Elsevier

Seminars in Immunology

Volume 21, Issue 1, February 2009, Pages 22-27
Seminars in Immunology

Review
Retinoic acid-dependent regulation of immune responses by dendritic cells and macrophages

https://doi.org/10.1016/j.smim.2008.07.007Get rights and content

Abstract

Dendritic cells (DCs) control the strength and quality of antigen-specific T and B cell responses. Recent advances point to a novel mechanism, in which metabolism of vitamin A into retinoic acid (RA) in DCs, regulate critical parameters of lymphocyte differentiation. First, RA enhances the induction of Foxp3+ T regulatory cells by DCs. Thus, specific subsets of intestinal DCs and macrophages constitutively express RA synthesizing enzymes, and induce T regulatory cells. In addition, RA programs DCs to imprint mucosal homing properties on activated T and B cells, and enhanced induction of immunoglobulin-A (IgA) by B cells. Here, we review these recent advances, in the context of the pleiotropic effects of RA in regulating diverse biological processes.

Introduction

A central problem in immunology is how the immune system launches robust immunity against invading pathogens, while maintaining tolerance to self. This problem assumes a particular significance in the intestine because of the trillions of commensal microorganisms and food antigens that confront the intestinal immune system every day. Recent advances suggest that dendritic cells (DCs) play a fundamental role in maintaining the balance between immunity and tolerance [1], [2], [3], [4], [5]. We now know that there are multiple subpopulations of DCs that differentially regulate the immune response, and that these subsets display tremendous functional plasticity in response to instructive signals from microbes and microenvironments [1], [2], [3], [4], [5], [6], [7], [8]. Thus, understanding the molecular mechanisms by which DCs regulate the balance between immunity and tolerance, and indeed of how DCs fine tune the immune response, will be useful in the rational design of therapies against various autoimmune disorders. Emerging evidence suggest that DCs play a role in suppressing immune responses through the generation of anergic or regulatory T cells in the gut, and fine tuning the response by altering the Th1/Th2/Th17 balance [1], [2], [3], [4], [5], [6], [7], [8]. However, the signaling pathways and transcription factors within DCs that regulate these responses are poorly understood. Emerging evidence suggests that the catalysis of vitamin A into RA in specific subsets of DCs, plays a vital role in the induction of Foxp3+ T regulatory cells. In addition, RA generation in DCs is also thought to imprint intestinal homing properties on activated T and B cells, and enhanced IgA secretion by B cells.

Section snippets

Vitamin A and the retinoic acid signaling pathway

Retinoic acid (RA) is an active derivative of vitamin A that regulates diverse biological processes such as cellular differentiation, apoptosis, embryonic development, reproduction, and vision [9], [10]. Importantly, it has been known for decades that vitamin A deficiency is associated with enhanced susceptibility to virtually all types of infections, and defects in both the innate and adaptive immune systems [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. However, it is only

Retinoic acid production in dendritic cells and macrophages

RA directly influences the development and effector functions of various immune cell types [2], [21], [22], [23], [40], [41], [42]. Emerging evidence suggest that RA plays a significant role in regulating the functions of APCs in the intestinal immune system. RA is produced by many subsets of intestinal APCs, and facilitates the induction of T regulatory cells by these APCs. Here we will review the emerging data on the importance of specific DC and macrophage subsets in the intestine that

Effect of RA on imprinting mucosal homing properties on T cells

Emerging evidence shows that activated T cells with distinct phenotypes can home to different tissues depending on the expression of specific homing receptors. For example, activated T cells expressing α4β7 and CCR9 preferentially migrate to the gut epithelium in response to thymus-expressed chemokine called TECK (also known as CCL25), and in response to the mucosal addressin cell adhesion molecule (MAdCAM)-1 [44], [47], [59], [60], [61], [62]. Early studies showed that antigenic stimulation T

Summary and future directions

The central role of RA in regulating diverse biological processes has been appreciated for a long time. Even immunologists have recognized for decades that vitamin A deficiency is associated with enhanced susceptibility to most infections, and defects in both the innate and adaptive immune systems [11], [12], [16], [18]. However, it is only recently that immunologists have begun to explore the cellular and molecular mechanisms by which vitamin A exerts its effects on the innate and adaptive

Acknowledgements

BP and SM were supported by the National Institutes of Health AI048638, AI05726601, DK057665, U54 AI057157 and AI-50019.

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