Development of novel immunotherapies using retinoid X agonists

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Retinoic acid (RA) enhances TGF-beta-dependent differentiation of Foxp3+ inducible regulatory T cells (iTreg) and inhibits Th17 differentiation by binding to the retinoic acid receptor (RAR). It remained unclear if RXR-mediated stimulation affected the iTreg and Th17 differentiation. We found here that the RXR agonists augmented the ability of RA or the RAR agonist to enhance CD4+CD25- T cells to acquire Foxp3 expression and suppressive function.RXR agonists alone suppressed ROR-gamma-t mRNA and IL-17 expression. The combination of an RXR agonist and RA additively suppressed Th17 differentiation when the concentration of RA was low. Accordingly, continuous treatment with an RXR agonist ameliorated experimental autoimmune encephalomyelitis. These results suggest that RXR stimulation enhances RAR-dependent and independent modulation of Foxp3+ iTreg and Th17 differentiation, respectively.