Transcriptional Profile of CD8+ Tregs during aging

Aging is a complex biological process that impacts various physiological functions, including the immune system. Our study investigated the impact of aging on CD8+ regulatory T cells (CD8+ Tregs), which showed a pattern of initial increase up to 12 months, then a decline by 24 months in a C57BL/6 mouse model, unlike memory T cells, which consistently increase with age. Functionally, CD8+ Tregs, irrespective of age, did not produce cytokines in response to TCR stimulation, highlighting a stark functional contrast with memory cells. However, upon IL-15 stimulation, CD8+ Tregs, unlike their memory cell counterparts, demonstrated enhanced cytokine production. Transcriptomic analysis revealed an abundance of Klrk1 (killer cell lectin-like receptor subfamily K member 1) gene transcripts in aging CD8+Tregs. Klrk1 gene encodes Natural Killer Group 2 Member D (NKG2D), an activating receptor NK cells express. This upregulation was specific to CD8+CD122hiLy49+ and absent in CD8+CD122hiLy49-. To explore this correlation further, we utilized a Klrk1-/- mouse and observed an increased CD8+Treg population, suggesting a potential negative regulatory role of NKG2D in CD8+Treg homeostasis. These findings provide critical insights into the aging immune system and underscore the importance of CD8+ Tregs in immune regulation and aging.