Modulation of T Cell and Innate Immune Responses by Retinoic Acid

Mathilde Raverdeau and Kingston H. G. Mills
J Immunol April 1, 2014, 192 (7) 2953-2958; DOI: https://doi.org/10.4049/jimmunol.1303245

Abstract

Retinoic acid (RA) is produced by a number of cell types, including macrophages and dendritic cells, which express retinal dehydrogenases that convert vitamin A to its main biologically active metabolite, all-trans RA. All-trans RA binds to its nuclear retinoic acid receptors that are expressed in lymphoid cells and act as transcription factors to regulate cell homing and differentiation. RA production by CD103+ dendritic cells and alveolar macrophages functions with TGF-β to promote conversion of naive T cells into Foxp3+ regulatory T cells and, thereby, maintain mucosal tolerance. Furthermore, RA inhibits the differentiation of naive T cells into Th17 cells. However, Th1 and Th17 responses are constrained during vitamin A deficiency and in nuclear RA receptor α–defective mice. Furthermore, RA promotes effector T cell responses during infection or autoimmune diseases. Thus, RA plays a role in immune homeostasis in the steady-state but activates pathogenic T cells in conditions of inflammation.

Introduction

Vitamin A or retinol (ROL) is essential for pre- and postnatal development, eyesight, and reproduction, and it plays a crucial role in the maintenance of the immune system (1–4). Exclusively provided through the diet, the different forms of ROL are absorbed by enterocytes and are predominantly stored in the liver (5, 6). In cells, ROL is either stored or hydrolyzed into retinal by ubiquitous alcohol dehydrogenases. A second and irreversible hydrolysis reaction allows the formation of retinoic acid (RA), the main biologically active metabolite of ROL (7). This limiting step is catalyzed by cell-specific retinaldehyde dehydrogenases (RALDH1, RALDH2, and RALDH3) and defines the range of action of RA (8).

RALDH enzymes produce two isoforms of RA: all-trans RA (atRA) and 9-cis RA (9cisRA) (9). Both atRA and 9cisRA are autocrine or paracrine ligands of the nuclear RA receptors (RARα, RARβ, and RARγ), whereas the nuclear rexinoid receptors (RXRα, RXRβ, and RXRγ) only bind to 9cisRA (10, 11). Nevertheless, 9cisRA has not been detected in vivo, with the exception of the pancreas, in which it has been implicated in glucose metabolism (12). It is commonly understood that RARs act as heterodimers with RXRs and that the activity of the RXR is dependent on the activation of their ligand-inducible RAR partners (13). However, more recent studies (14–17) described intra- and extranuclear pathways driven by RARs independently of RXRs. Nevertheless, the majority of known functions of RA in immunity can be attributed to the canonical RAR/RXR pathway, driven by atRA produced by RALDH2 and acting through RARα. In this brief review, we highlight the recent key findings on the effects of vitamin A on T cells and innate immune responses.

RA in innate immunity, including its influence on APCs

A number of studies demonstrated that atRA has an important modulating role in innate immunity, with the most recent reports showing that RA has a central function in the differentiation of dendritic cells (DCs), the key APCs for activating naive T cells. Indeed, DCs express the three isotypes of RAR, especially RARα, and are able to respond directly to RA (18). It was shown that RA regulates the development and homeostasis of splenic CD11b+CD8α−CD4−Esamhigh DCs and the developmentally related intestinal CD11b+CD103+ DCs but not other splenic or gut DC populations (19, 20). These two DC subtypes are specialized in MHC class II–restricted Ag presentation to CD4+ T cells both in vitro and in vivo and in the differentiation of IL-17–producing CD4+ T cells (Th17 cells) in vivo, respectively (21, 22). However the mechanism by which RA regulates the fate of these DCs remains to be determined. One hypothesis proposed by several groups is that RA influences the Notch-2 pathway; Notch-2 signaling is required for the differentiation of CD11b+CD8α−CD4−Esamhigh and CD11b+CD103+ DCs and is influenced by RA during development (22–25).

In addition to its impact on commitment of specific DC populations, RA influences the function of DCs. For example, atRA can modulate monocyte-derived DCs toward a mucosal-type DC, which secretes TGF-β and IL-6 and has the capacity to induce gut-homing receptors on T cells (26). atRA also enhances the migratory properties of DCs, which is crucial for their Ag-presenting function during infection. atRA induces expression of the matrix metalloproteinases (MMP) MMP-9 and MMP-14 but not MMP-2, and it decreases the production of their inhibitors (tissue inhibitor of matrix metalloproteinase; TIMP) TIMP-1, TIMP-2, and TIMP-3, as well as the surface expression of the adhesion molecule CD11a on DCs in vitro (27, 28). MMP-9 and MMP-14 are involved in DC migration (29–31), and it was demonstrated that atRA promotes the migration of DCs in vivo toward draining lymph nodes in a murine model of cancer (27). This property of atRA is mediated through RARα, because its repression leads to a reduction in MMP-9 expression, whereas expression of CD11a on DCs and adherence of the CD11c+ DCs are both increased (28, 31). The enhancement of MMP-9 expression by atRA is likely to be mediated directly through the binding of RARα to the regulatory sequences of Mmp9 (31), although further studies are required to confirm this hypothesis.

In a proinflammatory context, atRA also has a direct influence on the Ag-presenting capacity of DCs. The positive or negative influence of atRA seems to be dependent on the proinflammatory context and/or the type of DC. During the development of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis, atRA influences the APC function of splenic DCs by decreasing surface expression of MHC class II and the costimulatory molecules CD80 and CD86 (32). It was also shown that atRA can activate skin DCs called Langerhans cells; in the presence of the proinflammatory cytokines TNF-α and IL-1-β, atRA upregulates MHC class II and CD86 on Langerhans cells and induces binding of NF-κB to its response element on DNA (33).

