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

Abstract

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 diŠerentiation of regulatory T cells expressing forkhead box P3. We found that MLN-DCs from VA-deˆcient mice induced a distinct in‰ammatory T helper type 2 (Th2)-cell subset that produced abundant interleukin-13 (IL-13) and expressed receptors for homing to skin and in‰ammatory 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-su‹cient mice to induce a similar T-cell subset. IL-6 induced the diŠerentiation 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 deˆciency reduces Th2-dependent antibody responses. However, oral administration of an antigen to VA-deˆcient 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 in‰ammatory Th2 cells and that RA prevents them from inducing IL-13-dependent allergic or in‰ammatory responses to orally administered antigens.

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“…ATRA can only bind to RARs, while 9-cis retinoic acid can bind to both RARs and RXRs, indicating that both ATRA and 9-cis retinoic acid can transmit signals through RARs to downstream regulatory effects [42]. The effect of RA on IL-13 may be tissue-speci c. On the one hand, RA can prevent dendritic cells in the mesenteric lymph nodes (MLN-DCs) from inducing the production of IL-13 by in ammatory Th2 cells [43,44]. However, it was also found that ATRA and 9-cis RA promote the synthesis of IL-4, IL-5, and IL-13 in PBMC cells [42].…”