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Ahr in action: GPR15 is an orphan chemokine receptor that is critical for homing of CD4+ T cells to the large intestine, but regulation of GPR15 expression is not well understood. Xiong et al. identified a role for the aryl hydrocarbon receptor (Ahr) in driving expression of GPR15 in mice and humans. Ahr binds to open chromatin sites in the Gpr15 locus to enhance expression. In regulatory T cells (Tregs), the Foxp3 transcription factor can interact with Ahr to enhance binding to the Gpr15 locus and further increase expression. RORγt can compete with Ahr binding and inhibit GPR15 expression in Tregs and TH17 cells. These results reveal a mechanism by which GPR15 expression in CD4+ T cells is modulated by the Ahr-Foxp3-RORγt axis. 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 (Tregs) 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 Treg 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. [ABSTRACT FROM AUTHOR]