In addition to its influence on DC differentiation, RA is directly produced by DCs; these cells express the RALDH enzymes, in particular RALDH2 (34). The production of RA by DCs was first described for intestinal CD103+ DCs, located mainly in the lamina propria, but also in the associated Peyer’s patches and mesenteric lymph nodes (MLNs) (34–37). Interestingly, the effect of atRA on DCs probably results from the autocrine action of RA produced by DCs themselves (34–37). Nevertheless, there are other sources of RA in the gut, such as intestinal macrophages, which express both RALDH1 and RALDH2 (38). The imprinting of intestinal CD103+ DCs to produce RA is not directly influenced by dietary vitamin A, but instead seems to rely on the stores of ROL and occurs directly in the small intestine (39). A number of studies (37, 39–41) demonstrated the importance of RA production by CD103+ DCs in the gut and its associated lymphoid tissues (GALT). However, RA is also produced in other DC populations, particularly in DCs located at the environmental interfaces, such as the skin, the lungs, and the corresponding draining lymph nodes (42, 43). At the molecular level, RA signaling in DCs is enhanced by RA itself (44, 45), as well as by the cytokines GM-CSF (35, 44), IL-4 (35, 45, 46), IL-13 (44), the MAPK p38α (45, 47), and TLR activation (18, 35, 46). Manicassamy et al. (18) showed that specific activation of the TLR2-signaling pathway induces strong expression of RALDH2 in splenic DCs and, as a consequence, SOCS3 expression, which suppresses the production of proinflammatory cytokines, including IL-23. Moreover, IL-4 enhances expression of RALDH2 and RARβ at the transcriptional level, thus creating a positive-control loop on the RA pathway within inflammatory DCs (45). Interestingly, treatment of inflammatory DCs with IL-4 and atRA suppresses production of proinflammatory cytokines IL-6, IL-12p70, and TNF-α through a SOCS3-dependent mechanism (18, 45). In contrast, PGE2 appears to be a central negative regulator of RALDH expression in DCs, possibly through the induction of cAMP, a known repressor of RALDH (44). Importantly, recent studies (48, 49) showed a decrease in RALDH expression by intestinal and MLN DCs during infection with Trichuris muris and during colitis induced by T cell transfer in mice. These findings point to a crucial role for the inflammatory milieu in the regulation of RA production during inflammation. However, it is important to note that the influence of RA on the function of DCs in a proinflammatory context depends on the cytokines involved in the inflammation. For example, DePaolo et al. (50) demonstrated that IL-15 acts with RA on DCs to induce the phosphorylation of JNK, leading to the release of the proinflammatory cytokines IL-12p70 and IL-23.

Influence of RA on regulatory T cells and effector/pathogenic T cells

A study by Iwata et al. (34) was one of the first to describe a role for RA in the biology of T cells; they found that RA enhances the expression of the gut-homing molecules α4β7 and CCR9 on CD4+ T cells, thus promoting preferential migration into the intestinal lamina propria and GALT. This function is supported by the intestinal RA-producing CD103+ DCs through RARα and RARβ but not RARγ, whereas the activation of RXR enhances the effect but appears to be dispensable (34, 51). In fact, the RA/RARα pathway directly controls the expression of the integrin subunit α4 (52). Moreover, expression of the integrins α4β7 and α4β1 (also known as VLA-4 and implicated in the migration of T cells into tissues) is greatly decreased on the surface of T cells during a state of vitamin A deficiency (VAD), leading to defective migratory properties of these cells (52).

The observation that RA influences T cell migration was followed 3 y later by a major breakthrough on the function of RA in the maintenance of intestinal homeostasis, with the discovery that local RA produced by DCs and macrophages in the intestine and GALT promotes conversion of naive CD4+ T cells into induced regulatory T cells (iTregs) (37, 38, 40, 53). Moreover, RA confers gut-homing properties on the regulatory T cells (Tregs) by increasing their expression of α4β7 and CCR9 (40, 54), partly through a BATF-dependent mechanism (55). In both mice and humans, RA cooperates with TGF-β to promote conversion of naive CD4+ T cells into Foxp3+ iTregs (37, 53, 56), and this effect is mediated, at least in part, through RARα (53, 57). Interestingly, in a mouse model of Crohn’s disease, excessive stocks of vitamin A induced the conventional CCR9+α4β7+Foxp3+ population of Tregs, whereas a state of VAD generated CD103+CCR7+Foxp3+ Tregs; both Treg types helped to control intestinal inflammation (58).

The mechanism by which RA promotes iTregs is unclear, and there are a number of possibilities. RA appears to determine whether naive CD4+ T cells differentiate into iTregs or Th17 cells, both of which require TGF-β. atRA inhibits expression of IL-6Rα on naive T cells, which, together with TGF-β, promotes differentiation of naive T cells into Th17 cells; IL-6 has the reciprocal effect of inhibiting the expression of RARα (41, 59, 60). Moreover atRA acts through RARα in activated CD4+ T cells to promote the expression of Foxp3, independently of the cytokine IL-2, the TGF-β–signaling molecules SMAD3 and SMAD4, and the transcription factors STAT3 and STAT5 (59, 61, 62). Furthermore, RA enhances the expression of arginase 1 in DCs in vitro, an enzyme known to promote the production of Tregs (63). In contrast, atRA decreases T cell expression of RORγt, a transcription factor that is crucial for the differentiation of Th17 cells (60). It was reported recently that RA induces expression of the micro-RNA miR-10a in iTreg, which suppresses the negative effect of Bcl-6 and Ncor-2 on the stability of the iTreg population (64).

RA also induces iTreg conversion indirectly through inhibiting a population of CD4+CD44high memory T cells, which block the differentiation of naive T cells into Tregs, by secreting the cytokines IL-4, IL-21, and IFN-γ (59, 65, 66). In the absence of RARα-mediated modulation of CD4+CD44high memory T cells, the effect of RA on iTreg conversion is significantly decreased (59, 65). Interestingly, in the GALT, but not in lymph nodes and spleen, activation of CD44high T cells in the absence of TGF-β leads to the expression of the RA-degrading enzyme CYP26B1, which, in turn, inhibits the expression of CCR9 on T cells (67). Surprisingly, although enhancing the proportion of Tregs, both human and murine studies (68, 69) found that RA downregulates the expression of IL-10, an anti-inflammatory cytokine often produced by Treg during inflammation.

Because RA-producing DCs are found in organs at the environmental interfaces, it is important to note that in the skin a subset of DCs that, unlike RA-producing intestinal DCs, do not express CD103 but are CD11b+CD24+, express RALDH2, and produce RA (42). Moreover, these cells are able to induce Foxp3+ iTregs from naive CD4+ T cells (42). In the liver, hepatic stellate cells produce RA and are able to induce Foxp3+ Tregs in the presence of DCs and TGF-β1 (70). In the lungs, alveolar CD11c+F4/80+ macrophages promote the induction of Foxp3+ Tregs and mediate respiratory tolerance via the production of RA and TGF-β (71). A complementary study (72) showed that lung-resident tissue macrophages coexpress TGF-β and RALDH and have regulatory functions. Furthermore, in a model of experimental allergic asthma, treatment with atRA attenuates airways inflammation by inhibiting Th2 and Th17 responses (73).

Despite its role in promoting the differentiation of Tregs required to maintain mucosal homeostasis, recent studies established a central role for RA in the activation of effector CD4+ T cells during inflammation (Fig. 1). Thus, in a proinflammatory context, the RA-signaling pathway in CD4+ T cells is enhanced at the site of inflammation (74). CD4+ T cell effector function and migration to the site of inflammation were inhibited by conditional ablation of RA signaling in T cells (74). Hall et al. (75) showed that the RA–RARα axis is essential for the production of the proinflammatory cytokines IFN-γ and IL-17A by Th1 and Th17 cells in response to infection. Moreover, in a proinflammatory context involving cytokines, such as IL-15, RA acts through DCs to decrease conversion of naive T cells into Tregs and to enhance Th1 cell polarization (50). RA also has direct effects on CD8+ T cells; Allie et al. (76) found that the absence of functional RARα resulted in a lack of effector CD8+ T cells, whereas the population of central memory CD8+ T cells appeared to be increased. Importantly, both splenic and MLN DCs are able to enhance the RA pathway in CD8+ T cells (77), and both MLN and intestinal CD103+ DCs induced the RARα-dependent expression of the gut-homing molecules on activated CD8+ T cells (77–79).

