Innate-like Cytotoxic Function of Bystander-Activated CD8 ⁺ T Cells Is Associated with Liver Injury in Acute Hepatitis A

Acute hepatitis A (AHA) involves severe CD8 ⁺ T cell-mediated liver injury. Here we showed during AHA, CD8 ⁺ T cells specific to unrelated viruses became activated. Hepatitis A virus (HAV)-infected cells produced IL-15 that induced T cell receptor (TCR)-independent activation of memory CD8 ⁺ T cells. TCR-independent activation of non-HAV-specific CD8 ⁺ T cells were detected in patients, as indicated by NKG2D upregulation, a marker of TCR-independent T cell activation by IL-15. CD8 ⁺ T cells derived from AHA patients exerted innate-like cytotoxicity triggered by activating receptors NKG2D and NKp30 without TCR engagement. We demonstrated that the severity of liver injury in AHA patients correlated with the activation of HAV-unrelated virus-specific CD8 ⁺ T cells and the innate-like cytolytic activity of CD8 ⁺ T cells, but not the activation of HAV-specific T cells. Thus, host injury in AHA is associated with innate-like cytotoxicity of bystander-activated CD8 ⁺ T cells, a result with implications for acute viral diseases. During acute hepatitis A, hepatitis A virus (HAV)-infected cells produce IL-15 that induces TCR-independent bystander activation of non-HAV-specific memory CD8 ⁺ T cells. These CD8 ⁺ T cells exert innate-like cytotoxicity triggered by NKG2D and NKp30 without TCR engagement. The severity of liver injury is associated with activation and innate-like cytotoxicity of non-HAV-specific CD8 ⁺ T cells, but not the activation of HAV-specific T cells. Thus, IL-15-induced bystander-activated CD8 ⁺ T cells are implicated in host injury during acute viral infection.