Volume 45, Issue 5 p. 1287-1295

Mini-Review

Free Access

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

Chrysothemis C. Brown,

Corresponding Author

Chrysothemis C. Brown

Division of Transplantation Immunology and Mucosal Biology, Kings College London, United Kingdom

Full correspondence: Dr. Chrysothemis Brown, MRC Centre for Transplantation, Kings College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom

Fax: +44-20-7188-5660

e-mail: [email protected]

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Randolph J. Noelle,

Randolph J. Noelle

Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, NH, USA

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Chrysothemis C. Brown,

Corresponding Author

Chrysothemis C. Brown

Division of Transplantation Immunology and Mucosal Biology, Kings College London, United Kingdom

Full correspondence: Dr. Chrysothemis Brown, MRC Centre for Transplantation, Kings College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom

Fax: +44-20-7188-5660

e-mail: [email protected]

Search for more papers by this author

Randolph J. Noelle,

Randolph J. Noelle

Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, NH, USA

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First published: 23 March 2015

https://doi.org/10.1002/eji.201344398

Citations: 93

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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.

Introduction

Vitamin A, through its active derivative retinoic acid (RA), plays a critical role in embryogenesis, determining cell lineage, and fate commitment (reviewed in 1). In areas where malnutrition is endemic, vitamin A-deficient (VAD) children have been shown to bear a severe impairment in vision due to the critical role of RA in the retina, to which it owes its name. In addition, vitamin A deficiency is associated with an increased burden of infectious disease 2, highlighting the importance of vitamin A for immunity. The pivotal discovery that RA was constitutively synthesized by gut DCs 3 was closely followed by several studies showing that RA was able to enhance the development of inducible regulatory T cells (iT_reg) 4-6. This led to the view that RA might act to promote oral tolerance and shifted the attention away from the critical nature of RA in systemic immunity. In recent years a broader role for RA in peripheral, effector immune responses has reemerged. Several studies have demonstrated regional induction of RA synthesis and signaling upon inflammation 7, 8, and RA has been shown to play an essential role in Th1 responses in allograft rejection, vaccination, and gut infection 8, 9. In this review, we focus on these recent advances that have shed light on a broader role for RA in directing T-helper cell fate and revealed novel mechanisms by which RA regulates gene expression. Given the clinical availability of retinoids, their mechanisms of action and emerging roles as immunotherapeutic agents will be discussed.

Biological activity of retinoic acid

Multiple isoforms of RA exist. Of these, all-trans retinoic acid is the predominant biological form and is the subject of this review. RA is generated from retinol, which circulates in the plasma bound to retinol-binding protein. RA synthesis is restricted to cells that express the enzymes required for conversion of retinol to RA 10. First, retinol is converted to retinal by retinol dehydrogenase (RDH) (Fig. 1). Studies in rdh10^–/– mice suggest that RDH10 is the critical dehydrogenase isoform for retinal synthesis 11. Retinal is then irreversibly converted to RA by one of three retinaldehyde dehydrogenase isoforms: RALDH1, RALDH2, or RALDH3 encoded by aldh1a1, aldh1a2, and aldh1a3, respectively (Fig. 1) 12, 13.

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

Retinoic acid synthesis and signaling. Retinol is taken up from the blood and oxidized first to retinal by retinol dehydrogenases (RDH) and then to all-trans-retinoic acid (RA) by retinal dehydrogenases (RALDH). 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 the surrounding chromatin via histone modifications and DNA methylation.

All-trans RA signals through heterodimers of the RA receptors (RARs) and retinoid X receptors (RXRs) (Fig. 1, reviewed in 14). These receptors belong to the nuclear hormone receptor family. There are three isotypes for both RAR and RXR: α, β, and γ. RAR/RXR heterodimers bind to RA response elements, (RAREs) in target genes and act as ligand-dependent transcription factors 14. RAR/RXRs mediate transcriptional regulation through the binding of corepressor or coactivator complexes, dependent on the presence of ligand (Fig. 1). The widely accepted view is that unliganded RAR/RXR heterodimers inhibit transcription of their target gene, through recruitment of corepressors such as NCoR or SMRT. Binding of ligand to RAR leads to the release of corepressors and the recruitment of coactivators such as p300 and CBP, with subsequent transcriptional activation of the target gene (reviewed in 15). In addition, RA can mediate gene repression through the recruitment of ligand-dependent corepressors, such as RIP140 and PRAME, which recruit histone deacetylases to RAR/RXR complexes 16, 17. RARs can also modulate transcription indirectly, through inhibition of transcription factor complexes, such as activating protein-1 (AP-1) although the underlying mechanisms remain uncertain 18.

