title: 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.
authors: Laboratory of Immunology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki-shi, Kagawa 769-2193, Japan;
authors: Hajime
authors: H
authors: Takeuchi
authors: Aya
authors: A
authors: Yokota-Nakatsuma
authors: Yoshiharu
authors: Y
authors: Ohoka
authors: Hiroyuki
authors: H
authors: Kagechika
authors: Chieko
authors: C
authors: Kato
authors: Si-Young
authors: SY
authors: Song
authors: Makoto
authors: M
authors: Iwata
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D009947:Organotin Compounds / Q000494:pharmacology; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000819:agonists*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000378:metabolism*; D058504:Th17 Cells / Q000166:cytology* / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D014220:Trialkyltin Compounds / Q000494:pharmacology
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000071518:Liver X Receptors; D009947:Organotin Compounds; D057093:Orphan Nuclear Receptors; D047492:Peroxisome Proliferator-Activated Receptors; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D016212:Transforming Growth Factor beta; D014220:Trialkyltin Compounds; C011559:tributyltin; D014212:Tretinoin; C030665:triphenyltin