FIGURE 1.
FIGURE 1.

Immunomodulatory effects of RA. In the steady-state, RA produced by CD103+ DCs and alveolar macrophages helps to maintain immune homeostasis and mucosal tolerance by working with TGF-β to promote expansion of Tregs from naive T cells, while inhibiting Th1 and Th17 cells. In addition, RA constrains the inhibitory effect of CD4+CD44high T cells on Tregs. However, in conditions of inflammation (e.g., during autoimmunity or infection), when the inflammatory cytokines IL-1β, IL-12, IL-18, and IL-23 are produced, RA promotes IFN-γ production by Th1 cells, IL-17 production by Th17 cells, and IL-22 production by γδ T cells. During inflammation, RA also works with IL-15 to decrease conversion of naive T cells into Tregs.

Impact of RA on γδ T cells, NK cells, and innate lymphoid cells

In addition to its effect on T cells and DCs, RA modulates innate lymphoid cells (ILCs) and γδ T cells at the interface of innate and adaptive immunity. Consistent with the effect of CD4+ T cells, we found that RA inhibits IL-17A production by γδ T cells but, interestingly, enhances the production of IL-22 by γδ T cells and group 3 ILCs stimulated with IL-1β and IL-23 (80). Furthermore, in vivo administration of RA promotes recovery from intestinal inflammation induced by dextran sulfate sodium or following infection with Citrobacter rodentium, and this is associated with enhanced production of IL-22 and the antimicrobial peptides REG3β and REG3γ (80). Consistent with the protective effects of atRA, Chenery et al. (81) showed that mice lacking the RA-degrading enzyme CYP26B1 are protected against T cell–induced intestinal inflammation. In a model of autoimmune disease, experimental autoimmune uveitis, administration of atRA is associated with a decrease in expression of the activation markers CD25 and CD69 on pathogenic γδ T cells. Furthermore, because atRA reduces IL-17A production by γδ T cells (80) and because IL-17A and IL-21 produced by γδ T cells can activate Th17 cells (82), RA may decrease the ability of γδ T cells to activate autoreactive Th17 cells (83). This provides further evidence that RA can have direct and indirect effects on CD4+ effector T cells. Studies in humans (84) showed that the RA–RARα pathway induces expression of the gut-homing integrin α4β7 and its ligand addressin (MAdCAM-1) on circulating Vδ2+ γδ T cells, while decreasing their production of the skin-homing receptor cutaneous lymphocyte Ag.

There is also evidence that RA can influence the function of NK cells. RA enhances expression of the lipid Ag-presenting molecules CD1d on DCs, thereby promoting activation of NKT cells (85). Moreover, the number of circulating NK and NKT cells in humans is positively regulated by the level of the ROL stores (69). In tumor cells, RA also increases the expression of the RA early inducible genes RAE-1 and MICA/B, which activate NK cells through binding to NKG2D (86, 87).

Conclusions

Although the benefits of dietary vitamin A supplementation in controlling child mortality in developing countries is still controversial (88), there is evidence both from human and mouse studies that VAD is associated with defective immune responses to infection or following vaccination (75, 89). These studies led to the conclusion that vitamin A or its metabolite RA plays a role in driving adaptive immunity. Ironically, the early studies (37, 41) on the immunomodulatory functions of RA demonstrated a role, with TGF-β, in promoting the conversion of naive T cells to iTregs. RA produced by gut-resident CD103+ DCs helps to maintain intestinal tolerance by promoting expansion of Tregs in vitro and inhibiting Th17 cells both in vitro and in vivo (41). However, further investigation revealed that, in the context of inflammation, during infection or in autoimmunity, RA has the opposite effect of promoting effector T cell responses (75), explaining the original observations about VAD. Thus, the immunomodulatory effects of RA on the immune system is both tissue and context dependent and, although VAD may curtail effector T cell responses during infection or following vaccination, inhibition of RA binding to its receptor can reduce iTregs, which has the indirect effect of enhancing effector T cell responses during cancer (90).

In terms of therapeutic application of the immunomodulatory effects of RA or its inhibitors, we demonstrated that treatment with atRA is protective against intestinal inflammation induced by gut microbes through enhancement of IL-22 production by γδ T cells and group 3 ILCs (80). Furthermore, atRA is protective against experimental autoimmune encephalomyelitis (91), in which autoimmune inflammation is mediated by Th1 and Th17 cells. Conversely, treatment of children with vitamin A can enhance the efficacy of infectious disease vaccines (92). Furthermore, we demonstrated that treatment of mice with an RARα inhibitor can enhance the protective efficacy of a DC vaccine against B16 tumors, suppressing the induction of Tregs and promoting Th1 responses (90). Therefore, modulating RA signaling by dietary supplementation with vitamin A, treatment with agonists, or inhibitors of RAR has potential for enhancing natural and vaccine-induced immunity against infections or cancer, as well as in the treatment of immune-mediated diseases in humans.

Disclosures

K.H.G.M. is a cofounder and shareholder in Opsona Therapeutics and TriMod Therapeutics, university spin-out companies from Trinity College involved in the development of immunotherapeutics.

Footnotes

  • This work was supported by Science Foundation Ireland.

  • Abbreviations used in this article:

    atRA
    all-trans retinoic acid
    DC
    dendritic cell
    ILC
    innate lymphoid cell
    iTreg
    inducible regulatory T cell
    MLN
    mesenteric lymph node
    MMP
    metalloproteinase
    RA
    retinoic acid
    RALDH
    retinaldehyde dehydrogenase
    RAR
    retinoic acid receptor
    ROL
    retinol
    RXR
    rexinoid receptor
    TIMP
    tissue inhibitor of matrix metalloproteinase
    Treg
    regulatory T cell
    VAD
    vitamin A deficiency.

  • Received December 4, 2013.
  • Accepted January 13, 2014.