Retinoic acid: Mucosal immunity and beyond

A role for RA in mucosal immunity was established by the discovery that DCs within the MLN and Peyer's patches (PP) constitutively express aldh1a2 and aldh1a1, respectively, the genes that encode RALDH2 and RALDH1 3. RA generated by these MLN and PP DCs could imprint gut tropism through the induction of the gut-homing receptors CCR9 and α4β7 on T cells 3. Within both human and murine MLNs, DCs that express the highest levels of aldh1a2 are the CD103⁺ subset 19, 20. Recently, it was shown that expression of 4-1BB, a member of the TNF receptor superfamily, correlates with CD103 positivity in DCs, and that 4-1BB is therefore also able to identify MLN DCs with the highest levels of aldh1a2 21. Triggering of 4-1BB expression on MLN DCs was shown to induce RALDH activity in vitro and 4-1BB-deficient MLN DCs have weak RALDH activity, pointing to a functional role for 4-1BB in the induction of RA synthesis by this cell type.

Outside of the gut, examination of peripheral DC subsets have identified DCs expressing aldh1a2 residing in the lung and skin, pointing to a role for RA in steady-state immune responses at barrier sites 22, 23. Although the majority of peripheral DCs express negligible or low levels of RALDH, the identification of cytokines and pathogen-associated molecular patterns that can induce RALDH expression indicates that RA synthesis and signaling may be a widespread occurrence during the course of a peripheral immune response. For example, treatment of splenic DCs with zymosan, a TLR2 agonist, has been shown to result in the induction of aldh1a2 in vitro, and stimulation of WT but not TLR2^–/– splenic DCs with Candida albicans has a similar effect 24. In vitro, GM-CSF can induce both bone marrow-derived DCs and splenic DCs to express aldh1a2 25.

Several in vivo studies have now demonstrated local induction of RALDH activity amongst DCs in response to a diverse array of inflammatory stimuli, including respiratory viral infection, alloantigen, and tumor burden 7, 8, 26-28. In addition to RA synthesis by DCs, upregulation of aldh1a2 expression has been observed in alternatively activated macrophages following infection of mice with the helminth Shistosoma mansoni 29. These studies suggest that RA synthesis and signaling may be a universal feature of immune responses both in the gut and the periphery. Intriguingly, peripheral induction of T cell and B cell responses in the presence of RA still leads to induction of gut-homing receptors and the subsequent migration of these adaptive cells to the gut 26, 30. For example, the induction of CCR9 expression on lung-derived CD4⁺ T cells following intranasal influenza infection in mice resulted in trafficking of these cells to the small intestine 26. In this case, local production of IFN-γ resulted in alterations to the gut microbiota, which in turn led to increased numbers of intestinal Th17 cells 26. Although these findings explain the incidence of intestinal side effects observed in influenza patients, the functional relevance of gut homing to the primary immune response remains to be determined. Recent discoveries have shown that systemic immune responses at sites distal to the gut, such as those in autoimmune arthritis and experimental autoimmune encephalitis, are modulated through the gut microbiota 31, 32 and it is possible that lymphocyte trafficking through the gut is a necessary “rite of passage” for effector T cells. Regional RA production at peripheral sites of inflammation with subsequent induction of gut homing properties on lymphocytes may therefore play a key role in shaping the course of the immune response.

