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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 …