CD4+ T Cell Immunosuppression by HCV+ Hepatocytes

Hall, Caroline Haberstroh Tran, Department of Microbiology, University of Virginia
Hahn, Young, Department of Microbiology, University of Virginia
Braciale, Thomas, Department of Pathology, University of Virginia
Lorenz, Ulrike, Department of Microbiology, University of Virginia
Tung, Kenneth, Department of Pathology, University of Virginia

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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PHD (Doctor of Philosophy)
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