References

  1. ↵
    1. Warkany J.,
    2. E. Schraffenberger
    . 1946. Congenital malformations induced in rats by maternal vitamin A deficiency; defects of the eye. Arch. Ophthal. 35: 150–169.
    OpenUrlCrossRefPubMed
    1. Wolbach S. B.,
    2. P. R. Howe
    . 1925. Tissue Changes Following Deprivation of Fat-Soluble a Vitamin. J. Exp. Med. 42: 753–777.
    OpenUrlAbstract
    1. Dowling J. E.,
    2. G. Wald
    . 1958. Vitamin a Deficiency and Night Blindness. Proc. Natl. Acad. Sci. USA 44: 648–661.
    OpenUrlFREE Full Text
  4. ↵
    1. Ross A. C.,
    2. C. B. Stephensen
    . 1996. Vitamin A and retinoids in antiviral responses. FASEB J. 10: 979–985.
    OpenUrlAbstract
  5. ↵
    1. Harrison E. H.
    2012. Mechanisms involved in the intestinal absorption of dietary vitamin A and provitamin A carotenoids. Biochim. Biophys. Acta 1821: 70–77.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Blomhoff R.
    1994. Transport and metabolism of vitamin A. Nutr. Rev. 52: S13–S23.
    OpenUrlPubMed
  7. ↵
    1. Dowling J. E.,
    2. G. Wald
    . 1960. The Biological Function of Vitamin A Acid. Proc. Natl. Acad. Sci. USA 46: 587–608.
    OpenUrlFREE Full Text
  8. ↵
    1. Duester G.,
    2. F. A. Mic,
    3. A. Molotkov
    . 2003. Cytosolic retinoid dehydrogenases govern ubiquitous metabolism of retinol to retinaldehyde followed by tissue-specific metabolism to retinoic acid. Chem. Biol. Interact. 143-144: 201–210.
    OpenUrl
  9. ↵
    1. Lin M.,
    2. J. L. Napoli
    . 2000. cDNA cloning and expression of a human aldehyde dehydrogenase (ALDH) active with 9-cis-retinal and identification of a rat ortholog, ALDH12. J. Biol. Chem. 275: 40106–40112.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Durand B.,
    2. M. Saunders,
    3. P. Leroy,
    4. M. Leid,
    5. P. Chambon
    . 1992. All-trans and 9-cis retinoic acid induction of CRABPII transcription is mediated by RAR-RXR heterodimers bound to DR1 and DR2 repeated motifs. Cell 71: 73–85.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Heyman R. A.,
    2. D. J. Mangelsdorf,
    3. J. A. Dyck,
    4. R. B. Stein,
    5. G. Eichele,
    6. R. M. Evans,
    7. C. Thaller
    . 1992. 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 68: 397–406.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Kane M. A.,
    2. A. E. Folias,
    3. A. Pingitore,
    4. M. Perri,
    5. K. M. Obrochta,
    6. C. R. Krois,
    7. E. Cione,
    8. J. Y. Ryu,
    9. J. L. Napoli
    . 2010. Identification of 9-cis-retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion. Proc. Natl. Acad. Sci. USA 107: 21884–21889.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Germain P.,
    2. J. Iyer,
    3. C. Zechel,
    4. H. Gronemeyer
    . 2002. Co-regulator recruitment and the mechanism of retinoic acid receptor synergy. Nature 415: 187–192.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Dedieu S.,
    2. P. Lefebvre
    . 2006. Retinoids interfere with the AP1 signalling pathway in human breast cancer cells. Cell. Signal. 18: 889–898.
    OpenUrlCrossRefPubMed
    1. Piskunov A.,
    2. C. Rochette-Egly
    . 2012. A retinoic acid receptor RARα pool present in membrane lipid rafts forms complexes with G protein αQ to activate p38MAPK. Oncogene 31: 3333–3345.
    OpenUrlCrossRefPubMed
    1. Vernet N.,
    2. C. Dennefeld,
    3. F. Guillou,
    4. P. Chambon,
    5. N. B. Ghyselinck,
    6. M. Mark
    . 2006. Prepubertal testis development relies on retinoic acid but not rexinoid receptors in Sertoli cells. EMBO J. 25: 5816–5825.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Chen N.,
    2. B. Onisko,
    3. J. L. Napoli
    . 2008. The nuclear transcription factor RARalpha associates with neuronal RNA granules and suppresses translation. J. Biol. Chem. 283: 20841–20847.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Manicassamy S.,
    2. R. Ravindran,
    3. J. Deng,
    4. H. Oluoch,
    5. T. L. Denning,
    6. S. P. Kasturi,
    7. K. M. Rosenthal,
    8. B. D. Evavold,
    9. B. Pulendran
    . 2009. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nat. Med. 15: 401–409.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Klebanoff C. A.,
    2. S. P. Spencer,
    3. P. Torabi-Parizi,
    4. J. R. Grainger,
    5. R. Roychoudhuri,
    6. Y. Ji,
    7. M. Sukumar,
    8. P. Muranski,
    9. C. D. Scott,
    10. J. A. Hall,
    11. et al
    . 2013. Retinoic acid controls the homeostasis of pre-cDC-derived splenic and intestinal dendritic cells. J. Exp. Med. 210: 1961–1976.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Beijer M. R.,
    2. R. Molenaar,
    3. G. Goverse,
    4. R. E. Mebius,
    5. G. Kraal,
    6. J. M. den Haan
    . 2013. A crucial role for retinoic acid in the development of Notch-dependent murine splenic CD8− CD4− and CD4+ dendritic cells. Eur. J. Immunol. 43: 1608–1616.
    OpenUrlCrossRefPubMed
  21. ↵
    1. Persson E. K.,
    2. H. Uronen-Hansson,
    3. M. Semmrich,
    4. A. Rivollier,
    5. K. Hägerbrand,
    6. J. Marsal,
    7. S. Gudjonsson,
    8. U. Håkansson,
    9. B. Reizis,
    10. K. Kotarsky,
    11. W. W. Agace
    . 2013. IRF4 transcription-factor-dependent CD103(+)CD11b(+) dendritic cells drive mucosal T helper 17 cell differentiation. Immunity 38: 958–969.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Lewis K. L.,
    2. M. L. Caton,
    3. M. Bogunovic,
    4. M. Greter,
    5. L. T. Grajkowska,
    6. D. Ng,
    7. A. Klinakis,
    8. I. F. Charo,
    9. S. Jung,
    10. J. L. Gommerman,
