Aging Cell: Age-Dependent Bi-Phasic Dynamics of Ly49+CD8+ Regulatory T Cell Population (Rao)

ACELSaranya SrinivasanShruti MishraKenneth Ka-Ho FanLiwen WangJohn ImCourtney SeguraNeelam MukherjeeGang HuangManjeet RaoChaoyu MaNu Zhang

ABSTRACT

Aging is tightly associated with reduced immune protection but increased risk of autoimmunity and inflammatory conditions. Regulatory T cells are one of the key cells to maintaining immune homeostasis. The age-dependent changes in CD4+Foxp3+ regulatory T cells (Tregs) have been well documented. However, the nonredundant Foxp3−CD8+ Tregs were never examined in the context of aging. This study first established clear distinctions between phenotypically overlapping CD8+ Tregs and virtual memory T cells. Then, we elucidated the dynamics of CD8+ Tregs across the lifespan in mice and further extended our investigation to human peripheral blood mononuclear cells (PBMCs). In mice, we discovered a bi-phasic dynamic shift in the frequency of CD8+CD44hiCD122hiLy49+ Tregs, with a steady increase in young adults and a notable peak in middle age followed by a decline in older mice. Transcriptomic analysis revealed that mouse CD8+ Tregs upregulated a selected set of natural killer (NK) cell-associated genes, including NKG2D, with age. Importantly, NKG2D might negatively regulate CD8+ Tregs. Additionally, by analyzing a scRNA-seq dataset of human PBMC, we found a distinct CD8+ Treg-like subset (Cluster 10) with comparable age-dependent frequency changes and gene expression, suggesting a conserved aging pattern in CD8+ Treg across mice and humans. In summary, our findings highlight the importance of CD8+ Tregs in immune regulation and aging.

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