Retinoic acid prevents mesenteric lymph node dendritic cells from inducing IL-13-producing inflammatory Th2 cells.
The vitamin A (VA) metabolite retinoic acid (RA) affects the properties of T cells and dendritic cells (DCs). In VA-deficient mice, we observed that mesenteric lymph node (MLN)-DCs induce a distinct inflammatory T helper type 2 (Th2)-cell subset that particularly produces high levels of interleukin (IL)-13 and tumor necrosis factor-α (TNF-α). This subset expressed homing receptors for skin and inflammatory sites, and was mainly induced by B220(-)CD8α(-)CD11b(+)CD103(-) MLN-DCs in an IL-6- and OX40 ligand-dependent manner, whereas RA inhibited this induction. The corresponding MLN-DC subset of VA-sufficient mice induced a similar T-cell subset in the presence of RA receptor antagonists. IL-6 induced this subset differentiation from naive CD4(+) T cells upon activation with antibodies against CD3 and CD28. Transforming growth factor-β inhibited this induction, and reciprocally enhanced Th17 induction. Treatment with an agonistic anti-OX40 antibody and normal MLN-DCs enhanced the induction of general inflammatory Th2 cells. In VA-deficient mice, proximal colon epithelial cells produced TNF-α that may have enhanced OX40 ligand expression in MLN-DCs. The repeated oral administrations of a T cell-dependent antigen primed VA-deficient mice for IL-13-dependent strong immunoglobulin G1 (IgG1) responses and IgE responses that caused skin allergy. These results suggest that RA inhibits allergic responses to oral antigens by preventing MLN-DCs from inducing IL-13-producing inflammatory Th2 cells.
1] Laboratory of Immunology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Kagawa, Japan [2] JST, CREST, Tokyo, Japan.
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Yokota-Nakatsuma
1] Laboratory of Immunology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Kagawa, Japan [2] JST, CREST, Tokyo, Japan.
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Takeuchi
1] Laboratory of Immunology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Kagawa, Japan [2] JST, CREST, Tokyo, Japan.
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Ohoka
Institute of Neuroscience, Tokushima Bunri University, Kagawa, Japan.
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Kato
1] JST, CREST, Tokyo, Japan [2] Institute of Neuroscience, Tokushima Bunri University, Kagawa, Japan.
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Song
Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan.
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Hoshino
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
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Yagita
1] JST, CREST, Tokyo, Japan [2] Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
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Ohteki
1] Laboratory of Immunology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Kagawa, Japan [2] JST, CREST, Tokyo, Japan.
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Iwata
D000284:Administration, Oral; D000818:Animals; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology; D023201:CD40 Ligand / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D003106:Colon / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D007132:Immunoglobulin Isotypes / Q000276:immunology; D016130:Immunophenotyping; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D018793:Interleukin-13 / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology*; D008643:Mesentery / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010641:Phenotype; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014802:Vitamin A Deficiency / Q000276:immunology / Q000378:metabolism
D000941:Antigens; D016207:Cytokines; D007132:Immunoglobulin Isotypes; D018836:Inflammation Mediators; D018793:Interleukin-13; D018168:Receptors, Retinoic Acid; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D014212:Tretinoin