The orphan chemoattractant receptor GPR15 is important for homing T lymphocytes to the large intestine, thereby maintaining intestinal immune homeostasis. However, the molecular mechanisms underlying the regulation of GPR15 expression remain elusive. Here, we show a central role of the aryl hydrocarbon receptor (Ahr) in promoting GPR15 expression in both mice and human, thus gut homing of T lymphocytes. Mechanistically, Ahr directly binds to open chromatin regions of the Gpr15 locus to enhance its expression. Ahr transcriptional activity in directing GPR15 expression was modulated by two transcription factors, Foxp3 and RORγt, both of which are expressed preferentially by gut regulatory T cells (T_regs) in vivo. Specifically, Foxp3 interacted with Ahr and enhanced Ahr DNA binding at the Gpr15 locus, thereby promoting GPR15 expression. In contrast, RORγt plays an inhibitory role, at least in part, by competing with Ahr binding to the Gpr15 locus. Our findings thus demonstrate a key role for Ahr in regulating T_reg intestinal homing under the steady state and during inflammation and the importance of Ahr-RORγt-Foxp3 axis in regulating gut homing receptor GPR15 expression by lymphocytes.

孤儿趋化因子受体GPR15对于将T淋巴细胞归巢至大肠非常重要，从而保持了肠的免疫稳态。但是，GPR15表达调控的分子机制仍然难以捉摸。在这里，我们展示了芳烃受体（Ahr）在促进小鼠和人类GPR15表达中的中心作用，从而促进了T淋巴细胞的肠道归巢。机械上，Ahr直接结合到Gpr15基因座的开放染色质区域，以增强其表达。指导GPR15表达的Ahr转录活性受到两个转录因子Foxp3和RORγt的调节，二者均优先由肠道调节性T细胞（T _regs）体内。具体而言，Foxp3与Ahr相互作用并增强了Ghr15基因座上的Ahr DNA结合，从而促进了GPR15的表达。相反，RORγt至少部分地通过与与Ghr15基因座结合的Ahr竞争而发挥抑制作用。因此，我们的发现证明了Ahr在稳定状态和炎症过程中在调节T _reg肠归巢中的关键作用，以及Ahr-RORγt-Foxp3轴在调节淋巴细胞的肠道归巢受体GPR15表达中的重要性。