Retinoic acid expression associates with enhanced IL-22 production by γδ T cells and innate lymphoid cells and attenuation of intestinal inflammation

J Exp Med. 2013 Jun 3;210(6):1117-24. doi: 10.1084/jem.20121588. Epub 2013 May 20.


Retinoic acid (RA), a vitamin A metabolite, modulates mucosal T helper cell responses. Here we examined the role of RA in regulating IL-22 production by γδ T cells and innate lymphoid cells in intestinal inflammation. RA significantly enhanced IL-22 production by γδ T cells stimulated in vitro with IL-1β or IL-18 and IL-23. In vivo RA attenuated colon inflammation induced by dextran sodium sulfate treatment or Citrobacter rodentium infection. This was associated with a significant increase in IL-22 secretion by γδ T cells and innate lymphoid cells. In addition, RA treatment enhanced production of the IL-22-responsive antimicrobial peptides Reg3β and Reg3γ in the colon. The attenuating effects of RA on colitis were reversed by treatment with an anti-IL-22 neutralizing antibody, demonstrating that RA mediates protection by enhancing IL-22 production. To define the molecular events involved, we used chromatin immunoprecipitation assays and found that RA promoted binding of RA receptor to the IL-22 promoter in γδ T cells. Our findings provide novel insights into the molecular events controlling IL-22 transcription and suggest that one key outcome of RA signaling may be to shape early intestinal immune responses by promoting IL-22 synthesis by γδ T cells and innate lymphoid cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / immunology
  • Citrobacter rodentium / immunology
  • Colitis / genetics
  • Colitis / immunology
  • Colon / immunology*
  • Colon / metabolism
  • Dextran Sulfate / adverse effects
  • Enterobacteriaceae Infections / genetics
  • Enterobacteriaceae Infections / immunology
  • Enterobacteriaceae Infections / metabolism
  • Inflammation / genetics
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Interleukins / biosynthesis
  • Interleukins / genetics
  • Interleukins / immunology*
  • Lymphocytes / immunology*
  • Lymphocytes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Promoter Regions, Genetic / genetics
  • Promoter Regions, Genetic / immunology
  • Protein Binding / genetics
  • Protein Binding / immunology
  • Receptors, Antigen, T-Cell, gamma-delta / genetics
  • Receptors, Antigen, T-Cell, gamma-delta / immunology*
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism
  • Receptors, Retinoic Acid / immunology
  • Receptors, Retinoic Acid / metabolism
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism
  • Transcription, Genetic / genetics
  • Transcription, Genetic / immunology
  • Tretinoin / immunology*
  • Tretinoin / metabolism


  • Antibodies, Neutralizing
  • Interleukins
  • Receptors, Antigen, T-Cell, gamma-delta
  • Receptors, Retinoic Acid
  • Tretinoin
  • Dextran Sulfate
  • interleukin-22