Retinoic Acid Imprints Gut-Homing Specificity on T Cells

Abstract

For a preferential homing of T cells to the gut, expression of the integrin alpha4beta7 and the chemokine receptor CCR9 is essential and is induced by antigenic stimulation with dendritic cells from the gut-associated lymphoid organs. Here, we show that the vitamin A (retinol) metabolite, retinoic acid, enhances the expression of alpha4beta7 and CCR9 on T cells upon activation and imprints them with the gut tropism. Dendritic cells from the gut-associated lymphoid organs produced retinoic acid from retinol. The enhanced alpha4beta7 expression on T cells by antigenic stimulation with these dendritic cells was suppressed by the retinal dehydrogenase inhibitor citral and the retinoic acid receptor antagonist LE135. Accordingly, vitamin A deficiency caused a reduction in alpha4beta7(+) memory/activated T cells in lymphoid organs and a depletion of T cells from the intestinal lamina propria. These findings revealed a novel role for retinoic acid in the imprinting of gut-homing specificity on T cells.

Induction of organ‐selective CD4+ regulatory T cell homing

“…Similar to our observations for the co-cultures with organ-specific DC, induction of P-lig expression on Treg under the influence of polarizing factors was less stringently controlled, with IL-12 having only an additive effect. This was in contrast to E-lig expression, which was suppressed upon addition of RA, as has been reported previously for conventional T cells [25]. Although it had been reported that in conventional T cells both regulation and function of E-and P-lig is largely overlapping [11,52], our current findings suggest that Treg display a differential regulation of the two functional selectin ligands.…”

“…Among the molecular factors that control the induction of HR on T cells, RA has recently been shown to play a critical role for the generation of gut-tropic T cells [25]. Only intestinal DC, but not splenic DC expressed retinoid dehydrogenase enzymes, catalyzing the sequential oxidation of vitamin A via retinal to RA, which in turn induced T cell expression of a 4 b 7 and CCR9.…”

“…As polarizing compounds, RA and IL-12 were used, which have been shown to induce a 4 b 7 and P-lig on activated T cells, respectively [25,26]. In vitro activation of CFSE-labeled naïve-like Treg in the presence of RA induced high a 4 b 7 levels on the vast majority of Treg (Fig.…”

“…Tissuespecific DC have been shown in a number of in vitro and in vivo studies to be involved in the instruction of naïve T cells [4,[17][18][19][20][22][23][24]. Recently, Iwata et al [25] reported that GALT DC were capable of converting metabolites of dietary vitamin A into retinoic acid (RA), which in turn induced T cell expression of a 4 b 7 and CCR9, leading to the generation of gut-tropic T cells. However, the factors, which are involved in the generation of skin-specific T cell homing in vivo, are largely unknown, although important roles for cytokines including IL-12 and TGF-b have been suggested from in vitro studies [26][27][28].…”

Curcumin induces the tolerogenic dendritic cell that promotes differentiation of intestine‐protective regulatory T cells

“…Dietary components likely also influence the development of the mucosal immune system in many ways, including stabilization of the microbiota. RA, a metabolite of dietary component vitamin A, has been shown to educate the mucosal DC to imprint primed T cells and B cells with gut tropism [21][22][23][24]. Recent reports further demonstrated that intestine is enriched for DC expressing RA metabolizing enzyme ALDH1a and that RA is a key regulator of TGF-b dependent immune responses by promoting Treg differentiation and inhibiting Th17 cell development [9,11].…”