Retinoic acid can enhance conversion of naive into regulatory T cells independently of secreted cytokines

Abstract

It has been reported that retinoic acid (RA) enhances regulatory T (T reg) cell conversion by inhibiting the secretion of cytokines that interfere with conversion. This report shows that these conclusions provide a partial explanation at best. First, RA not only interfered with cytokine secretion but also with the ability of these cytokines to inhibit T reg cell conversion of naive T cells. Furthermore, RA enhanced conversion even in the absence of inhibitory cytokines. The latter effect depended on the RA receptor α (RARα) but did not require Smad3, despite the fact that RA enhanced Smad3 expression. The RARα1 isoform was not essential for RA-dependent enhancement of transforming growth factor β–driven conversion, suggesting that conversion can also be mediated by RARα2. Interleukin (IL)-6 strongly reduced RARα expression levels such that a deficiency of the predominant RARα1 isoform leaves too little RARα2 for RA to inhibit the generation of Th17 cells in the presence of IL-6.

Recent thymic emigrants are the preferential precursors of regulatory T cells differentiated in the periphery

“…Others have already argued how unlikely it is that a single molecule or pathway would explain the functional differences between immature and mature T cells (37). Importantly, our findings are also compatible with the notion that mucosa, a microenvironment rich in TGF-β and retinoic acid where inflammation is maintained at check, efficiently supports the differentiation of Tregs (31,38). The concept brought about by our analysis is that systemic peripheral conversion (i.e., in situations of limited retinoic acid and TGF-β and/or in inflammatory context) is restricted to RTEs.…”

Leukocyte Homing, Fate, and Function Are Controlled by Retinoic Acid

“…Recent reports showed that CNS1 contains binding sites for transcription factors NFAT, Smad3, and RAR/RXR. Further studies revealed that RA enhances TGF-␤ signaling by increasing the expression and phosphorylation of Smad3 (146,217). Indeed, RA actions involve the binding of RAR/ RXR to CNS1.…”

Modulation of T Cell and Innate Immune Responses by Retinoic Acid

“…atRA inhibits expression of IL-6Ra on naive T cells, which, together with TGF-b, promotes differentiation of naive T cells into Th17 cells; IL-6 has the reciprocal effect of inhibiting the expression of RARa (41,59,60). Moreover atRA acts through RARa in activated CD4 + T cells to promote the expression of Foxp3, independently of the cytokine IL-2, the TGF-b-signaling molecules SMAD3 and SMAD4, and the transcription factors STAT3 and STAT5 (59,61,62). Furthermore, RA enhances the expression of arginase 1 in DCs in vitro, an enzyme known to promote the production of Tregs (63).…”

“…high memory T cells, the effect of RA on iTreg conversion is significantly decreased (59,65). Interestingly, in the GALT, but not in lymph nodes and spleen, activation of CD44 high T cells in the absence of TGF-b leads to the expression of the RA-degrading enzyme CYP26B1, which, in turn, inhibits the expression of CCR9 on T cells (67).…”