MECHANISMS PROMOTING BYSTANDER ACTIVATED CD8+ T CELL-MEDIATED DISEASE DURING VIRAL INFECTION

Abstract

Viral infections can lead to severe tissue damage and long-term health consequences, even when the virus does not directly target the affected tissues. While viral replication is often considered the primary driver of pathology, growing evidence suggests that immune responses and inflammation contribute substantially to collateral damage. Using a mouse model of Zika virus (ZIKV) infection, we investigate the contributions of viral replication and immune activation to ZIKV-induced neuropathology. We find that disease severity does not correlate with viral load but is associated with infiltration of bystander activated CD8+ T cells in the CNS of ZIKV-infected mice. These T cells are stimulated by inflammatory cytokines independent of TCR engagement and promote tissue damage through antigen-independent, NKG2D-mediated cytotoxicity. Although the amount of infectious virus did not correlate with disease, we find that viral infection of the CNS is required for recruitment of bystander activated CD8+ T cells. We further demonstrate that microglia are required for ZIKV-induced neuropathology but do not influence bystander T cell recruitment to the CNS. Instead, microglia are required for induction of NKG2D ligand expression on neurons, which are subsequently targeted and eliminated by NKG2D+ bystander activated CD8+ T cells. Finally, we examine the role of biological sex in bystander CD8+ T cell activation by ex vivo cytokine stimulation of human peripheral blood mononuclear cells. We find that CD8+ T cells from male donors exhibit greater IL-15-driven bystander activation, NKG2D expression, and antigen-independent cytotoxicity compared to T cells from female donors. These data suggest that sex differences in bystander CD8+ T cell activation may contribute to the observed sex biases in disease severity of viral infections. Overall, our findings reveal a novel mechanism of immune-mediated pathology during viral infection and highlight potential therapeutic targets to limit tissue damage caused by bystander CD8+ T cell activation.