T cell-mediated immunopathologic mechanism of liver injury in acute viral hepatitis

Abstract

In acute viral infection, CD8+ T cells perform important role in immune responses against virus. CD8+ T cells recognize and lyse virus-infected cells, and secrete anti-viral cytokines to clear virus. When CD8+ T cells are unnecessarily over-activated, severe host injury results (CD8+ T cell-mediated immunopathology). To elucidate the mechanism by which CD8+ T cells injure the host in acute viral infection, Acute hepatitis A (AHA) was selected. Severe CD8+ T cell-mediated liver injury occurs during AHA. Serum alanine aminotransferase represent liver injury objectively. In current study, it was demonstrated that in acute phase of AHA, liver injury strongly correlated with ac-tivation of CD8+ T cells. Cytotoxicity of activated CD8+ T cells might mediate liver injury. We found that during AHA, CD8+ T cells specific to hepatitis A virus (HAV)-unrelated viruses such as influenza virus, Epstein-Barr virus (EBV), or cytomegalovirus (CMV) became activated even in the absence of EBV or CMV reactivation. It means that non-HAV-specific CD8+ T cells are able to be activated without T cell receptor (TCR) engagement. Unexpectedly, the severity of liver injury correlated with the activation of these non-HAV-specific T cells, not with activation of HAV-specific T cells. In contrast, viral clearance correlated with HAV-specific T cell response, not with activation of non-HAV-specific T cells. These findings implicate the distinct role of HAV-specific and non-HAV-specific CD8+ T cells during AHA. To know how non-HAV-specific CD8+ T cells were activated independent of TCR engagement, cytokines were measured in AHA patients. Serum IL-15 increased significantly in AHA patients and HAV-infected cells produced IL-15 which induced antigen-independent activation of CD8+ T cells similar to phenotype of activated CD8+ T cells in AHA. In AHA, the activated CD8+ T cells could be recruited to the effector site via CXCR3. IL-15-activated CD8+ T cells or CD8+ T cells derived from HA...