Comprehensive profiling of aging immune system reveals clonal GZMK+ CD8 T cells as conserved hallmark of inflammaging
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Aging is associated with systemic chronic inflammation (inflammaging) that leads to impaired physiological functions and vulnerability to several diseases. However, underlying alterations in aged immune system resulting in gradual loss of immune fitness remain unclear. Using a combination of single-cell RNA/TCR/BCR-sequencing and extensive FACS/CyTOF-based validation, we comprehensively characterize age-associated alterations in immune cells in four mouse organs and human blood. We identified both organ-specific and common changes in immune cell populations and their transcriptional programs and found age-associated subpopulation of CD8+ T cells marked with expression of GZMK. The GZMK+ CD8+ T cells progressively accumulate in various tissues in old mice and show increased clonality shared across organs. These cells have a distinct epigenetic signature, express markers of exhaustion but, paradoxically, show an increased capacity to produce mediators of inflammation that can induce senescence-associated secretory phenotype (SASP) in stromal cells. In humans, we show that clonal GZMK+ CD8+ T cells are expanded during healthy aging and share transcriptional signature with mouse age-associated CD8+ T cells. Our findings suggest that accumulation of GZMK+ CD8+ T cells is a conserved hallmark of inflammaging.