Retinoic Acid Enhances Foxp3 Induction Indirectly by Relieving Inhibition from CD4+CD44hi Cells

Abstract

Summary The CD4+Foxp3+ lineage of regulatory T (Treg) cells plays a key role in controlling immune and autoimmune responses. Treg cells originate primarily during T cell differentiation in the thymus, but conversion of mature T lymphocytes to Foxp3-positivity can be elicited by several means, including activation in the presence of transforming growth factor (TGF)β in vitro. Retinoic Acid (RA), the ubiquitous morphogen that exerts a particular shepherding effect on the gut immune system, increases TGFβ–induced expression of Foxp3, an effect shown here to be mediated through RA receptor (RAR)α. Part of RA’s influence may be due to it’s ability to down-modulate the receptor for IL-6, a cytokine that inhibits Foxp3 expression, but this effect appeared to be of relatively minor importance. Rather, RA negatively affected a population of CD4+ cells with a CD44hi phenotype, akin to that of memory or effector cells, which inhibited the TGFβ-induced conversion of naïve CD4+ T cells. This “contra-conversion” activity was mediated, at least in part, through the synthesis of a set of cytokines (IL-4, IL-21, IFNγ), which in combination had a potent dampening effect on Foxp3 induction. RA, via RARα, elicited a coordinated shut-down of the whole program of cytokine expression in CD44hi cells. The in vivo relevance of this observation was established by transferring RA-sensitive OT-II T cells, which showed less effective conversion to Foxp3+ in RARα-deficient hosts. Thus, CD44hi T cells can actively restrain the induction of Foxp3, and this balance can be shifted or fine tuned by RA.

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

“…40,41 It remains unclear whether RAPA selectively suppresses the expansion of non-Treg cells, thereby indirectly promoting the expansion of Foxp3 1 Treg cells. 16 Although a comparison study has shown that both RAPA and atRA had similar effects on promoting and stabilizing Treg cells during their expansion, 42 a more recent study demonstrated that atRA exhibits superior efficacy relative to RAPA for stabilizing nTreg cells under inflammatory conditions. 23 The mechanism by which atRA stabilizes nTreg cells is discussed below.…”

“…Recent studies revealed that atRA regulates the differentiation of Th cells and Foxp3 1 Treg 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.…”

Transcriptional regulatory networks in Th17 cell differentiation

“…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]. Foxp3 inhibits RORγt-directed IL-17 expression in mouse T cells, but it remains to be determined whether this also occurs in humans.…”