AUTHOR=Raynor Jana , Sholl Allyson , Plas David R., Bouillet Philippe , Chougnet Claire A., Hildeman David A.

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

JOURNAL=Frontiers in Immunology

VOLUME=4

YEAR=2013

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2013.00161

DOI=10.3389/fimmu.2013.00161

ISSN=1664-3224

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