Aryl Hydrocarbon Receptor Signaling Cell Intrinsically Inhibits Intestinal Group 2 Innate Lymphoid Cell Function

Immunity. 2018 Nov 20;49(5):915-928.e5. doi: 10.1016/j.immuni.2018.09.015. Epub 2018 Nov 13.


Innate lymphoid cells (ILCs) are important for mucosal immunity. The intestine harbors all ILC subsets, but how these cells are balanced to achieve immune homeostasis and mount appropriate responses during infection remains elusive. Here, we show that aryl hydrocarbon receptor (Ahr) expression in the gut regulates ILC balance. Among ILCs, Ahr is most highly expressed by gut ILC2s and controls chromatin accessibility at the Ahr locus via positive feedback. Ahr signaling suppresses Gfi1 transcription-factor-mediated expression of the interleukin-33 (IL-33) receptor ST2 in ILC2s and expression of ILC2 effector molecules IL-5, IL-13, and amphiregulin in a cell-intrinsic manner. Ablation of Ahr enhances anti-helminth immunity in the gut, whereas genetic or pharmacological activation of Ahr suppresses ILC2 function but enhances ILC3 maintenance to protect the host from Citrobacter rodentium infection. Thus, the host regulates the gut ILC2-ILC3 balance by engaging the Ahr pathway to mount appropriate immunity against various pathogens.

Keywords: Ahr; IL-33; ILC; ST2; chromatin; gene expression; gut immunity.

Publication types

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

MeSH terms

  • Animals
  • Biomarkers
  • Chromatin / genetics
  • Chromatin / metabolism
  • Citrobacter rodentium / immunology
  • Enterobacteriaceae Infections / immunology
  • Enterobacteriaceae Infections / microbiology
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Genetic Loci
  • Host-Parasite Interactions / immunology
  • Immunity, Innate*
  • Immunity, Mucosal / genetics
  • Immunophenotyping
  • Interleukin-1 Receptor-Like 1 Protein / metabolism
  • Interleukin-33 / metabolism
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Lymphocyte Subsets / immunology*
  • Lymphocyte Subsets / metabolism*
  • Mice
  • Mice, Knockout
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Transcriptome


  • Biomarkers
  • Chromatin
  • Il1rl1 protein, mouse
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Receptors, Aryl Hydrocarbon