IL-15 receptor α signaling constrains the development of IL-17-producing γδ T cells

The development and homeostasis of gamma delta T cells is highly dependent on distinct cytokine networks. Here we examine the role of IL-15 and its unique receptor, IL-15R alpha, in the development of IL-17-producing gamma delta (gamma delta-17) T cells. Phenotypic analysis has shown that CD44(high)gamma delta-17 cells express IL-15R alpha and the common gamma chain (CD132), yet lack the IL-2/15R beta chain (CD122). Surprisingly, we found an enlarged population of gamma delta-17 cells in the peripheral and mesenteric lymph nodes of adult IL-15R alpha KO mice, but not of IL-15 KO mice. The generation of mixed chimeras from neonatal thymocytes indicated that cell-intrinsic IL-15R alpha expression was required to limit IL-17 production by gamma delta T cells gamma delta-17 cells also were increased in the peripheral lymph nodes of transgenic knock-in mice, where the IL-15R alpha intracellular signaling domain was replaced with the intracellular portion of the IL-2R alpha chain (that lacks signaling capacity). Finally, an analysis of neonatal thymi revealed that the CD44(lo/int) precursors of gamma delta-17 cells, which also expressed IL-15R alpha, were increased in newborn mice deficient in IL-15R alpha signaling, but not in IL-15 itself. Thus, these findings demonstrate that signaling through IL-15R alpha regulates the development of gamma delta-17 cells early in ontogeny, with long-term effects on their peripheral homeostasis in the adult.