RA regulation of T-helper cell fate and plasticity

RA enhances Foxp3 expression and stability

Following the initial study that identified RA synthesis by gut DCs, several groups went on to show that RA could dramatically enhance the TCR-TGF-β-mediated conversion of naïve CD4⁺ T cells to iTreg cells in vitro (Fig. 2) 4-6. TGF-β-mediated Foxp3 induction is dependent on Smad3 signaling 33, 34. In addition to directly regulating the expression of Smad3 35, RA regulation of Foxp3 expression is in part mediated by binding of RAR/RXR heterodimers to a RA response element in the enhancer 1 (CNS1) region (Fig. 1) of the Foxp3 gene, which facilitates binding of phosphorylated Smad3 to the enhancer region 36. The first in vivo evidence supporting a role for the RA/TGF-β-Smad3 pathway in the generation of peripheral Treg (pTreg) cells in the GALT comes from a recent study utilizing mice lacking the Smad3-binding site within the CNS1 region 37. Aged mice lacking this binding site develop deficiencies in Foxp3⁺ cells in the LP and PP but not at other sites; however, the functional significance of this is unclear since no negative impact of the pTreg-cell deficiency was observed in T-independent or T-cell dependent models of colitis 37. Further studies are required to understand the in vivo contribution of RA to immune tolerance, both in the gut as well as at peripheral sites of immune responses.

In addition to enhancing TCR-TGF-β-mediated Foxp3 expression, RA has also been shown to confer increased stability of Foxp3 expression in the face of inflammatory cytokines and costimulation among both iTreg cells and thymic Treg (tTreg) cells 4, 35, 38. iTreg cells generated in the presence of RA have been shown to express reduced levels of the receptor for IL-6, a Th17-instructing cytokine 35. Recently, RA and TGF-β were shown to induce expression of the microRNA miR-10a, which in turn inhibits expression of the follicular helper T-cell (T_FH) master transcription factor, Bcl-6 39. Conversion of Treg cells to T_FH cells has been described in PP in mice 40, and miR10-a overexpression in iTreg cells was able to reduce this conversion in vivo 39. RA may therefore reinforce lineage stability by regulating opposing pathways that instruct alternative T-helper cell fates.

A newly described role for RA in the conversion of CD4⁺ T cells to CD4⁺CD8αα⁺ T cells within the intestinal epithelium (IELs) provides a further mechanism by which RA promotes anti-inflammatory responses within the gut 41. Cd4^crednRara^lsl/lsl mice conditionally expressing a dominant negative form of the retinoic acid receptor RARα (dnRara) in T cells (henceforth referred to as dnRara mice) have severely impaired numbers of CD4⁺CD8α⁺ IELs, which appear to play a critical role in preventing intestinal inflammation. dnRara-expressing CD4⁺ T cells failed to upregulate T-bet, which directs the expression of the CD8 lineage transcription factor, Runx3, and inhibits ThPok, allowing reprogramming of CD4⁺ cells toward CD8α⁺ IELs 41.

Retinoic acid is critical for Th1 lineage stability

A role for RA in the generation of Treg cells seemed counterintuitive given the wealth of epidemiological data supporting a role for RA in immunity to infectious disease. Emerging data examining the effects of RA on effector lymphocytes in vivo have gone some way to resolving this paradox by demonstrating a broader role for RA in Th-cell responses (Fig. 2). Experiments in VAD mice implicated RA in Th1 responses 9. VAD mice infected with Toxoplasma gondii were found to have significantly reduced Th1 cells in their GALT and spleen 9. In the same study, VAD mice were also shown to have deficient Th1-cell responses upon vaccination with OVA and E. coli toxin. In our own studies using dnRara mice, RA signaling on T cells was found to be critical for Th1-mediated immunity during a range of inflammatory responses including allograft rejection, systemic infection with Listeria monocytogenes, and oral antigen induced intestinal inflammation 8, 42. Temporal analysis of Th1 differentiation in dnRara CD4⁺ T cells showed that RA was dispensable for initial commitment to the Th1 lineage but was critical for long-term Th1 lineage stability 42. In contrast to Th17 and Treg cells, Th1 cells have shown limited potential for developmental plasticity. An unanticipated finding of our studies was that RA signaling was required to suppress an endogenous Th17 program during Th1 differentiation and repress transdifferentiation of Th1 cells toward Th17 cells upon reactivation 42. These findings highlight a previously unappreciated flexibility in the Th1 lineage and identify RA as a critical regulator of CD4⁺ T cell plasticity. Transition of Th1 cells toward the Th17 lineage resulted in a hybrid Th1-Th17 cell that produced both Th1 and Th17 signature cytokines and this shift in the Th1-Th17 axis was associated with enhanced pathology in a model of oral antigen induced inflammation 42.