    11. et al
    . 2011. Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity 35: 780–791.
    OpenUrlCrossRefPubMed
    1. Wingert R. A.,
    2. R. Selleck,
    3. J. Yu,
    4. H. D. Song,
    5. Z. Chen,
    6. A. Song,
    7. Y. Zhou,
    8. B. Thisse,
    9. C. Thisse,
    10. A. P. McMahon,
    11. A. J. Davidson
    . 2007. The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros. PLoS Genet. 3: 1922–1938.
    OpenUrlCrossRefPubMed
    1. Mitsiadis T. A.,
    2. M. Lardelli,
    3. U. Lendahl,
    4. I. Thesleff
    . 1995. Expression of Notch 1, 2 and 3 is regulated by epithelial-mesenchymal interactions and retinoic acid in the developing mouse tooth and associated with determination of ameloblast cell fate. J. Cell Biol. 130: 407–418.
    OpenUrlAbstract/FREE Full Text
  25. ↵
    1. Ying M.,
    2. S. Wang,
    3. Y. Sang,
    4. P. Sun,
    5. B. Lal,
    6. C. R. Goodwin,
    7. H. Guerrero-Cazares,
    8. A. Quinones-Hinojosa,
    9. J. Laterra,
    10. S. Xia
    . 2011. Regulation of glioblastoma stem cells by retinoic acid: role for Notch pathway inhibition. Oncogene 30: 3454–3467.
    OpenUrlCrossRefPubMed
  26. ↵
    1. Saurer L.,
    2. K. C. McCullough,
    3. A. Summerfield
    . 2007. In vitro induction of mucosa-type dendritic cells by all-trans retinoic acid. J. Immunol. 179: 3504–3514.
    OpenUrlAbstract/FREE Full Text
  27. ↵
    1. Darmanin S.,
    2. J. Chen,
    3. S. Zhao,
    4. H. Cui,
    5. R. Shirkoohi,
    6. N. Kubo,
    7. Y. Kuge,
    8. N. Tamaki,
    9. K. Nakagawa,
    10. J. Hamada,
    11. et al
    . 2007. All-trans retinoic acid enhances murine dendritic cell migration to draining lymph nodes via the balance of matrix metalloproteinases and their inhibitors. J. Immunol. 179: 4616–4625.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Lackey D. E.,
    2. S. L. Ashley,
    3. A. L. Davis,
    4. K. A. Hoag
    . 2008. Retinoic acid decreases adherence of murine myeloid dendritic cells and increases production of matrix metalloproteinase-9. J. Nutr. 138: 1512–1519.
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Ratzinger G.,
    2. P. Stoitzner,
    3. S. Ebner,
    4. M. B. Lutz,
    5. G. T. Layton,
    6. C. Rainer,
    7. R. M. Senior,
    8. J. M. Shipley,
    9. P. Fritsch,
    10. G. Schuler,
    11. N. Romani
    . 2002. Matrix metalloproteinases 9 and 2 are necessary for the migration of Langerhans cells and dermal dendritic cells from human and murine skin. J. Immunol. 168: 4361–4371.
    OpenUrlAbstract/FREE Full Text
    1. Yang M. X.,
    2. X. Qu,
    3. B. H. Kong,
    4. Q. L. Lam,
    5. Q. Q. Shao,
    6. B. P. Deng,
    7. K. H. Ko,
    8. L. Lu
    . 2006. Membrane type 1-matrix metalloproteinase is involved in the migration of human monocyte-derived dendritic cells. Immunol. Cell Biol. 84: 557–562.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Lackey D. E.,
    2. K. A. Hoag
    . 2010. Vitamin A upregulates matrix metalloproteinase-9 activity by murine myeloid dendritic cells through a nonclassical transcriptional mechanism. J. Nutr. 140: 1502–1508.
    OpenUrlAbstract/FREE Full Text
  32. ↵
    1. Zhan X. X.,
    2. Y. Liu,
    3. J. F. Yang,
    4. G. Y. Wang,
    5. L. Mu,
    6. T. S. Zhang,
    7. X. L. Xie,
    8. J. H. Wang,
    9. Y. M. Liu,
    10. Q. F. Kong,
    11. et al
    . 2013. All-trans-retinoic acid ameliorates experimental allergic encephalomyelitis by affecting dendritic cell and monocyte development. Immunology 138: 333–345.
    OpenUrlCrossRefPubMed
  33. ↵
    1. Geissmann F.,
    2. P. Revy,
    3. N. Brousse,
    4. Y. Lepelletier,
    5. C. Folli,
    6. A. Durandy,
    7. P. Chambon,
    8. M. Dy
    . 2003. Retinoids regulate survival and antigen presentation by immature dendritic cells. J. Exp. Med. 198: 623–634.
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Iwata M.,
    2. A. Hirakiyama,
    3. Y. Eshima,
    4. H. Kagechika,
    5. C. Kato,
    6. S. Y. Song
    . 2004. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21: 527–538.
    OpenUrlCrossRefPubMed
  35. ↵
    1. Yokota A.,
    2. H. Takeuchi,
    3. N. Maeda,
    4. Y. Ohoka,
    5. C. Kato,
    6. S. Y. Song,
    7. M. Iwata
    . 2009. GM-CSF and IL-4 synergistically trigger dendritic cells to acquire retinoic acid-producing capacity. Int. Immunol. 21: 361–377.
    OpenUrlAbstract/FREE Full Text
    1. Hammerschmidt S. I.,
    2. M. Ahrendt,
    3. U. Bode,
    4. B. Wahl,
    5. E. Kremmer,
    6. R. Förster,
    7. O. Pabst
    . 2008. Stromal mesenteric lymph node cells are essential for the generation of gut-homing T cells in vivo. J. Exp. Med. 205: 2483–2490.
    OpenUrlAbstract/FREE Full Text
  37. ↵
    1. Coombes J. L.,
    2. K. R. Siddiqui,
    3. C. V. Arancibia-Cárcamo,
    4. J. Hall,
    5. C. M. Sun,
    6. Y. Belkaid,
    7. F. Powrie
    . 2007. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J. Exp. Med. 204: 1757–1764.
    OpenUrlAbstract/FREE Full Text
  38. ↵
    1. Denning T. L.,
    2. Y. C. Wang,
    3. S. R. Patel,
    4. I. R. Williams,
    5. B. Pulendran
    . 2007. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat. Immunol. 8: 1086–1094.
    OpenUrlCrossRefPubMed
  39. ↵
    1. Jaensson-Gyllenbäck E.,
    2. K. Kotarsky,
    3. F. Zapata,
    4. E. K. Persson,
    5. T. E. Gundersen,
    6. R. Blomhoff,
    7. W. W. Agace
    . 2011. Bile retinoids imprint intestinal CD103+ dendritic cells with the ability to generate gut-tropic T cells. Mucosal Immunol. 4: 438–447.
    OpenUrlCrossRefPubMed
  40. ↵
    1. Benson M. J.,
