Hence, immunoregulation may revolve around highly specific host–microbial molecular interactions, presumably reflecting a long and intimate co-evolution of the symbiotic relationship. The vitamin A metabolite, retinoic acid (RA), plays a major role in the GI tract, via its capacity to enhance the TGF-β-mediated generation of forkhead box P3 (FoxP3+) Tregs from naive T cells by gut DCs [42]. Reciprocally, RA can inhibit the generation of Th17 cells [43], suggesting that it may play an important role in maintaining the balance between effector and regulatory populations in the GI tract. Several populations of mucosal APC can induce Tregs via RA,

although only the CD103 subset is equipped with the enzymatic machinery to generate RA. Retinoic acid can also imprint gut homing AUY-922 molecules on various populations of lymphocytes. Defined microenvironments may have evolved self-contained strategies in which local mediators (such as RA) can imprint homing properties while also favouring the induction or function of Tregs. It is therefore tempting to speculate PKC inhibitor that a link between homing and regulatory function induction may represent a more general mechanism.

Such a strategy could allow the constant generation and migration of Tregs to defined compartments. These Tregs would be expected to have the prerequisite antigen specificities (e.g. persistent microorganisms, flora antigens), status of activation and survival requirement that many allow them to regulate a defined microenvironment. Although the capacity of gut-associated lymphoid tissue (GALT) DCs or macrophages to imprint gut-homing receptors and induce FoxP3+ Tregs is associated with their capacity to release RA, it remains unclear if these cells are the main producers of this metabolite in the gut. Synthesis of RA from stored or dietary retinol depends on

the direct expression of the appropriate enzymes by GALT DCs. Certainly, DCs from Peyer’s patches and mesenteric lymph nodes (MLNs) express Aldh1a1 and Aldh1a2, respectively, and CD103+ DCs from the lamina propria express a large array of this family of enzymes; moreover, Peyer’s patch and MLN DCs can convert retinol directly to RA in culture. However, other cells, including IELs, can express enzymes associated with vitamin A metabolism, suggesting that DCs may also acquire retinoic acid from other sources and store it. A recent study demonstrated that monocyte-derived DCs pretreated with RA can acquire several attributes characteristic of mucosal DCs, such as secretion of TGF-β and IL-6, and the capacity to augment mucosal homing receptor expression and IgA responses in lymphocytes [44]. In this particular study, these gut-derived features acquired by DCs were associated with the capacity of DCs to become carriers and not producers of RA.