Srinivasan Saranya, Mishra Shruti, Fan Kenneth Ka-Ho, Wang Liwen, Im John, Segura Courtney, Mukherjee Neelam, Huang Gang, Rao Manjeet, Ma Chaoyu, Zhang Nu
Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
Gilead Sciences Inc, California, USA.
Aging Cell. 2025 Apr;24(4):e14461. doi: 10.1111/acel.14461. Epub 2024 Dec 18.
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.
衰老与免疫保护功能下降密切相关，但自身免疫和炎症性疾病的风险增加。调节性T细胞是维持免疫稳态的关键细胞之一。CD4Foxp3调节性T细胞（Tregs）随年龄变化的情况已有充分记载。然而，非冗余的Foxp3CD8 Tregs在衰老背景下从未被研究过。本研究首先明确区分了表型重叠的CD8 Tregs和虚拟记忆T细胞。然后，我们阐明了小鼠一生中CD8 Tregs的动态变化，并将研究进一步扩展到人类外周血单个核细胞（PBMCs）。在小鼠中，我们发现CD8CD44CD122Ly49 Tregs频率呈现双相动态变化，在年轻成年小鼠中稳步增加，在中年达到显著峰值，随后在老年小鼠中下降。转录组分析显示，小鼠CD8 Tregs随着年龄增长上调了一组选定的自然杀伤（NK）细胞相关基因，包括NKG2D。重要的是，NKG2D可能对CD8 Tregs起负调节作用。此外，通过分析人类PBMC的单细胞RNA测序数据集，我们发现了一个独特的CD8 Treg样亚群（簇10），其年龄依赖性频率变化和基因表达具有可比性，表明CD8 Treg在小鼠和人类中存在保守的衰老模式。总之，我们的研究结果突出了CD8 Tregs在免疫调节和衰老中的重要性。
