A genome-wide analysis identifies a Notch-RBP-Jk-IL-7Ra axis that controls IL-17-Producing γδ T cell homeostasis in mice

Notch signaling is an important regulator for the development and function of both ab and γδ T cells, whereas roles of Notch signaling in T cell maintenance remain unclear. We reported previously that the Notch-Hes1 pathway was involved in the intrathymic development of naturally occurring IL-17-producing (IL-17+) γδ T cells. To gain insight into additional roles for the Notch axis in the homeostasis of γδ T cells, we performed a genome-wide analysis of Notch target genes and identified the novel promoter site of IL-7Ra driven by the Notch-RBP-Jk pathway. Constitutive Notch signaling had the potential to induce IL-7Ra expression on γδ T cells in vivo, as well as in vitro, whereas conditional deletion of RBP-Jk abrogated IL-7Ra expression, but not Hes1 expression, by γδ T cells and selectively reduced the pool size of IL-7Rahigh IL-17+ γδ T cells in the periphery. In the absence of IL-7Ra-mediated signaling, IL-17+ γδ T cells were barely maintained in adult mice. Addition of exogenous IL-7 in vitro selectively expanded IL-17+ γδ T cells. Thus, our results revealed a novel role for the Notch-RBP-Jk-IL-7Ra axis that is independent of Hes1 for homeostasis of IL-17+ γδ T cells.