A RORE-dependent Intronic Enhancer in the IL-7 Receptor-a Locus Controls Glucose Metabolism via Vg4⁺ gdT17 Cells

The IL-7R regulates the homeostasis, activation, and distribution of T cells in peripheral tissues. Although several transcriptional enhancers that regulate IL-7Ra expression in ab T cells have been identified, enhancers active in gd T cells remain unknown. In this article, we discovered an evolutionarily conserved noncoding sequence (CNS) in intron 2 of the IL-7Ra-chain (IL-7Ra) locus and named this region CNS9. CNS9 contained a conserved retinoic acid receptor-related orphan receptor (ROR)-responsive element (RORE) and exerted RORgt-dependent enhancer activity in vitro. Mice harboring point mutations in the RORE in CNS9 (CNS9-RORmut) showed reduced IL-7Ra expression in IL-17-producing Vg4⁺ gd T cells. In addition, the cell number and IL-17A production of Vg4⁺ gd T cells were reduced in the adipose tissue of CNS9-RORmut mice. Consistent with the reduction in IL-17A, CNS9-RORmut mice exhibited decreased IL-33 expression in the adipose tissue, resulting in fewer regulatory T cells and glucose intolerance. The CNS9-ROR motif was partially responsible for IL-7Ra expression in RORgt⁺ regulatory T cells, whereas IL-7Ra expression was unaffected in RORgt-expressing Vg2⁺ gd T cells, Th17 cells, type 3 innate lymphoid cells, and invariant NKT cells. Our results indicate that CNS9 is a RORE-dependent, Vg4⁺ gd T cell-specific IL-7Ra enhancer that plays a critical role in adipose tissue homeostasis via regulatory T cells, suggesting that the evolutionarily conserved RORE in IL-7Ra intron 2 may influence the incidence of type 2 diabetes.