Retinoic acid (RA) is produced from vitamin A (retinol) via a two-step enzymatic pathway that oxidizes retinol to retinaldehyde and then retinaldehyde to RA. Oxidation of retinol to retinaldehyde requires the activities of several alcohol dehydrogenases (ADH-1,-4,-5) and subsequently, retinaldehyde is oxidized to retinoic acid by retinal dehydrogenases (RALDH). RA produced by DCs acts on T- and B-lymphocytes, and induces the mucosal homing receptors α4β7-integrin, and CCR9. RA in the presence of TGF-β promotes the conversion of naïve T cells in to Foxp3+ regulatory T cells, and at high concentration inhibits the differentiation of Th-17 cells. In addition, RA synergizes with IL-6 and IL-5 and promotes class switching to IgA in B cells.

Recent studies show the existence of multiple subsets of antigen-presenting cells in the lamina propria (LP), mesenteric lymph node (MLN) and Peyers patches (PP). In the lamina propria CD11b⁺ intestinal macrophages induce the differentiation of Foxp3+ regulatory T cells via retinoic acid, via a mechanism dependent on both RA and IL-10[52] and these cells can also inhibit the induction of Th-17 responses induced by CD11b+ DCs in the lamina propria [52,56]. In contrast, it has also been shown that lamina propria DCs induce Foxp3+ T regulatory cells [51]. In the MLN, CD103⁺ DCs that produce RA promote the differentiation of Foxp3+ regulatory T cells [49], as well as IgA-secreting B cells [64]. In contrast, CD103⁻ DCs in the MLN do not promote Foxp3+ T regulatory cells, but can be stimulated to produce greater levels of the pro-inflammatory cytokines TNF-α, IL-6, IL-12p40 and IL-23 [49], raising the possibility that they may induce Th1/Th17 responses. In the PP, CD11c⁺CD11b⁻CD8α⁺ DCs can be induced to secrete high amounts of IL-12p70 promote Th1 responses [43,74,75]; in contrast, CD11c⁺CD11b⁺CD8α⁻ DCs secrete high amounts of IL-10 promote Th2 responses [43,74,75]. Solid lines represent published data. Dotted lines represent speculations.