Non-specific cytotoxicity of aged memory CD8 T cells drives excessive tissue damage 3669

Abstract Description Aging profoundly impacts the immune system, yet the underlying mechanisms driving age-related immunopathologies remain poorly understood. Previous studies have demonstrated that CD8 T cells undergo significant remodeling with age, where memory CD8 T cells largely replace the naïve cells and form two distinct subsets defined by PD1 expression. However, the data connecting these cells to physiological outcomes remained scarce. In this study, we report striking functional differences between young and aged PD1- memory CD8 T cells. We found that aged PD1- memory CD8 T cells lose antigen specificity upon activation and engage in MHC I-independent killing. Despite lacking canonical surface markers of activated or effector T cells, aged PD1- memory CD8 T cells exhibit a transcriptional profile and surface markers resembling pathogenic CXCR6+ CD8 T cells, known mediators of liver damage in the NASH model. In aged mice, these pathogenic cells accumulate systemically and drive widespread tissue damage. Mechanistically, this process is mediated by Fas-FasL interactions and regulated by IL-15 in an antigen-independent manner. This novel cellular mechanism offers a potential explanation for the extensive tissue damage observed in elderly individuals during inflammatory conditions and underscores the therapeutic potential of targeting CD8 T cells to mitigate age-associated diseases. Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)