T cell-mediated immunopathologic mechanism of liver injury in acute viral hepatitis (HUM8P.336)

CD8+ T cells play an important role in immune responses against intracellular infection. They recognize and lyse infected cells, and secrete anti-viral cytokines to control infection. However, excessive immune responses may lead to tissue damage during infection. In particular, severe CD8+ T cell-mediated liver injury is known as a primary cause of tissue damage in hepatitis A virus (HAV) infection. In this study, we demonstrate that during acute viral hepatitis, CD8+ T cells specific to HAV-unrelated viruses such as influenza virus, Epstein-Barr virus (EBV), or cytomegalovirus (CMV) became activated even in the absence of those viral reactivations, which means that non-HAV-specific CD8+ T cells are able to be activated even without cognate antigen. Interestingly, the severity of liver injury correlated with the activation of these non-HAV-specific T cells, not with activation of HAV-specific T cells. HAV-infected cells produced IL-15, which induced antigen-nonspecific activation of CD8+ T cells. IL-15-activated CD8+ T cells exerted NK-like cytolytic activity by NKG2D dependent manner, even without T cell receptor engagement. HAV-infected hepatocytes overexpressed NKG2D ligands and, thus, could be cytolytic targets during HAV infection. We report a human viral disease in which host injury is attributed to NK-like cytolytic activity of IL-15-activated CD8+ T cells not specific to the infecting virus.