RARα is the predominant RAR isoform expressed by CD4⁺ T cells 9. Genome wide analysis of RARα targets in Th1 cells revealed that several Th1 genes, including T-bet, STAT4, and IFN-γ, were bound by RARα and their expression was dependent on RA signaling 42. A number of genes that direct or enhance the Th17 program, such as Il6ra and Runx1 were repressed by RA-RARα. IRF8, a transcription factor previously shown to suppress Th17 differentiation 43, was upregulated in Th1 cells in an RA-dependent manner. Further studies are required to understand how IRF8 contributes to the transcriptional network in Th1 cells.

In vitro experiments conducted with CD4⁺ T cells isolated from RARα^–/– mice suggested that disruption of RA signaling leads to impaired activation-induced proliferation 9. However, CD4⁺ T cells from mice expressing dnRara have been shown to have normal proliferative capacity 8, 42. One possible explanation for this discrepancy is that unliganded RARs inhibit transcription through the recruitment of corepressors 44, thus deletion of RAR may lead to a loss of inhibition of RAR targets with a paradoxical upregulation of RA target genes in the absence of RA. In zebrafish, deletion of RAR isoforms was shown to result in a paradoxical increase in RA signaling with compensatory increases in expression of alternative RARs 45. RARα does appear to be the critical receptor in mediating the effects of RA on CD4⁺ T cells, as deletion of RARγ in mouse hematopoietic cells has no impact on the development of Th1-type responses following infection with Listeria monocytogenes 46.

In contrast to a physiological role for RA in supporting Th1-cell differentiation, RA treatment of naive CD4⁺ T cells polarized under Th1 conditions in vitro has been shown to inhibit IFN-γ production when administered during early stages of Th1 differentiation 47. As discussed later, these apparently conflicting findings may be explained by dose dependent and temporal effects of RA.

Retinoic acid and Th17 differentiation

In addition to inhibiting a Th17 program during Th1 responses, RA has also been shown to inhibit Th17-cell differentiation during iTreg induction. The earliest studies linking RA to TGF-β-mediated Foxp3+ expression identified a reciprocal role for RA in the inhibition of Th17 cells that had been differentiated from naïve T cells with TGF-β and IL-6 in vitro (Fig. 2) 6, 35. RA inhibition of TGF-β directed Th17-cell differentiation appears to be mediated in part through alterations in the balance between STAT5 and STAT3, which play antagonistic roles in shaping Th17 and Treg programs 48. RA opposes STAT3 activation in part by downmodulating IL-6R and IL-23R in responder T cells 35. In addition, RA promotes IL-2 production by Th17 differentiating cells 49, which in turn activates STAT5. The inhibitory effects of RA on Th17-cell differentiation are most prominent in the presence of IL-2 39, 49 and inhibition of Th17 generation by RA can be overcome by the proinflammatory cytokine IL-1β, which potentiates STAT3 activation 49.

In accordance with these in vitro findings, RA administration to mice has been shown to inhibit the development of Th17 responses and disease severity in EAE 35, a Th17-mediated model of multiple sclerosis. However, it is still not clear how endogenous levels of RA impact on Th17 responses in vivo. Studies in VAD mice describe a near absence of Th17 cells both during homeostasis and in response to immune-mediated inflammation 9, 50 supporting an in vivo role for RA in driving the generation or maintenance of Th17 cells. Corroborating these in vivo findings, one study has shown that low dose RA (<10 nM) can actually enhance Th17 differentiation in vitro 39. This appears to conflict with findings from other studies in which similarly low doses of RA inhibited Th17 differentiation. This discrepancy may in part reflect differences in Th17 polarization conditions which are known to drive phenotypically distinct Th17 cells (reviewed in 51). In addition, it may not be possible to compare concentration-dependent effects of RA across in vitro studies where DCs are utilized in cocultures since induction of RA synthesis by DCs is observed in inflammatory settings. dnRara CD4⁺ T cells differentiated in vitro under Th17 conditions do not show enhanced Th17 responses, rather a reduction in IL17 frequencies 42, suggesting that RA signaling is required for optimal TGF-β directed Th17 differentiation.

