[Retinoic Acid Prevents Dendritic Cells from Inducing Novel Inflammatory T Cells That Produce Abundant Interleukin-13].

Vitamin A (VA) plays critical roles in gut homeostasis. Dendritic cells in mesenteric lymph nodes (MLN-DCs) can metabolize VA to retinoic acid (RA), thereby inducing gut-tropic lymphocytes and enhancing peripheral differentiation of regulatory T cells expressing forkhead box P3. We found that MLN-DCs from VA-deficient mice induced a distinct inflammatory T helper type 2 (Th2)-cell subset that produced abundant interleukin-13 (IL-13) and expressed receptors for homing to skin and inflammatory sites but not to the intestine. IL-6-neutralizing antibodies or RA abrogated the induction of this subset. On the other hand, RA receptor antagonists allowed MLN-DCs from VA-sufficient mice to induce a similar T-cell subset. IL-6 induced the differentiation of this subset from naive CD4 ⁺ T cells upon activation with antibodies against CD3 and CD28, and RA receptor antagonists enhanced this induction. It has been considered that VA deficiency reduces Th2-dependent antibody responses. However, oral administration of an antigen to VA-deficient mice failed to induce immune tolerance but primed strong IL-13-dependent immunoglobulin G1 (IgG1) responses and IgE responses that caused skin allergy. These results suggest that MLN-DCs possess the latent ability to induce IL-13-producing inflammatory Th2 cells and that RA prevents them from inducing IL-13-dependent allergic or inflammatory responses to orally administered antigens.