Retinoid X Receptor Agonists Modulate Foxp3+ Regulatory T Cell and Th17 Cell Differentiation with Differential Dependence on Retinoic Acid Receptor Activation

Abstract

Retinoic acid (RA) enhances TGF-β–dependent differentiation of Foxp3+ inducible regulatory T cells (iTregs) and inhibits Th17 differentiation by binding to the RA receptor (RAR)/retinoid X receptor (RXR) heterodimer. The major physiologic RA, all-trans-RA, binds to RAR but not to RXR at physiological concentrations. It remained unclear whether RXR-mediated stimulation affected the iTregs and Th17 differentiation. We found in this study that the RXR agonists, PA024 and tributyltin, augmented the ability of all-trans-RA or the RAR agonist Am80 to enhance CD4+CD25− T cells to acquire Foxp3 expression and suppressive function. However, they failed to enhance Foxp3 expression in the presence of the RAR antagonist LE540, suggesting that the effect depends on RAR-mediated signals. They exerted the effect largely by augmenting the ability of all-trans-RA to suppress the production of IL-4, IL-21, and IFN-γ that inhibited Foxp3 expression. Agonists of peroxisome proliferator-activated receptors and liver X receptors (LXRs), permissive partners of RXR, failed to enhance Foxp3 expression. In contrast, RXR agonists and LXR agonists suppressed IL-17 expression. The RXR-mediated suppression was not canceled by blocking RAR stimulation but was likely to involve permissive activation of LXRs. All-trans-RA and an agonist of RXR or LXR additively suppressed IL-17 expression when the all-trans-RA concentration was low. RXR agonists also suppressed Ccr6 expression that is essential for Th17 cells to enter the CNS. Accordingly, tributyltin treatment of mice ameliorated experimental autoimmune encephalomyelitis through regulating Th17 cell activities. These results suggest that RXR stimulation modulates Foxp3+ iTreg and Th17 differentiation with differential dependence on RAR-mediated stimulation.

The role of all-trans retinoic acid in the biology of Foxp3+ regulatory T cells

“…22 The effect of atRA on Treg and Th17 cells is dependent upon the RA receptor/retinoid X receptor heterodimer. 49,50 Because the pathogenesis and development of many autoimmune diseases is affected by the imbalance between Treg and Th17 cells, the role of atRA in regulating this balance may greatly affect the progress of autoimmune diseases.…”

The role of nuclear receptors in regulation of Th17/Treg biology and its implications for diseases

“…42,43 Consistent with RAR-RXR heterodimer formation, treatment with an RXR agonist augments RAR-dependent enhancement of Foxp3 expression. 44 Furthermore, this effect was abrogated in the presence of an RXR antagonist. Several mutual and nonexclusive mechanisms have been proposed for atRAdependent Foxp3 enhancement in T cells.…”

A Novel mTORC1-Dependent, Akt-Independent Pathway Differentiates the Gut Tropism of Regulatory and Conventional CD4 T Cells

“…1 A and B). This bimodal distribution of CCR9 + and CCR9 − nTreg was observed both at physiological (1 nM) (27) and supra-physiological (1000 nM) concentrations of ATRA (Fig. 1C), with a dose-response increase in the proportion of CCR9 + cells evident for both Tconv and Treg populations, although to a different extent.…”