Activation of retinoic acid receptor‐α favours regulatory T cell induction at the expense of IL‐17‐secreting T helper cell differentiation

Abstract

Autoimmunity is thought to reflect an imbalance between regulatory T helper lymphocytes (Treg) and pathogenic, IL-17-secreting T helper (Th17) cells. Induction of both adaptive Treg and Th17 cells requires signalling from TGF-b. We now show that, in the context of TGF-b signalling, all-trans retinoic acid (ATRA) leads to increased induction of CD4 + T cells expressing the Treg specification factor forkhead box protein P3 (FoxP3) and decreased frequency of cells expressing IL-17, even in the presence of IL-6. Using a specific agonist and antagonist, as well as retroviral over-expression, we also provide evidence that the effects of ATRA are likely to be at least partially mediated by the nuclear retinoic acid receptor-a (RARa). These findings indicate that signalling through a specific nuclear retinoic acid receptor can favour the decision to adopt the Treg fate at the expense of Th17 fate. Specific agonists of RARa could, therefore, be considered candidates for the treatment of autoimmunity.

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

“…Several studies have demonstrated that RA can negatively affect the differentiation of T H 17 cells [26][27][28][29] although the precise mechanisms remain unclear. Based on our data showing heightened IL-17A production by HIC1-deficeint T H 17 cells in vitro and in vivo, we hypothesized that expression of HIC1 would be required for the RA-dependent reduction in T H 17-cell differentiation.…”

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.…”

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

“…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.…”