Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens

摘要

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 counter-example is celiac disease, where genetically susceptible individuals expressing 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, was shown to play a critical role in the induction of intestinal regulatory responses^–. We found that in conjunction with IL-15, a cytokine greatly upregulated in the gut of celiac disease patients, retinoic acid rapidly activated dendritic cells to induce JNK 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 unveil an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens.