Biological Sex Influences Human Bystander CD8⁺ T Cell Activation

The recent COVID-19 pandemic has highlighted a significant sex bias in disease outcome, where male sex is associated with greater disease severity and mortality. Interestingly, studies have also identified a role for antigen-independent "bystander-activated" CD8⁺ T cells in the severity of COVID-19 and other viral infections. However, whether biological sex contributes to the magnitude of bystander T cell activation has not been investigated. To assess sex differences in bystander CD8⁺ T cell activation, we isolated PBMCs from age-matched male and female donors and stimulated the cells with cytokines IL-12/15/18 to induce bystander T cell activation. Male CD8⁺ T cells stimulated with IL-15 exhibited greater bystander activation, including increased NKG2D expression and greater antigen-independent cytotoxicity against tumor cells compared with female CD8⁺ T cells. In contrast, IL-12/18 and IL-12/15/18 stimulation of CD8⁺ T cells did not reveal evidence of sex differences in bystander IFN-γ production. Our data suggest that underlying sex differences in bystander CD8⁺ T cell activation and cytotoxicity may contribute to the observed sex biases in disease severity of viral infections.