| First Author | Tani-Ichi S | Year | 2024 |
| Journal | J Immunol | Volume | 213 |
| Issue | 3 | Pages | 283-295 |
| PubMed ID | 39140825 | Mgi Jnum | J:359660 |
| Mgi Id | MGI:7711474 | Doi | 10.4049/jimmunol.2300450 |
| Citation | Tani-Ichi S, et al. (2024) A RORE-dependent Intronic Enhancer in the IL-7 Receptor-alpha Locus Controls Glucose Metabolism via Vgamma4+ gammadeltaT17 Cells. J Immunol 213(3):283-295 |
| abstractText | The IL-7R regulates the homeostasis, activation, and distribution of T cells in peripheral tissues. Although several transcriptional enhancers that regulate IL-7Ralpha expression in alphabeta T cells have been identified, enhancers active in gammadelta T cells remain unknown. In this article, we discovered an evolutionarily conserved noncoding sequence (CNS) in intron 2 of the IL-7Ralpha-chain (IL-7Ralpha) locus and named this region CNS9. CNS9 contained a conserved retinoic acid receptor-related orphan receptor (ROR)-responsive element (RORE) and exerted RORgammat-dependent enhancer activity in vitro. Mice harboring point mutations in the RORE in CNS9 (CNS9-RORmut) showed reduced IL-7Ralpha expression in IL-17-producing Vgamma4+ gammadelta T cells. In addition, the cell number and IL-17A production of Vgamma4+ gammadelta 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-7Ralpha expression in RORgammat+ regulatory T cells, whereas IL-7Ralpha expression was unaffected in RORgammat-expressing Vgamma2+ gammadelta T cells, Th17 cells, type 3 innate lymphoid cells, and invariant NKT cells. Our results indicate that CNS9 is a ROREpsilon-dependent, Vgamma4+ gammadelta T cell-specific IL-7Ralpha enhancer that plays a critical role in adipose tissue homeostasis via regulatory T cells, suggesting that the evolutionarily conserved ROREpsilon in IL-7Ralpha intron 2 may influence the incidence of type 2 diabetes. |
