Hepatitis Virus-specific and Bystander CD8+ T Cells in Viral Hepatitis

In viral hepatitis, activation of bystander CD8+ T cells has been reported, but their roles have not been elucidated. Recently, we reported that bystander CD8+ T cells contribute to the liver injury in acute hepatitis A virus (HAV) infection (Immunity 2018, 48:161). In patients with acute HAV infection, CD8+ T cells specific to unrelated viruses, including CMV, EBV, and influenza virus, become activated by IL-15. Activated bystander CD8+ T cells exert innate-like cytotoxicity triggered by activating receptors NKG2D and NKp30 without TCR engagement. Importantly, the severity of liver injury is associated with activation and innate-like cytotoxicity of HAV-unrelated virus-specific CD8+ T cells, but not the activation of HAV-specific T cells, indicating that bystander-activated CD8+ T cells are implicated in host injury during acute viral hepatitis.
More recently, we also examined tissue-resident memory (Trm) phenotypes of hepatitis virus-specific and non-hepatotropic virus-specific CD8+ T cells among liver sinusoidal mononuclear cells (J Hepatol 2020, 72:1170). There are two different Trm-like CD8+ T cell populations, CD69+CD103+ and CD69+CD103-. Interestingly, CD69+CD103+CD8+ T cells include only hepatitis virus-specific cells whereas CD69+CD103-CD8+ T cells include both hepatitis virus-specific and non-hepatotropic virus-specific cells, indicating that tissue-tropism of viruses is associated with tissue-resident features of CD8+ T cells in the liver.