IL-15 fostersage-driven regulatory T cell accrual in the face of declining IL-2 levels

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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) T reg 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-2Rα) 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 IL-2 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-15Rβ) 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 CD25lo 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. © 2013 Raynor, Sholl, Plas, Bouillet, Chougnet and Hildeman.

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Raynor, J., Sholl, A., Plas, D. R., Bouillet, P., Chougnet, C. A., & Hildeman, D. A. (2013). IL-15 fostersage-driven regulatory T cell accrual in the face of declining IL-2 levels. Frontiers in Immunology, 4(JUN).

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