Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway

Abstract

IntroductionImmune responses are orchestrated by subsets of CD4 ϩ helper and effector T cells. Classically, differentiated T cells have been classified as belonging either to T-helper 1 (Th1) or Th2 lineages. 1 Th1 cells secrete interferon-gamma (IFN-␥) in response to interleukin-12 (IL-12) and require the transcription factors T-box21 (T-bet) and signal transducer and activator of transcription 4 (Stat4) 2 and Stat1, whereas Th2 cells secrete IL-4, IL-5, and IL-13 and require the transcription factors GATA-binding protein 3 (GATA-3) and Stat6. 3 While this simple paradigm was instrumental in understanding immune responses to model pathogens, it was less clear how such a model explained the pathogenesis of autoimmune disease.More recently, additional fates for CD4 ϩ T cells have emerged that provide more insights into the mechanisms of tolerance and immune-mediated disease. One of these new subsets of T cells, expressing the transcription factor FoxP3, is termed regulatory T cells (Tregs) and serves to inhibit immune responses. Deficiency of FoxP3 in mice and humans is associated with fatal autoimmune disease. 4,5 FoxP3 ϩ Tregs normally develop in the thymus, but FoxP3 expression and Treg function also develop when naive CD4 ϩ T cells are stimulated in vitro with transforming growth factor-␤1 (TGF-␤1) and IL-2. 6 Development and differentiation of Tregs and expression of FoxP3 are dependent upon another transcription factor, Stat5. 7,8 Another new subset of T cells that may be related to Tregs is a subset that produces the proinflammatory cytokine IL-17 (Th17 cells). Overproduction of IL-17 has been noted in a variety of models of autoimmune disease, including experimental autoimmune encephalomyelitis and collagen-induced arthritis. 9-13 Importantly, increased levels of IL-17 are also seen in human diseases, such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. 14-16 Th17 cells are generated by the cytokines TGF-␤1 and IL-6, the latter of which acts via Stat3 to induce the transcription factor retinoic acid orphan receptor gamma (ROR␥t). 17 Overexpression of ROR␥t induces IL-17 production, whereas deficiency of this transcription factor virtually abrogates Th17 differentiation.ROR␥t belongs to a superfamily of retinoid nuclear receptors that include the retinoic acid receptors (RARs), retinoid X receptors (RXRs), and other RORs. 18 A connection between retinoids and CD4 ϩ T-cell differentiation has long been recognized. Memory T cells from vitamin A-deficient mice have been found to overproduce . 19 In contrast, administration of the active metabolite of vitamin A, retinoic acid (RA), has been reported to suppress memory cell IFN-␥ production and increase IL-4 secretion. 20 Later, it emerged that vitamin A can be metabolized into retinoic acid isomers with different ligand-receptor affinities: 9-cis retinoic acid, with a higher affinity for the RXR family, and all-trans retinoic acid (ATRA), with a higher affinity for the RAR family. 21 Acting through RXR␣, 9-cis retinoic acid skews n...

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

“…52 Vitamin A deficiency results in immune dysfunction via excessive IFN-c production and impaired antibody responses. A recent study reported that atRA inhibits Th17 cell differentiation but promotes Foxp3 1 Treg cells, 17,18,53 although the role of atRA in CD4 1 and CD8 1 iTreg cell differentiation may be different. 21 The orphan nuclear receptor, RORct, has been implicated in the gene transcription of Th17 cells.…”

“…16,17 Additionally, atRA promotes the development and function of CD4 1 iTreg cells, although its effect on CD8 1 iTreg cells is minimal. [18][19][20][21] Moreover, atRA also helps preserve nTreg cell stability under inflammatory conditions. 22,23 In this review, we summarize our understanding of the role of atRA in Treg cell biology, its related molecular mechanisms and potential clinical application for patients with autoimmune diseases and who need organ transplantation.…”

LIF in the regulation of T-cell fate and as a potential therapeutic

“…This employs all-trans retinoic acid (ATRA) where it has been reported that ATRA inhibits TH17 polarisation and enhances Foxp3 expression in CD4 þ T cells. 81,82 Others have shown that ATRA promotes in vivo expansion of Foxp3 þ Tregs associated with suppression of INFg-producing T cells, though without affecting TH17 cells. 83 Recently reviewed by Noelle, 84 ATRA is a nuclear hormone that binds the retinoic acid receptor (RAR, for example, RARa) to form an active transcription factor complex able to activate homeotic genes.…”

“…85 In development, endogenous ATRA is required for homeostasis in the immune system and for gut homing of T lymphocytes and their increased expression of Foxp3. As ATRA promotes the Treg lineage, 81,82,84,[86][87][88] it is worth asking, is there any evidence for cross-regulation between ATRA and LIF? Importantly, LIF influences oxidative conversion of vitamin A to ATRA in mouse embryonic stem cell; 89 also, LIF synergises with ATRA in differentiation of neural precursor cells to astrocytes 90 and ATRA induces LIF expression in oligodendrocytes: 91 furthermore LIF is induced by ATRA in mouse embryonic stem cell.…”

Transcriptional regulatory networks in Th17 cell differentiation

“…This is especially relevant in the gut environment where, upon encountering commensal bacteria, dendritic cells secrete proinflammatory cytokines. High concentrations of TGF-β, together with retinoic acid (RA), may be required for induction of Foxp3 + Tregs to suppress potentially detrimental inflammatory Th17 cell responses [57][58][59][60][61][62]. The inhibition of IL-6 receptor (IL-6Rα) expression by RA, suggested by a recent study, provides at least in part an explanation for how RA antagonizes Th17 cell differentiation [63].…”