Two recent studies have identified a role for RA in the generation of a type 3 innate lymphoid cells (ILC3s), which mirror Th17 cells in their cytokine profile. VAD mice and wild-type mice treated with an RA antagonist were shown to have impaired ILC3 responses both at steady state and in response to intestinal infection with Citrobacter rodentium 52. Given that ILC3s produce Th17-associated cytokines, their absence in VAD mice may contribute to the impaired development of Th17 cells at the mucosal surface. Taking all these observations together, it is clear that further studies are required in dnRara mice to establish the role of RA in Th17-cell generation across different in vivo settings.

The absence of ILC3s in VAD mice has widespread implications on adaptive immune responses since a subset of ILC3s, called lymphoid tissue inducer (LTi) cells, play a critical role in the development of secondary lymphoid organs and Peyer's patches. Maternal consumption of vitamin A and subsequent fetal RA signaling were found to directly regulate the expression of RORγt in fetal CD4⁻ILCs, instructing the development of fetal LTi cells 53. Mice exposed to an RA-deficient environment in utero were shown to have smaller secondary lymphoid organs, a condition that persists throughout adult life with consequent impaired adaptive immune responses 53. Studies utilising VAD mice as a model for studying RA-regulated T-cell responses, may need to be reevaluated in light of the homeostatic defects observed in these mice.

Influence of retinoic acid on Th2 differentiation

In addition to Th1- and Th17-mediated immune responses, RA synthesis has been reported in parasite infections in mice, suggesting a possible role for RA in shaping Th2 responses. Dietary vitamin A levels have been shown to affect Th2 responses with enhanced production of Th2-associated cytokines and concomitant reduction in IFN-γ production by CD4⁺ T cells isolated from Trichinella spiralis-infected, VAD mice (Fig. 2) 54. However, in a further twist, in the earlier study examining ILC dysregulation in the absence of RA signaling, VAD was shown to induce the expansion of ILC2s with enhanced ILC2-derived, Th2-type cytokines (Fig. 2) 52. The presence of ILC2s appears to be critical for Th2-type allergen responses in vivo 55, thus the previously reported effects of dietary RA on Th2-cell responses in VAD mice may not be due to direct effects of RA on T cells, but may rather act via the enhancement of ILC2 expansion. Studies in which RA levels are manipulated through the administration of RA are conflicting, with both enhanced and reduced Th2 responses reported in murine models of asthma following RA treatment 56, 57. Genetic approaches that allow one to dissect the impact of RA signaling on defined lineages of hematopoietic cells will help to clarify the physiological role of RA in the regulation of Th2-mediated immunity.

Retinoic acid as an immune morphogen—Two possible models

Over the past few years, RA has achieved recognition as a morphogen, as it has become clear that synthesis and metabolism of RA during embryogenesis is tightly controlled, resulting in concentration-dependent effects on target tissues 58. Given that the RA-RARα axis is a highly conserved signaling pathway, which plays a critical role in regulating cell fate specification during embryogenesis and cell differentiation, it is perhaps not surprising that RA has been implicated in all aspects of T-helper cell differentiation. Pleiotropic roles for RA in the generation of Treg, Th1, Th17, and Th2 cells are not mutually exclusive but rather suggest context-dependent actions. The key to therapeutic targeting of the RA signaling pathway is an understanding of the dominant action of RA on T-cell responses in different in vivo settings. RA appears in part to alter the sensitivity of cells to alternative cell fates through the regulation of cytokine receptors. Thus the dominant effects of RA may well be dependent on the instructive cytokine milieu. In such a model, rather than directly specifying T-cell fate, RA enhances or stabilizes the actions of cytokines and transcription factors that guide T-helper cell programming. In this way, synthesis of RA by APCs provides an additional checkpoint for the stabilization of T-cell fate commitment. A key unanswered question is how RARα integrates with cytokine signals and transcriptional networks to confer lineage-specific effects. Genome wide analysis of RARα binding in different T-helper cell lineages will go some way toward addressing this question.

An alternative model is that, similar to the morphogenic properties of RA during embryogenesis, the RA concentration sensed by naïve T cells undergoing differentiation determines the dominant action of RA on T-cell fate. The preponderance of data from in vitro experiments in which dose titration comparisons were performed on Th1, Th2, and Th17 polarization suggest dose-dependent effects of RA on hematopoietic cell fate 39, 47, 59. The paradoxical effects of RA on opposing T-cell fates may therefore be explained by concentration-dependent effects of RA, allowing T cells to act as an environmental sensor through the strength of its RA signal. Further studies of RA gradients within lymphoid tissue are required to test this hypothesis. However, the overriding message is that administration of RA either in vitro or to vitamin A-replete hosts in vivo may not provide insight into the physiological actions of RA on T-cell responses.

