title: Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens.
abstract: Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens. A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte antigen (HLA) HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T-cell and antibody responses against dietary gluten, a protein present in wheat. The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, has been shown to have a critical role in the induction of intestinal regulatory responses. Here we find in mice that in conjunction with IL-15, a cytokine greatly upregulated in the gut of coeliac disease patients, retinoic acid rapidly activates dendritic cells to induce JNK (also known as MAPK8) phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings reveal an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: DePaolo
authors.forename: V
authors.initials: V
authors.lastname: Abadie
authors.forename: F
authors.initials: F
authors.lastname: Tang
authors.forename: H
authors.initials: H
authors.lastname: Fehlner-Peach
authors.forename: J A
authors.initials: JA
authors.lastname: Hall
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.forename: E V
authors.initials: EV
authors.lastname: Marietta
authors.forename: D D
authors.initials: DD
authors.lastname: Kasarda
authors.forename: T A
authors.initials: TA
authors.lastname: Waldmann
authors.forename: J A
authors.initials: JA
authors.lastname: Murray
authors.forename: C
authors.initials: C
authors.lastname: Semrad
authors.forename: S S
authors.initials: SS
authors.lastname: Kupfer
authors.forename: Y
authors.initials: Y
authors.lastname: Belkaid
authors.forename: S
authors.initials: S
authors.lastname: Guandalini
authors.forename: B
authors.initials: B
authors.lastname: Jabri
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000818:Animals; D002446:Celiac Disease / Q000139:chemically induced / Q000209:etiology / Q000276:immunology*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D004032:Diet; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005903:Gliadin / Q000008:administration & dosage / Q000276:immunology; D005983:Glutens / Q000008:administration & dosage / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007249:Inflammation / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology*; D053759:Interleukin-23 / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D053707:Receptors, Interleukin-12 / Q000172:deficiency; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014212:Tretinoin / Q000276:immunology / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D019409:Interleukin-15; D053759:Interleukin-23; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D014212:Tretinoin; D005983:Glutens; D005903:Gliadin; D048055:Mitogen-Activated Protein Kinase 8