IL-7R调节体内平衡,激活,以及T细胞在外周组织中的分布。尽管已经鉴定了几种调节αβT细胞中IL-7Rα表达的转录增强子,在γδT细胞中活跃的增强子仍然未知。在这篇文章中,我们在IL-7Rα链(IL-7Rα)基因座的内含子2中发现了一个进化上保守的非编码序列(CNS),并将该区域命名为CNS9。CNS9包含保守的视黄酸受体相关的孤儿受体(ROR)响应元件(RORE),并在体外发挥RORγt依赖性增强剂活性。在CNS9(CNS9-RORmut)的RORE中携带点突变的小鼠在产生IL-17的Vγ4γδT细胞中显示IL-7Rα表达降低。此外,CNS9-RORmut小鼠脂肪组织中Vγ4γδT细胞的细胞数量和IL-17A的产生减少。与IL-17A的减少一致,CNS9-RORmut小鼠脂肪组织中IL-33表达降低,导致较少的调节性T细胞和葡萄糖耐受不良。CNS9-ROR基序部分负责RORγt+调节性T细胞中IL-7Rα的表达,而IL-7Rα表达在RORγt表达Vγ2+γδT细胞中不受影响,Th17细胞,3型先天淋巴细胞,和不变的NKT细胞。我们的结果表明,CNS9是RORE依赖的,Vγ4+γδT细胞特异性IL-7Rα增强子,通过调节性T细胞在脂肪组织稳态中起关键作用,提示IL-7Rα内含子2中进化保守的RORE可能影响2型糖尿病的发病率。
The IL-7R regulates the homeostasis, activation, and distribution of T cells in peripheral tissues. Although several transcriptional enhancers that regulate IL-7Rα expression in αβ T cells have been identified, enhancers active in γδ T cells remain unknown. In this article, we discovered an evolutionarily conserved noncoding sequence (CNS) in intron 2 of the IL-7Rα-chain (IL-7Rα) locus and named this region CNS9. CNS9 contained a conserved retinoic acid receptor-related orphan receptor (ROR)-responsive element (RORE) and exerted RORγt-dependent enhancer activity in vitro. Mice harboring point mutations in the RORE in CNS9 (CNS9-RORmut) showed reduced IL-7Rα expression in IL-17-producing Vγ4+ γδ T cells. In addition, the cell number and IL-17A production of Vγ4+ γδ 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-7Rα expression in RORγt+ regulatory T cells, whereas IL-7Rα expression was unaffected in RORγt-expressing Vγ2+ γδ T cells, Th17 cells, type 3 innate lymphoid cells, and invariant NKT cells. Our results indicate that CNS9 is a RORΕ-dependent, Vγ4+ γδ T cell-specific IL-7Rα enhancer that plays a critical role in adipose tissue homeostasis via regulatory T cells, suggesting that the evolutionarily conserved RORΕ in IL-7Rα intron 2 may influence the incidence of type 2 diabetes.