A further layer of complexity in the form of biphasic effects of RA on Th1- and Th2-cell differentiation reported in vitro surrounds the issue of RA regulation of Th-cell fate 42, 47. In Th1-cell differentiation, induction of T-bet is dependent on IFN-γ-STAT1 signaling, whereas maintenance of T-bet expression is dependent on IL-12-STAT4 activation 60. Analysis of these pathways in RA signaling deficient T cells, suggested that RA has distinct roles in the regulation of these two signaling pathways 42. Similarly, a biphasic model for Th17-cell differentiation is emerging with early commitment dependent on TGF-β and IL-6 signaling but maintenance and stability dependent on IL-21 and IL-23 signaling (reviewed in 51). Animal models that allow temporal control of RA signaling will be invaluable for dissecting out the role of RA in early versus late phase differentiation.

Retinoic acid signaling: Novel mechanisms of transcriptional regulation

In addition to its classical role as a transcriptional regulator, recent studies in murine embryonic stem cells have identified RA-RARα as an epigenetic regulator. Retinoids have been shown to regulate epigenetic changes including histone modifications and DNA methylation, through the recruitment of coactivators with chromatin-modifying properties (reviewed in 61). p300, for example, possesses histone acetyltransferase activity and mediates the acetylation of H3K27, a marker of active cis-regulatory regions, termed enhancers. Global mapping of enhancers in wild-type and dnRara Th1 cells demonstrated RA-RARα dependent p300 recruitment at enhancers of lineage specific genes. Epigenetic modifications have been suggested to be the determinants of heritable gene expression and lineage stability. The findings of the foregoing study implicate RARα as a key component of the network of regulators that coordinate chromatin changes during lineage specification. Given the emerging data implicating RARα in alternative Th cell lineages as well as ILC subsets, it will be important to evaluate a wider role for RA-RARα in the regulation of lineage-specific enhancers.

Recent studies have also shed light on nongenomic actions of RAR 62. For instance, in murine neuronal dendrites it has been shown that unliganded RARα can bind directly to mRNA and inhibit translation 63. Binding of RA to its receptor leads to the dissociation of RARα from the mRNA and relief of translational repression 63. In addition, RA has also been shown to activate MAPK in a number of cell types 62. This occurs within minutes of administration, suggesting direct activation rather than transcriptional regulation 64. Activation of p38MAPK leads to phosphorylation of the RARα present in the membrane and cytosol, which in turn promotes recruitment of RAR to promoter regions of target genes. In this way, RA is able to link events at the cell membrane to its transcriptional regulation. Intriguingly, TCR-ligation and subsequent T-cell activation is required to observe RA-mediated effects on lymphocytes and this nonclassical pathway of RA signaling may play a key role in linking T-cell activation to subsequent transcriptional regulation by RA-RAR. However, at this stage, little is known about the importance of the nongenomic actions of RA relative to its classical regulation of transcription in hematopoietic cells. In other cell types studied, only a small fraction of RAR is available for nongenomic activities 64, suggesting that nontranscriptional activities of RA play a minor role in its overall activities.

Immunotherapy with retinoids

Retinoids as immunosuppressive agents

Topical and oral retinoids have long been used in the treatment of psoriasis with presumed benefits related to their effects on keratinocyte differentiation and proliferation. Accumulating evidence has implicated the Th17 pathway in the pathogenesis of psoriasis 65, 66, and it may be that the therapeutic effect of retinoids in psoriasis are related to their immunoregulatory effects. The ability of RA to induce Treg cells in vitro, coupled with the suppression of Th1 and Th17 responses observed with high dose retinoids, points to a potential role for retinoids as immunosuppressive agents. In support of this, retinoids have been shown to ameliorate disease in two mouse models of systemic lupus erythematosus 67, 68. Reduction in SLE disease was associated with the inhibition of Th1 responses. RA treatment has also been shown to significantly reduce the incidence of diabetes in a spontaneous mouse model of type 1 diabetes (NOD) with established insulitis 69. Adoptive transfer of NOD splenocytes into NOD/scid recipients leads to the onset of diabetes following infiltration of the pancreas by Th1, Th17, and IFN-γ⁺ CD8⁺ T cells. Treatment of recipient mice with RA inhibits the development of Th1 responses with a reciprocal increase in islet infiltrating Treg cells 69. Retinoids have also shown beneficial effect in mouse models of rheumatoid arthritis 70, 71. A reduction in disease severity was associated with reduced IL-17 and IL-21 levels within the synovial fluid, as well as reduced antibody production 71. One limitation to current retinoid therapy is the adverse toxicity profile, teratogenicity being of particular concern in female patients. Retinoids in current clinical use are pan-RAR agonists. Agonists selective for RARα, the isotype implicated in effector T-cell responses, are currently in clinical development, and would be predicted to have a better side effect profile with fewer off target effects.

