NKT cells require IL-7, not IL-15, for survival and homeostasis (LYM4P.761)

Abstract NKT cells are thymus-generated T lineage cells with shared phenotypic and functional characteristics of innate NK cells. Both T and NK cells require γc cytokines for their survival and homeostasis with T cells being dependent on IL-7 while NK cells being dependent on IL-15. As NKT cells carry features of both T and NK cells, it has been a long standing question which γc cytokine would drive the survival and homeostasis of NKT cells. In contrast to the current view, here we report that NKT cells survival is not dependent on IL-15 but requires IL-7. Specifically, we found that IL-15-deficient mice have intact numbers of peripheral NKT cells and that overexpression of IL-15 failed to expand NKT cell numbers even as it significantly increased CD8 T cell numbers. On the other hand, using a new in vivo model of IL-7-deficiency selectively in peripheral lymphoid tissues (K7 mice), we demonstrated that IL-7 is a non-redundant survival factor for NKT cells. Furthermore, transgenic IL-7 expression dramatically increased peripheral NKT cell numbers, suggesting that IL-7 availability determines size of the NKT cell pool. Mechanistically, we identified STAT5 as the transcriptional effector molecule downstream of IL-7 signaling to promote survival and maintain NKT cell homeostasis. Collectively, these data provide a new perspective on γc cytokine requirements for NKT cell survival, proposing a new role for IL-7 in NKT cell biology.