Retinoic acid prevents mesenteric lymph node dendritic cells from inducing IL-13-producing inflammatory Th2 cells

Abstract

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.

T helper subsets in allergic eye disease

“…Evidence from our lab has pointed to a key role for CD11b + DCs in ocular allergy pathogenesis (25–28). This is consistent with what has been reported in allergic airway inflammation (71–75). Recent work from Medzhitov and colleagues has suggested a role for IRF4 expression by DCs inmediating Th2 activity, although the exact DC subset governed in this manner is not completely known (76).…”

All-trans retinoic acid prevents the development of type 1 diabetes by affecting the levels of interferon gamma and interleukin 4 in streptozotocin-induced murine diabetes model

“…Increased ATRA levels induce IL-4 gene expression in myelin basic protein-specific T cells, which consequently express a Th1-like phenotype (Lovett-Racke and Racke, 2002), while ATRA deficiency has been found to result in an increase in the number of Th1 cells (Nozaki et al, 2006). Retinoic acid has been shown to delay the differentiation and maturation of dendritic cells, reduce the activity of lymphocyte reaction, reduce Thl cytokine production, and increase Th2 cytokines, thereby causing a shift of the immune response to Th2 (Bai et al, 2010;Wansley et al, 2013;Wu et al, 2013;Yokota-Nakatsuma et al, 2014). These observations suggest that ATRA regulates the Th1/Th2 balance by regulating the expression of cytokines, specifically by inhibiting Th1 cell activity and elevating the number of Th2 cells.…”

The Influence of the Microbiome on Allergic Sensitization to Food

“…In support of this model, in the absence of gut homing, or in animals lacking CX3CR1 macrophages, oral tolerance is abrogated (41). Other work shows that oral antigen exposure induces an allergic phenotype in mice with vitamin A deficiency (43). RA deficient mLN DCs drive naïve T cells towards a pathogenic Th2 phenotype instead of Tregs (43).…”

“…Other work shows that oral antigen exposure induces an allergic phenotype in mice with vitamin A deficiency (43). RA deficient mLN DCs drive naïve T cells towards a pathogenic Th2 phenotype instead of Tregs (43). Collectively, this data supports the concept that food antigen specific Tregs are critical for protection from dietary allergies (41, 42).…”