Immune responses and immunopathology in acute and chronic viral hepatitis
Eui-Cheol Shin Affiliation : KAIST Place : Engineering Building E104 Contact : email@example.com
Both hepatitis A virus (HAV) and hepatitis C virus (HCV) are RNA viruses and display hepatotropism; that is, they preferentially infect hepatocytes and cause liver inflammation. HAV infection often causes severe liver injury in adults, whereas it results in asymptomatic subclinical infection in children. However, HAV infection is effectively controlled by the host and does not progress to chronic infection.
In the present study, we investigated bystander activation of CD8+ memory T cells and their contribution to tissue damage in acute hepatitis A (AHA), which is caused by HAV and manifested by severe liver injury in adults. We show bystander activation of CD8+ memory T cells specific to irrelevant viruses such as cytomegalovirus, Epstein-Barr virus and influenza A virus during acute necroinflammatory phase of AHA. We also demonstrate an unexpected correlation of the bystander activation to the liver injury, indicating a role of activated bystander CD8+ T cells in the liver injury. In contrast, HAV-specific T cell response was associated with viral clearance rather than the liver injury. Intriguingly, IL-15 is produced by HAV infection, and expression of IL-15 and IL-15R increased in AHA. Furthermore, in vitro IL-15 treatment of healthy donors’ lymphocytes recapitulated the activated phenotype of the bystander CD8+ memory T cells observed in AHA. CD8+ T cells activated in vitro by IL-15 or obtained from the liver of AHA patients exerted NK-like cytolytic activity triggered by NKG2D and/or NKp30 without TCR engagement. In addition, hepatocytes of the AHA liver over-expressed NKG2D ligands, and therefore could be cytolytic targets of activated bystander CD8+ T cells. Taken together, we report here a human viral disease in which bystander CD8+ memory T cells are activated by IL-15 and contribute to tissue damage by NK-like cytolytic activity without antigen specificity.