One possible future use for retinoids is the ex vivo generation of stable Treg cells for cellular immunotherapy in the context of autoimmune disease and transplantation. The stability of ex vivo expanded Treg cells has been a significant concern; RA treatment of Treg cells has been shown to constrain their plasticity within an inflammatory setting 38, 72. RA treatment could thus foreseeably be incorporated into protocols for Treg-cell expansion. RA-mediated induction of CCR9 and α4β7 may also generate Treg cells with enhanced capacity for gut homing, which could be advantageous in the setting of inflammatory bowel disease.

Recent studies that have identified a role for RARα in constraining developmental plasticity of Th cells, point toward a therapeutic role for RARα agonists in diseases where Th cell plasticity may contribute to disease pathogenesis. For example, hybrid Th1–Th17 cells have been implicated in the pathogenicity of a number of autoimmune disease including Crohn's disease, multiple sclerosis and juvenile idiopathic arthritis 73-75 and instability of Treg cells has been implicated in the pathogenesis of rheumatoid arthritis 76. Further studies are required to test the utility of RARα agonists in these settings.

Concluding remarks

Recent advances have led to an increased understanding of why vitamin A is so critical for immunological health and has extended the importance of this vitamin beyond the malnourished patient. Given the pleiotropic effects of RA, the challenge for the successful use of RA in immunotherapy will rely on a detailed understanding of the molecular mechanisms through which RA receptors mediate their effects, opening the door for new immunomodulatory drugs.

Acknowledgments

This work was supported the Wellcome Trust (Research Training Fellowship to CB and Program Grant to RJN) and the NIH (R01AT005382 to RJN).

Conflict of interest

The authors declare no financial or commercial conflict of interest.

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Abbreviations

ILC3s: type 3 innate lymphoid cell
IEL: intraepithelial lymphocyte
LTi: lymphoid tissue inducer
PP: Peyer's patches
RA: retinoic acid
RAR: RA receptor
RDH: retinol dehydrogenase
RXR: retinoid X receptor
VAD: vitamin A-deficient

Citing Literature

Volume45, Issue5

May 2015

Pages 1287-1295

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

Abstract

Introduction

Biological activity of retinoic acid

Retinoic acid: Mucosal immunity and beyond

RA regulation of T-helper cell fate and plasticity

RA enhances Foxp3 expression and stability

Retinoic acid is critical for Th1 lineage stability

Retinoic acid and Th17 differentiation

Influence of retinoic acid on Th2 differentiation

Retinoic acid as an immune morphogen—Two possible models

Retinoic acid signaling: Novel mechanisms of transcriptional regulation

Immunotherapy with retinoids

Retinoids as immunosuppressive agents

Concluding remarks

Acknowledgments

Conflict of interest

References

Abbreviations

Citing Literature

Figures

References

Information

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

Abstract

Introduction

Biological activity of retinoic acid

Retinoic acid: Mucosal immunity and beyond

RA regulation of T-helper cell fate and plasticity

RA enhances Foxp3 expression and stability

Retinoic acid is critical for Th1 lineage stability

Retinoic acid and Th17 differentiation

Influence of retinoic acid on Th2 differentiation

Retinoic acid as an immune morphogen—Two possible models

Retinoic acid signaling: Novel mechanisms of transcriptional regulation

Immunotherapy with retinoids

Retinoids as immunosuppressive agents

Concluding remarks

Acknowledgments

Conflict of interest

References

Abbreviations

Citing Literature

Figures

References

Related

Information