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Review
. 2011 Jul 22;35(1):13-22.
doi: 10.1016/j.immuni.2011.07.002.

The role of retinoic acid in tolerance and immunity

Jason A Hall  1 , John R Grainger, Sean P Spencer, Yasmine Belkaid
Affiliations
Review

The role of retinoic acid in tolerance and immunity

Jason A Hall et al. Immunity. .

Abstract

Vitamin A elicits a broad array of immune responses through its metabolite, retinoic acid (RA). Recent evidence indicates that loss of RA leads to impaired immunity, whereas excess RA can potentially promote inflammatory disorders. In this review, we discuss recent advances showcasing the crucial contributions of RA to both immunological tolerance and the elicitation of adaptive immune responses. Further, we provide a comprehensive overview of the cell types and factors that control the production of RA and discuss how host perturbations may affect the ability of this metabolite to control tolerance and immunity or to instigate pathology.

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Figures

Figure 1
Figure 1. Vitamin A metabolism and major cellular sources of retinoic acid during homeostasis
(A) Dietary vitamin A is absorbed in the intestine and transported through the lymphatics into blood circulation where it enters the liver for storage. Retinol chaperoned by retinol binding protein (RBP) is constitutively deployed from the liver into circulation. It is also secreted in bile that drains into the small intestine. Upon entry into cells, retinol is reversibly oxidized into retinal via the alcohol dehydrogenase (ADH) family. Depending on the cell type (see table in B), retinal can undergo irreversible metabolism into retinoic acid (RA) via retinal dehydrogenases (RALDH). (B) Overview of major cellular sources of RA during steady-state conditions. Table includes cellular location, the isoform(s) of RALDH that are expressed, and the factors know to induce RALDH expression in each cell type.
Figure 2
Figure 2. The role of retinoic acid in the regulation of CD4+ T cell homeostasis and immunity in the GI tract
The GALT is a retinoic acid (RA) rich environment, containing a vast presence of RA synthesizing cells, including: resident epithelia (IEC) and stroma (SC), as well as migratory CD103+ DCs. RA produced by IEC may confer characteristic features to Lp DCs, while RA produced by SC in the draining mesenteric lymph nodes may reinforce lymphocyte acquisition of mucosal homing markers and potentially other effector functions. (A) During steady-state conditions RA sustains oral tolerance and helps maintain barrier integrity. These processes are mediated in large part by the ability of RA to support the induction of Foxp3+ iTreg and Th17 cells. Lamina propria CD103+ DCs are important for the induction and recruitment of heterogeneous CD4+ T cell populations during steady-state, as result of their ability to respond to commensal microbial signals and produce both RA and TGF-β. This dual capacity likely involves autocrine, or paracrine, RA signaling through retinoic acid receptors, such as RARα, which drives RA synthesis. An RA rich intestinal milieu also potentially limits the pathogenic potential and turnover of Th17 cells through down regulation of IL-6R and IL-23R. (B) During inflammation or infection, the inflammatory milieu triggers altered cytokine production by CD103+ DCs, leading to RARα-dependent effector CD4+ T cell activation and differentiation. Innate cell populations, including antigen presenting cells, are recruited during inflammation and may support RA production. Factors in the inflammatory milieu including TLR-ligands and the cytokine, GM-CSF, promote RALDH activity in CD103+ DCs and potentially in recruited innate cells.
Figure 3
Figure 3. RA synergizes with an inflammatory milieu to promote pathology
During inflammation, RA signaling can induce the production of inflammatory cytokines by DCs, and in turn promote effector T cell differentiation. Direct interactions of RA with T cells may further contribute to the activation status of the cells and promote localization to inflamed tissues. RA may also engender the formation of tertiary lymphoid structures and facilitate chronic inflammation.
See this image and copyright information in PMC

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