    2. K. Pino-Lagos,
    3. M. Rosemblatt,
    4. R. J. Noelle
    . 2007. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J. Exp. Med. 204: 1765–1774.
    OpenUrlAbstract/FREE Full Text
  41. ↵
    1. Mucida D.,
    2. Y. Park,
    3. G. Kim,
    4. O. Turovskaya,
    5. I. Scott,
    6. M. Kronenberg,
    7. H. Cheroutre
    . 2007. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317: 256–260.
    OpenUrlAbstract/FREE Full Text
  42. ↵
    1. Guilliams M.,
    2. K. Crozat,
    3. S. Henri,
    4. S. Tamoutounour,
    5. P. Grenot,
    6. E. Devilard,
    7. B. de Bovis,
    8. L. Alexopoulou,
    9. M. Dalod,
    10. B. Malissen
    . 2010. Skin-draining lymph nodes contain dermis-derived CD103(−) dendritic cells that constitutively produce retinoic acid and induce Foxp3(+) regulatory T cells. Blood 115: 1958–1968.
    OpenUrlAbstract/FREE Full Text
  43. ↵
    1. Ruane D.,
    2. L. Brane,
    3. B. S. Reis,
    4. C. Cheong,
    5. J. Poles,
    6. Y. Do,
    7. H. Zhu,
    8. K. Velinzon,
    9. J. H. Choi,
    10. N. Studt,
    11. et al
    . 2013. Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract. J. Exp. Med. 210: 1871–1888.
    OpenUrlAbstract/FREE Full Text
  44. ↵
    1. Stock A.,
    2. S. Booth,
    3. V. Cerundolo
    . 2011. Prostaglandin E2 suppresses the differentiation of retinoic acid-producing dendritic cells in mice and humans. J. Exp. Med. 208: 761–773.
    OpenUrlAbstract/FREE Full Text
  45. ↵
    1. Zhu B.,
    2. T. Buttrick,
    3. R. Bassil,
    4. C. Zhu,
    5. M. Olah,
    6. C. Wu,
    7. S. Xiao,
    8. W. Orent,
    9. W. Elyaman,
    10. S. J. Khoury
    . 2013. IL-4 and retinoic acid synergistically induce regulatory dendritic cells expressing Aldh1a2. J. Immunol. 191: 3139–3151.
    OpenUrlAbstract/FREE Full Text
  46. ↵
    1. Elgueta R.,
    2. F. E. Sepulveda,
    3. F. Vilches,
    4. L. Vargas,
    5. J. R. Mora,
    6. M. R. Bono,
    7. M. Rosemblatt
    . 2008. Imprinting of CCR9 on CD4 T cells requires IL-4 signaling on mesenteric lymph node dendritic cells. J. Immunol. 180: 6501–6507.
    OpenUrlAbstract/FREE Full Text
  47. ↵
    1. Huang G.,
    2. Y. Wang,
    3. H. Chi
    . 2013. Control of T cell fates and immune tolerance by p38α signaling in mucosal CD103+ dendritic cells. J. Immunol. 191: 650–659.
    OpenUrlAbstract/FREE Full Text
  48. ↵
    1. Hurst R. J.,
    2. K. J. Else
    . 2013. The retinoic acid-producing capacity of gut dendritic cells and macrophages is reduced during persistent T. muris infection. Parasite Immunol. 35: 229–233.
    OpenUrlCrossRefPubMed
  49. ↵
    1. Laffont S.,
    2. K. R. Siddiqui,
    3. F. Powrie
    . 2010. Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells. Eur. J. Immunol. 40: 1877–1883.
    OpenUrlCrossRefPubMed
  50. ↵
    1. DePaolo R. W.,
    2. V. Abadie,
    3. F. Tang,
    4. H. Fehlner-Peach,
    5. J. A. Hall,
    6. W. Wang,
    7. E. V. Marietta,
    8. D. D. Kasarda,
    9. T. A. Waldmann,
    10. J. A. Murray,
    11. et al
    . 2011. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471: 220–224.
    OpenUrlCrossRefPubMed
  51. ↵
    1. Takeuchi H.,
    2. A. Yokota,
    3. Y. Ohoka,
    4. H. Kagechika,
    5. C. Kato,
    6. S. Y. Song,
    7. M. Iwata
    . 2010. Efficient induction of CCR9 on T cells requires coactivation of retinoic acid receptors and retinoid X receptors (RXRs): exaggerated T cell homing to the intestine by RXR activation with organotins. J. Immunol. 185: 5289–5299.
    OpenUrlAbstract/FREE Full Text
  52. ↵
    1. Kang S. G.,
    2. J. Park,
    3. J. Y. Cho,
    4. B. Ulrich,
    5. C. H. Kim
    . 2011. Complementary roles of retinoic acid and TGF-β1 in coordinated expression of mucosal integrins by T cells. Mucosal Immunol. 4: 66–82.
    OpenUrlCrossRefPubMed
  53. ↵
    1. Kang S. G.,
    2. H. W. Lim,
    3. O. M. Andrisani,
    4. H. E. Broxmeyer,
    5. C. H. Kim
    . 2007. Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells. J. Immunol. 179: 3724–3733.
    OpenUrlAbstract/FREE Full Text
  54. ↵
    1. Siewert C.,
    2. A. Menning,
    3. J. Dudda,
    4. K. Siegmund,
    5. U. Lauer,
    6. S. Floess,
    7. D. J. Campbell,
    8. A. Hamann,
    9. J. Huehn
    . 2007. Induction of organ-selective CD4+ regulatory T cell homing. Eur. J. Immunol. 37: 978–989.
    OpenUrlCrossRefPubMed
  55. ↵
    1. Wang C.,
    2. S. Thangamani,
    3. M. Kim,
    4. B. H. Gu,
    5. J. H. Lee,
    6. E. J. Taparowsky,
    7. C. H. Kim
    . 2013. BATF is required for normal expression of gut-homing receptors by T helper cells in response to retinoic acid. J. Exp. Med. 210: 475–489.
    OpenUrlAbstract/FREE Full Text
  56. ↵
    1. Sun C. M.,
    2. J. A. Hall,
    3. R. B. Blank,
    4. N. Bouladoux,
    5. M. Oukka,
    6. J. R. Mora,
    7. Y. Belkaid
    . 2007. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204: 1775–1785.
    OpenUrlAbstract/FREE Full Text
  57. ↵
    1. Schambach F.,
    2. M. Schupp,
    3. M. A. Lazar,
    4. S. L. Reiner
    . 2007. Activation of retinoic acid receptor-alpha favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation. Eur. J. Immunol. 37: 2396–2399.
    OpenUrlCrossRefPubMed
  58. ↵
    1. Kang S. G.,
    2. C. Wang,
    3. S. Matsumoto,
    4. C. H. Kim
    . 2009. High and low vitamin A therapies induce distinct FoxP3+ T-cell subsets and effectively control intestinal inflammation. Gastroenterology 137: 1391–1402.e1–6.
    OpenUrlCrossRefPubMed
  59. ↵
    1. Nolting J.,
    2. C. Daniel,
    3. S. Reuter,
    4. C. Stuelten,
    5. P. Li,
