Ahr-Foxp3-RORγt axis controls gut homing of CD4+ T cells by regulating GPR15.

Lifeng Xiong, Joseph W Dean, Zheng Fu, Kristen N Oliff, John W Bostick, Jian Ye, Zongming E Chen, Marcus Mühlbauer, Liang Zhou

Science immunology 2020 Jun 12

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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. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Citation

Lifeng Xiong, Joseph W Dean, Zheng Fu, Kristen N Oliff, John W Bostick, Jian Ye, Zongming E Chen, Marcus Mühlbauer, Liang Zhou. Ahr-Foxp3-RORγt axis controls gut homing of CD4+ T cells by regulating GPR15. Science immunology. 2020 Jun 12;5(48)