A double-edged sword: bystander CD8+ T cells cause collateral damage in the brain during infection 3922

Abstract Description We investigated CNS-infiltrating T cells during infection with the attenuated Venezuelan equine encephalitis virus vaccine strain TC83 (TC83), which replicates to high viral titers in the brain of wild-type mice without lethality. Thus, we could study the immune response throughout the infection cycle in the CNS. Upon TC83 infection, many T cells rapidly (3-5 dpi) infiltrate the CNS in an antigen-independent manner. During infection, CD8+ T cells (∼40% of CNS-infiltrating T cells) in the brain express high levels of innate-memory markers. These bystander CD8+ T cells can produce IFNγ and granzyme B. IL12, IL18, and IL15 (cytokines known to support bystander T cells) are upregulated upon TC83 infection, and genetic ablation of IL15 results in decreased CNS infiltration by bystander CD8+ T cells. IC injection of IL15 alone recruits bystander CD8+ T cells, suggesting that IL15 is sufficient for CNS bystander responses. IC type 1 interferon (T1IFN) treatment recruits bystander CD8+ T cells and induces IL15 and IL12 expression, implicating T1IFN in the response. Interestingly, prior LCMV infection leads to CNS recruitment of bystander CD8+ T cells specific to LCMV epitopes. Finally, bystander CD8+ T cells cause CNS cell death, as antibody-mediated CD8+ T cell depletion decreases cleaved caspase 3 expression on neurons, astroglia, and microglia. These data implicate bystander CD8+ T cells in collateral CNS damage during viral infection. Funding Sources Supported by NIH T32-AI07405; NIH RO1-NS123431 Topic Categories Neuroimmunology (NEUR)