    6. H. Sucov,
    7. B. G. Kim,
    8. J. J. Letterio,
    9. K. Kretschmer,
    10. H. J. Kim,
    11. H. von Boehmer
    . 2009. Retinoic acid can enhance conversion of naive into regulatory T cells independently of secreted cytokines. J. Exp. Med. 206: 2131–2139.
    OpenUrlAbstract/FREE Full Text
  60. ↵
    1. Zhou X.,
    2. N. Kong,
    3. J. Wang,
    4. H. Fan,
    5. H. Zou,
    6. D. Horwitz,
    7. D. Brand,
    8. Z. Liu,
    9. S. G. Zheng
    . 2010. Cutting edge: all-trans retinoic acid sustains the stability and function of natural regulatory T cells in an inflammatory milieu. J. Immunol. 185: 2675–2679.
    OpenUrlAbstract/FREE Full Text
  61. ↵
    1. Mucida D.,
    2. K. Pino-Lagos,
    3. G. Kim,
    4. E. Nowak,
    5. M. J. Benson,
    6. M. Kronenberg,
    7. R. J. Noelle,
    8. H. Cheroutre
    . 2009. Retinoic acid can directly promote TGF-beta-mediated Foxp3(+) Treg cell conversion of naive T cells. Immunity 30: 471–472, author reply 472–473.
    OpenUrlCrossRefPubMed
  62. ↵
    1. Elias K. M.,
    2. A. Laurence,
    3. T. S. Davidson,
    4. G. Stephens,
    5. Y. Kanno,
    6. E. M. Shevach,
    7. J. J. O’Shea
    . 2008. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood 111: 1013–1020.
    OpenUrlAbstract/FREE Full Text
  63. ↵
    1. Chang J.,
    2. S. Thangamani,
    3. M. H. Kim,
    4. B. Ulrich,
    5. S. M. Morris Jr..,
    6. C. H. Kim
    . 2013. Retinoic acid promotes the development of Arg1-expressing dendritic cells for the regulation of T-cell differentiation. Eur. J. Immunol. 43: 967–978.
    OpenUrlCrossRefPubMed
  64. ↵
    1. Takahashi H.,
    2. T. Kanno,
    3. S. Nakayamada,
    4. K. Hirahara,
    5. G. Sciumè,
    6. S. A. Muljo,
    7. S. Kuchen,
    8. R. Casellas,
    9. L. Wei,
    10. Y. Kanno,
    11. J. J. O’Shea
    . 2012. TGF-β and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells. Nat. Immunol. 13: 587–595.
    OpenUrlCrossRefPubMed
  65. ↵
    1. Hill J. A.,
    2. J. A. Hall,
    3. C. M. Sun,
    4. Q. Cai,
    5. N. Ghyselinck,
    6. P. Chambon,
    7. Y. Belkaid,
    8. D. Mathis,
    9. C. Benoist
    . 2008. Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi cells. Immunity 29: 758–770.
    OpenUrlCrossRefPubMed
  66. ↵
    1. Takeuchi H.,
    2. A. Yokota-Nakatsuma,
    3. Y. Ohoka,
    4. H. Kagechika,
    5. C. Kato,
    6. S. Y. Song,
    7. M. Iwata
    . 2013. Retinoid X receptor agonists modulate Foxp3+ regulatory T cell and Th17 cell differentiation with differential dependence on retinoic acid receptor activation. J. Immunol. 191: 3725–3733.
    OpenUrlAbstract/FREE Full Text
  67. ↵
    1. Takeuchi H.,
    2. A. Yokota,
    3. Y. Ohoka,
    4. M. Iwata
    . 2011. Cyp26b1 regulates retinoic acid-dependent signals in T cells and its expression is inhibited by transforming growth factor-β. PLoS ONE 6: e16089.
    OpenUrlCrossRefPubMed
  68. ↵
    1. Maynard C. L.,
    2. R. D. Hatton,
    3. W. S. Helms,
    4. J. R. Oliver,
    5. C. B. Stephensen,
    6. C. T. Weaver
    . 2009. Contrasting roles for all-trans retinoic acid in TGF-beta-mediated induction of Foxp3 and Il10 genes in developing regulatory T cells. J. Exp. Med. 206: 343–357.
    OpenUrlAbstract/FREE Full Text
  69. ↵
    1. Ahmad S. M.,
    2. M. J. Haskell,
    3. R. Raqib,
    4. C. B. Stephensen
    . 2009. Markers of innate immune function are associated with vitamin a stores in men. J. Nutr. 139: 377–385.
    OpenUrlAbstract/FREE Full Text
  70. ↵
    1. Dunham R. M.,
    2. M. Thapa,
    3. V. M. Velazquez,
    4. E. J. Elrod,
    5. T. L. Denning,
    6. B. Pulendran,
    7. A. Grakoui
    . 2013. Hepatic stellate cells preferentially induce Foxp3+ regulatory T cells by production of retinoic acid. J. Immunol. 190: 2009–2016.
    OpenUrlAbstract/FREE Full Text
  71. ↵
    1. Coleman M. M.,
    2. D. Ruane,
    3. B. Moran,
    4. P. J. Dunne,
    5. J. Keane,
    6. K. H. Mills
    . 2013. Alveolar macrophages contribute to respiratory tolerance by inducing FoxP3 expression in naive T cells. Am. J. Respir. Cell Mol. Biol. 48: 773–780.
    OpenUrlCrossRefPubMed
  72. ↵
    1. Soroosh P.,
    2. T. A. Doherty,
    3. W. Duan,
    4. A. K. Mehta,
    5. H. Choi,
    6. Y. F. Adams,
    7. Z. Mikulski,
    8. N. Khorram,
    9. P. Rosenthal,
    10. D. H. Broide,
    11. M. Croft
    . 2013. Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance. J. Exp. Med. 210: 775–788.
    OpenUrlAbstract/FREE Full Text
  73. ↵
    1. Wu J.,
    2. Y. Zhang,
    3. Q. Liu,
    4. W. Zhong,
    5. Z. Xia
    . 2013. All-trans retinoic acid attenuates airway inflammation by inhibiting Th2 and Th17 response in experimental allergic asthma. BMC Immunol. 14: 28.
    OpenUrlCrossRefPubMed
  74. ↵
    1. Pino-Lagos K.,
    2. Y. Guo,
    3. C. Brown,
    4. M. P. Alexander,
    5. R. Elgueta,
    6. K. A. Bennett,
    7. V. De Vries,
    8. E. Nowak,
    9. R. Blomhoff,
    10. S. Sockanathan,
    11. et al
    . 2011. A retinoic acid-dependent checkpoint in the development of CD4+ T cell-mediated immunity. J. Exp. Med. 208: 1767–1775.
    OpenUrlAbstract/FREE Full Text
  75. ↵
    1. Hall J. A.,
    2. J. L. Cannons,
    3. J. R. Grainger,
    4. L. M. Dos Santos,
    5. T. W. Hand,
    6. S. Naik,
    7. E. A. Wohlfert,
    8. D. B. Chou,
    9. G. Oldenhove,
    10. M. Robinson,
    11. et al
    . 2011. Essential role for retinoic acid in the promotion of CD4(+) T cell effector responses via retinoic acid receptor alpha. Immunity 34: 435–447.
    OpenUrlCrossRefPubMed
  76. ↵
