistent infection and is associated with the development of chronic liver disease. Impaired T cell responses facilitate and maintain persistent HCV infection. Importantly, CD4 + regulatory T cells detected in chronically HCV-infected patients act by dampening antiviral T cell responses to HCV infection. However, the underlying mechanism for induction and/or expansion of regulatory T cell responses has yet to be identified. To this end, we examined whether HCV-expressing hepatocytes, as the primary target for HCV infection and replication, are able to induce a regulatory T cell phenotype. The liver environment was modeled by establishing the co-culture of the human hepatoma cell line, Huh7.5, containing the full-length genome of HCV genotype 1a (Huh7.5-FL) with activated CD4 + T cells. The production of IFN-and CD4 + T cell proliferation was diminished following co-culture with Huh7.5-FL as compared to controls. Notably, CD4 + T cells in contact with Huh7.5-FL expressed an increased level of the regulatory T cell markers, CD25, Foxp3, CTLA-4 and LAP, and were able to suppress the proliferation of effector T cells. In addition, Fas-mediated apoptosis increased in CD4 + T cells in co-culture with Huh7.5- FL. Importantly, HCV + hepatocytes upregulated the production of TGF- and blockade of TGF- abrogated regulatory T cell phenotype and function. Hepatocytes may further contribute to T cell activity by the production of MIP-1, IL-21 or co-stimulatory molecules such as ICOSL or OX-40. Conclusion: These results suggest that HCV infected hepatocytes directly mediate the induction of regulatory T cells, leading to impaired host T cell responses. iii Dedication To John and Calvin, you both make my life so rich, and to my parents and sisters, who have always proven to be a thoughtful sounding board and have provided endless support.

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