IL-15 trans-presentation regulates homeostasis of CD4(+) T lymphocytes

Interleukin-15 (IL-15) is essential for the survival of memory CD8(+) and CD4(+) T cell subsets, and natural killer and natural killer T cells. Here, we describe a hitherto unreported role of IL-15 in regulating homoeostasis of naive CD4(+) T cells. Adoptive transfer of splenocytes from non-obese diabetic (NOD) mice results in increased homeostatic expansion of T cells in lymphopenic NOD.scid.Il15(-/-) mice when compared to NOD.scid recipients. The increased accumulation of CD4(+) T cells is also observed in NOD.Il15(-/-) mice, indicating that IL-15-dependent regulation also occurs in the absence of lymphopenia. NOD.scid mice lacking the IL-15Rα chain, but not those lacking the common gamma chain, also show increased accumulation of CD4(+) T cells. These findings indicate that the IL-15-mediated regulation occurs directly on CD4(+) T cells and requires trans-presentation of IL-15. CD4(+) T cells expanding in the absence of IL-15 signaling do not acquire the characteristics of classical regulatory T cells. Rather, CD4(+) T cells expanding in the absence of IL-15 show impaired antigen-induced activation and IFN-γ production. Based on these findings, we propose that the IL-15-dependent regulation of the naive CD4(+) T-cell compartment may represent an additional layer of control to thwart potentially autoreactive cells that escape central tolerance, while permitting the expansion of memory T cells.