    1. Allie S. R.,
    2. W. Zhang,
    3. C. Y. Tsai,
    4. R. J. Noelle,
    5. E. J. Usherwood
    . 2013. Critical role for all-trans retinoic acid for optimal effector and effector memory CD8 T cell differentiation. J. Immunol. 190: 2178–2187.
    OpenUrlAbstract/FREE Full Text
  77. ↵
    1. Svensson M.,
    2. B. Johansson-Lindbom,
    3. F. Zapata,
    4. E. Jaensson,
    5. L. M. Austenaa,
    6. R. Blomhoff,
    7. W. W. Agace
    . 2008. Retinoic acid receptor signaling levels and antigen dose regulate gut homing receptor expression on CD8+ T cells. Mucosal Immunol. 1: 38–48.
    OpenUrlCrossRefPubMed
    1. Eksteen B.,
    2. J. R. Mora,
    3. E. L. Haughton,
    4. N. C. Henderson,
    5. L. Lee-Turner,
    6. E. J. Villablanca,
    7. S. M. Curbishley,
    8. A. I. Aspinall,
    9. U. H. von Andrian,
    10. D. H. Adams
    . 2009. Gut homing receptors on CD8 T cells are retinoic acid dependent and not maintained by liver dendritic or stellate cells. Gastroenterology 137: 320–329.
    OpenUrlCrossRefPubMed
  79. ↵
    1. Tan X.,
    2. J. L. Sande,
    3. J. S. Pufnock,
    4. J. N. Blattman,
    5. P. D. Greenberg
    . 2011. Retinoic acid as a vaccine adjuvant enhances CD8+ T cell response and mucosal protection from viral challenge. J. Virol. 85: 8316–8327.
    OpenUrlAbstract/FREE Full Text
  80. ↵
    1. Mielke L. A.,
    2. S. A. Jones,
    3. M. Raverdeau,
    4. R. Higgs,
    5. A. Stefanska,
    6. J. R. Groom,
    7. A. Misiak,
    8. L. S. Dungan,
    9. C. E. Sutton,
    10. G. Streubel,
    11. et al
    . 2013. Retinoic acid expression associates with enhanced IL-22 production by γδ T cells and innate lymphoid cells and attenuation of intestinal inflammation. J. Exp. Med. 210: 1117–1124.
    OpenUrlAbstract/FREE Full Text
  81. ↵
    1. Chenery A.,
    2. K. Burrows,
    3. F. Antignano,
    4. T. M. Underhill,
    5. M. Petkovich,
    6. C. Zaph
    . 2013. The retinoic acid-metabolizing enzyme Cyp26b1 regulates CD4 T cell differentiation and function. PLoS ONE 8: e72308.
    OpenUrlCrossRefPubMed
  82. ↵
    1. Sutton C. E.,
    2. S. J. Lalor,
    3. C. M. Sweeney,
    4. C. F. Brereton,
    5. E. C. Lavelle,
    6. K. H. Mills
    . 2009. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 31: 331–341.
    OpenUrlCrossRefPubMed
  83. ↵
    1. Liang D.,
    2. A. Zuo,
    3. H. Shao,
    4. W. K. Born,
    5. R. L. O’Brien,
    6. H. J. Kaplan,
    7. D. Sun
    . 2013. Retinoic acid inhibits CD25+ dendritic cell expansion and γδ T-cell activation in experimental autoimmune uveitis. Invest. Ophthalmol. Vis. Sci. 54: 3493–3503.
    OpenUrlAbstract/FREE Full Text
  84. ↵
    1. McCarthy N. E.,
    2. Z. Bashir,
    3. A. Vossenkämper,
    4. C. R. Hedin,
    5. E. M. Giles,
    6. S. Bhattacharjee,
    7. S. G. Brown,
    8. T. J. Sanders,
    9. K. Whelan,
    10. T. T. MacDonald,
    11. et al
    . 2013. Proinflammatory Vδ2+ T cells populate the human intestinal mucosa and enhance IFN-γ production by colonic αβ T cells. J. Immunol. 191: 2752–2763.
    OpenUrlAbstract/FREE Full Text
  85. ↵
    1. Szatmari I.,
    2. A. Pap,
    3. R. Rühl,
    4. J. X. Ma,
    5. P. A. Illarionov,
    6. G. S. Besra,
    7. E. Rajnavolgyi,
    8. B. Dezso,
    9. L. Nagy
    . 2006. PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J. Exp. Med. 203: 2351–2362.
    OpenUrlAbstract/FREE Full Text
  86. ↵
    1. Cerwenka A.,
    2. A. B. Bakker,
    3. T. McClanahan,
    4. J. Wagner,
    5. J. Wu,
    6. J. H. Phillips,
    7. L. L. Lanier
    . 2000. Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice. Immunity 12: 721–727.
    OpenUrlCrossRefPubMed
  87. ↵
    1. Jinushi M.,
    2. T. Takehara,
    3. T. Tatsumi,
    4. T. Kanto,
    5. V. Groh,
    6. T. Spies,
    7. R. Kimura,
    8. T. Miyagi,
    9. K. Mochizuki,
    10. Y. Sasaki,
    11. N. Hayashi
    . 2003. Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid. Int. J. Cancer 104: 354–361.
    OpenUrlCrossRefPubMed
  88. ↵
    1. Awasthi S.,
    2. R. Peto,
    3. S. Read,
    4. S. Clark,
    5. V. Pande,
    6. D. Bundy,
    7. DEVTA (Deworming and Enhanced Vitamin A) team
    . 2013. Vitamin A supplementation every 6 months with retinol in 1 million pre-school children in north India: DEVTA, a cluster-randomised trial. Lancet 381: 1469–1477.
    OpenUrlCrossRefPubMed
  89. ↵
    1. Ahmad S. M.,
    2. M. J. Haskell,
    3. R. Raqib,
    4. C. B. Stephensen
    . 2009. Vitamin A status is associated with T-cell responses in Bangladeshi men. Br. J. Nutr. 102: 797–802.
    OpenUrlCrossRefPubMed
  90. ↵
    1. Galvin K. C.,
    2. L. Dyck,
    3. N. A. Marshall,
    4. A. M. Stefanska,
    5. K. P. Walsh,
    6. B. Moran,
    7. S. C. Higgins,
    8. L. S. Dungan,
    9. K. H. Mills
    . 2013. Blocking retinoic acid receptor-α enhances the efficacy of a dendritic cell vaccine against tumours by suppressing the induction of regulatory T cells. Cancer Immunol. Immunother. 62: 1273–1282.
    OpenUrlCrossRefPubMed
  91. ↵
    1. Racke M. K.,
    2. D. Burnett,
    3. S. H. Pak,
    4. P. S. Albert,
    5. B. Cannella,
    6. C. S. Raine,
    7. D. E. McFarlin,
    8. D. E. Scott
    . 1995. Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course. J. Immunol. 154: 450–458.
    OpenUrlAbstract
  92. ↵
    1. Sudfeld C. R.,
    2. A. M. Navar,
    3. N. A. Halsey
    . 2010. Effectiveness of measles vaccination and vitamin A treatment. Int. J. Epidemiol. 39(Suppl. 1): i48–i55.
    OpenUrlAbstract/FREE Full Text
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