Mechanisms of antigen-dependent CD8 T cell dysfunction in chronic HBV infection

Project Summary

Chronic Hepatitis B virus (HBV) infection causes immune-mediated necro-inflammatory disease that can progress to liver cirrhosis, end-stage liver disease or ultimately to liver cancer. In chronic Hepatitis B, HBV-specific CD8 T cells are functionally impaired and fail to control HBV infection. However, residual functionality of these cells is a main driver of HBV-associated immunopathology. We have observed major differences in the frequency, phenotype and function between CD8 T cell populations targeting different HLA-A*02-restricted HBV epitopes in chronic HBV infection. In particular, the degree of dysfunction of HBV-specific CD8 T cells differs with respect to the targeted epitopes and this may potentially also contribute to the immune-mediated liver inflammation. We now aim to further explore the mechanisms underlying the impaired HBV-specific CD8 T cell responses targeting different epitopes in chronic HBV infection with respect to their residual protective and still pathogenic role. Insights into the mechanisms underlying CD8 T cell dysfunction in chronic HBV infection will have potential implications for the translation into the design of T cell-based immunotherapeutic interventions in HBV cure and thus to stop HBV-associated immunopathology.