The aryl hydrocarbon receptor regulates expression of mucosal trafficking receptor GPR15

GPR15 is a chemoattractant receptor that facilitates colon homing of regulatory and effector CD4⁺ T cells in health and colitis. The molecular mechanisms that control GPR15 expression are not fully known. Here we report the presence of two highly conserved aryl hydrocarbon receptor (AHR) binding sequences in a 3' enhancer of GPR15, leading us to investigate AHR function in regulating GPR15 expression. Using luciferase reporter assays, we show that AHR activation increased GPR15 expression and requires both the AHR binding sites. Consistent with a transcriptional regulatory role, treatment with AHR agonists induce GPR15 expression on human CD4⁺ T cells. Using AHR-deficient mice, we demonstrate that the lack of AHR signaling drastically reduces GPR15 expression on effector/memory and Foxp3⁺ CD4⁺ T cells. In mixed bone marrow chimeras of AHR-deficient and wildtype cells, GPR15 expression was similarly diminished on AHR-deficient CD4⁺ effector/memory and regulatory T cells in the colon and small intestine. Furthermore, administration of AHR agonists upregulated GPR15 expression on CD4⁺ effector/memory T cells and increased their homing capability, especially to the colon. Collectively, our studies reveal a novel function of the AHR in regulation of GPR15 expression and increased colon trafficking of CD4⁺ T cells expressing GPR15.