Defining molecular gene profiles that underpin superior virus-specific CD8+ T cell immunity in nonagenarian and centenarians 3494

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Abstract Description Centenarians and nonagenarians exemplify healthy aging, yet it is unknown whether longevity is linked to optimal anti-viral immunity. We defined anti-viral immunity in centenarians and nonagenarians and compared to children, adults and older adults to understand transcriptional profiles of epitope-specific CD8+ T cells in long-lived nonagenarians and centenarians to gain insight on their reduced susceptibility to life-threatening viral infections. We performed scRNAseq and measured the cell-surface proteome of CD8+ T cells specific for peptide/HLA-I tetramers for influenza A and B, SARS-CoV-2, EBV and CMV to define epitope-specific CD8+ T cells from children (5-15y), adults (24-39y), older adults (68-75y) and long-lived individuals (93-102y) to establish their key transcriptomic and protein signatures. Our analyses of virus-specific CD8+ T cell trajectory across age groups revealed more differentiated memory CD8+ T cell subsets in centenarians and nonagenarians that had unique transcriptomic signatures. Strikingly, 90+ year olds displayed differential clustering of terminally differentiated CD8+ T cells. Unique age-specific signatures were also observed for epitope-specific CD8+ T cell populations in both chronic and acute viruses. We identified immune profiles for virus-specific CD8+ T cells across the human lifespan and provide key insights into biomarkers associated with healthy immune aging that may identify potential therapeutic targets to reduce disease severity. Funding Sources National Health and Medical Research Council (NHMRC), Australian Research Council (ARC). Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)

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