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Review
. 2015 May;45(5):1287-95.
doi: 10.1002/eji.201344398.

Seeing through the dark: New insights into the immune regulatory functions of vitamin A

Chrysothemis C Brown  1 , Randolph J Noelle  2
Affiliations
Review

Seeing through the dark: New insights into the immune regulatory functions of vitamin A

Chrysothemis C Brown et al. Eur J Immunol. 2015 May.

Abstract

The importance of vitamin A for host defense is undeniable and the study of its mechanisms is paramount. Of the estimated 250 million preschool children who are vitamin A-deficient (VAD), 10% will die from their increased susceptibility to infectious disease. Vitamin A supplementation was established in the 1980s as one of the most successful interventions in the developing world. Understanding how vitamin A controls immunity will help curb the mortality and morbidity associated with vitamin A deficiency and exploit the immune-enhancing capacity of vitamin A to heighten host resistance to infectious disease. The discoveries that retinoic acid (RA) imprints the homing of leukocytes to the gut and enhances the induction of regulatory T cells, highlighted a potential role for RA in mucosal tolerance. However, more recently emerging data tell of a more profound systemic impact of RA on leukocyte function and commitment. In animal models using genetic manipulation of RA signaling, we learned when and how RA controls T cell fate. Here, we review the role for RA as a critical checkpoint regulator in the differentiation of CD4(+) T cells within the immune system.

Keywords: CD4+ T cells; Dendritic cells; Gut immunity; Innate lymphoid cells; Retinoic acid; T-cell polarization; Vitamin A metabolism.

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Figures

Fig. 1
Fig. 1. Retinoic acid synthesis and signaling
Retinol is taken up from the blood and oxidized first to retinal by retinol dehydrogenases (RDHs) and then to all-trans-retinoic acid (RA) by retinal dehydrogenases (RALDHs). Within the immune system, RALDH2 is the predominant isoform expressed by dendritic cells. Retinoic acid receptors (RARs) are nuclear hormone receptors that function as ligand-dependent transcription factors. RARs form heterodimers with retinoid X receptors (RXRs). RA binds to RAR and triggers a conformational change that promotes recruitment of coactivator complexes to initiate transcription and modify surrounding chromatin.
Fig. 2
Fig. 2. Retinoic acid gradients regulate naïve CD4+ T-cells and cytokine responses in effector CD4+ T-cells
Retinoic acid (RA) plays a physiological role in the differentiation of naive CD4+ T-cells. Administration of exogenous RA often has opposing effects on T-cell polarisation and inhibits production of inflammatory cytokines by effector CD4+ T-cells.
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