Interactions between the T cell receptor and its cognate epitope determine memory CD8+ T cell functional fates 3107

Abstract Description Effective CD8+ T cell priming requires T cell receptor (TCR) recognition of cognate antigen, costimulation, and inflammatory signals, which leads to clonal expansion, potent effector functions, and memory CD8+ T (TM) cells. While stronger cognate antigen signals drive larger primary effector and memory pools, the current dogma is that changes to TCR stimulation do not affect CD8+ TM cell functions. We used transgenic TCR mouse models, flow cytometry, epigenetic profiling, and adoptive T cell transfers to investigate if modulating TCR interactions with its cognate antigen impacts the phenotypic and functional characteristics of CD8+ TM cells. By mutating specific residues in model epitopes, we reveal that altering TCR interactions with its cognate epitope, but not decreasing TCR signaling strength, changes the fates of CD8+ TM cells. These cells demonstrated increased expression of central/stem cell TM cell (TCM/TSCM) markers (e.g., CD62L, EOMES, BCL2), enhanced chromatin accessibility in stemness-related genes (e.g., Lef1, Bcl6), and superior functions such as greater ability to re-expand, generate diverse progeny, and clear pathogens. Our findings show TCR signaling is a major driver of CD8+ T cell differentiation and dictates TM cell functional programming. This work challenges the notion that stronger epitopes are the most effective in inducing long-lasting TM cells, potentially reshaping our thinking of epitope selection for vaccine design and adoptive T cell therapies. Funding Sources Supported by NIH T32GM7288 and NIH/NIAID F31AI172421 Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)