Regulation of FoxP3 regulatory T cells and Th17 cells by retinoids

Abstract

Vitamin A has both positive and negative regulatory functions in the immune system. While vitamin A is required for normal formation of immune cells and epithelial cell barriers, vitamin A deficiency can lead to increased inflammatory responses and tissue damage. The mechanism with which vitamin A and its metabolites such as retinoids negatively regulate inflammatory responses has not been clearly defined. Recently, it has been established that retinoids promote the generation of immune-suppressive FoxP3+ regulatory T cells while they suppress the T cell differentiation into inflammatory Th17 cells in the periphery such as intestine. These novel functions of retinoids provide a potentially important immune regulatory mechanism. In this review, we discuss the functions of retinoids in the development of the FoxP3+ cells and Th17 cells, the phenotype and functions of retinoid-induced FoxP3+ T cells, and the impact of retinoid-induced FoxP3+ T cells on the immune tolerance.

Figure 1

Synthesis of retinoic acid in the dendritic cells of the intestine. Vitamin A is consumed as retinyl ester and hydrolyzed by retinyl ester hydrolase (REH). Retinol, entered into cells, is oxidized to retinaldehyde by alcohol dehydrogenase (ADH) or short-chain dehydrogenase/reductase (SDR). The reverse reaction is mediated by aldo-keto reductase (AKR) or SDR. Retinaldehyde can be converted to retinoic acid (all-trans retinoic acid or At-RA) by retinaldehyde dehydrogenase (RALDH). Retinoic acid is degraded in cells by cytochrome P450 (CYP26). It is known that dendritic cells in the gut-associated lymphoid tissues (GALT) such as Peyer's patches and MLN express high levels of ADH1, ADH4, RALDH1, and/or RALDH2. The retinoic acid produced by dendritic cells can be exported for other cells such as T cells during the cognate interaction between dendritic cells and T cells.

Figure 2

Control of gene expression by retinoic acid. RAR-RXR heterodimers serve as the nuclear receptors for retinoic acid. When RAR ligands (e.g., At-RA) are not available, the RAR-RXR heterodimers attract corepressors and histone acetyl deacetylases to the genes which are under the control of retinoic acid response elements (RARE: direct repeats of AGGTCA with a 5-bp spacer; also called DR-5), resulting in a closed conformation of the chromosome and blocked transcription. When RAR ligands are available in a tissue microenvironment (e.g., produced from dendritic cells in the intestine), they would enter into T cells and activate RAR-RXR heterodimers. This is followed by the release of corepressors and attraction of coactivators, which, in turn, recruit histone acetyl transferases, resulting in an open conformation of the chromosome and transcription of the genes. In this regard, the human and mouse FoxP3 promoters have several RARE's and become acetylated at histones in response to retinoic acid.

Figure 3

Induction and homing of retinoid-induced FoxP3⁺ T cells. Gut homing FoxP3⁺ T cells are made in gut-associated lymphoid tissues (GALT) but not in the thymus. FoxP3⁺ T cells made in the thymus have the naïve T cell phenotype in expression of homing receptors and migrate to secondary lymphoid tissues. In the presence of retinoic acid, these naïve FoxP3⁺ T cells become gut homing memory FoxP3⁺ T cells. Also, naïve FoxP3⁻ T cells become FoxP3⁺ T cells in the GALT to become gut homing FoxP3⁺ T cells. These FoxP3⁺ T cells express CCR9 and α4β7 among other trafficking receptors and are highly efficient in migration to the small intestine. The differentiation of these T cells into gut homing FoxP3⁺ T cells is mediated by subsets of dendritic cells and macrophages because they can present antigens and produce retinoic acid. Additionally, the epithelial cell interacting adhesion molecule αEβ7 is upregulated on FoxP3⁺ T cells if the tissue microenvironments have high levels of TGF-β1. Intestine is such a tissue site that produces both retinoic acid and TGF-β1.

Figure 4

Reciprocal regulation of FoxP3⁺ T cells and Th17 cells by retinoic acid. IL-2 and TGF-β1 promote the generation of FoxP3⁺ T cells from naïve T cells in the periphery, while IL-6 and TGF-β1 promote the generation of Th17 cells, an inflammatory T cell subset that produces IL-17A, IL-17F, IL-21, and IL-22 as the major effector cytokines. IL-2 and the cytokines that promote T cell proliferation into Th1 or Th2 cells (IL-4, IL-12, IFN-γ, and IL-27) would suppress the generation of Th17 cells, while the pro-Th17 cell cytokines, IL-6 and IL-21, can suppress the generation of FoxP3⁺ T cells. Importantly, retinoic acid suppresses the generation of Th17 cells but promotes the induction of FoxP3⁺ T cells.