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

Sci Immunol. 2020 Jun 12;5(48):eaaz7277. doi: 10.1126/sciimmunol.aaz7277.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • Female
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology*
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology*
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / immunology*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / immunology*
  • Receptors, Peptide / genetics
  • Receptors, Peptide / immunology*


  • AHR protein, human
  • Ahr protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • GPR15 protein, human
  • Gpr15 protein, mouse
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RORC protein, human
  • Receptors, Aryl Hydrocarbon
  • Receptors, G-Protein-Coupled
  • Receptors, Peptide
  • Rorc protein, mouse