Age-Dependent Bi-Phasic Dynamics of Ly49CD8 Regulatory T Cell Population.

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 CD4Foxp3 regulatory T cells (Tregs) have been well documented. However, the nonredundant Foxp3CD8 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 CD8CD44CD122Ly49 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.