IL-15 Fosters Age-Driven Regulatory T Cell Accrual in the Face of Declining IL-2 Levels.

We and others have shown that regulatory T cells (T-reg) accumulate dramatically with age in both humans and mice. Such T-reg accrual contributes to age-related immunosenescence as they reduce the response to tumors and parasite infection. While we reported earlier that aged T-reg have decreased expression of the pro-apoptotic molecule Bim and germline deletion of Bim promoted earlier accumulation of T-reg, it remains unclear whether the effects of Bim are: (i) Treg intrinsic and (ii) dominant to other BH3-only pro-apoptotic molecules. Further, the mechanism(s) controlling Bim expression in aged T-reg remain unclear. Here we show that T-reg-specific loss of Bim is sufficient to drive T-reg accrual with age and that additional loss of the downstream apoptotic effectors Bax and Bak did not exacerbate T-reg accumulation. Further, our results demonstrate that a subpopulation of T-reg expands with age and is characterized by lower expression of CD25 (IL-2R alpha) and Bim. Mechanistically, we found that IL-2 levels decline with age and likely explain the emergence of CD25(lo)Bim(lo) T-reg because T-reg in IL-2(-/-) mice are almost entirely comprised of CD25(lo)Bim(lo) cells, and 1152 neutralization increases CD25(lo)Bim(lo) T-reg in both young and middle-aged mice. Interestingly, the T-reg population in aged mice had increased expression of CD122(IL-2/IL-15FR beta)and neutralization or genetic loss of IL-15(-/-) led to less T-reg accrual with age. Further, the decreased T-reg accrual in middle-aged IL-15(-/-) mice was restored by the additional loss of Bim (IL-15(-/-)Bim(-/-)). Together, our data show that aging favors the accrual of CD25(lo) T-reg whose homeostasis is supported by IL-15 as IL-2 levels become limiting. These data have implications for manipulating T-reg to improve immune responses in the elderly.