title: Retinoic acid expression associates with enhanced IL-22 production by γδ T cells and innate lymphoid cells and attenuation of intestinal inflammation.
abstract: 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.
authors.affiliation: Immunology Research Centre, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Mielke
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Jones
authors.forename: Mathilde
authors.initials: M
authors.lastname: Raverdeau
authors.forename: Rowan
authors.initials: R
authors.lastname: Higgs
authors.forename: Anna
authors.initials: A
authors.lastname: Stefanska
authors.forename: Joanna R
authors.initials: JR
authors.lastname: Groom
authors.forename: Alicja
authors.initials: A
authors.lastname: Misiak
authors.forename: Lara S
authors.initials: LS
authors.lastname: Dungan
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Sutton
authors.forename: Gundula
authors.initials: G
authors.lastname: Streubel
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Bracken
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D044082:Citrobacter rodentium / Q000276:immunology; D003092:Colitis / Q000235:genetics / Q000276:immunology; D003106:Colon / Q000276:immunology* / Q000378:metabolism; D016264:Dextran Sulfate / Q000009:adverse effects; D004756:Enterobacteriaceae Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology; D014212:Tretinoin / Q000276:immunology* / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D057134:Antibodies, Neutralizing; D016264:Dextran Sulfate; D007378:Interleukins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D000097043:Interleukin-22