Vitamin A is a multifunctional vitamin implicated in a wide range of biological processes. Its control over the immune system and functions are perhaps the most pleiotropic not only for development but also for the functional fate of almost every cell involved in protective or regulatory adaptive or innate immunity. This is especially key at the intestinal border, where dietary vitamin A is first absorbed. Most effects of vitamin A are exerted by its metabolite, retinoic acid (RA), which through ligation of nuclear receptors controls transcriptional expression of RA target genes. In addition to this canonical function, RA and RA receptors (RARs), either as ligand-receptor or separately, play extranuclear, nongenomic roles that greatly expand the multiple mechanisms employed for their numerous and paradoxical functions that ultimately link environmental sensing with immune cell fate. This review discusses RA and RARs and their complex roles in innate and adaptive immunity.


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Literature Cited

  1. Semba RD. 1.  2012. On the ‘discovery’ of vitamin A. Ann. Nutr. Metab. 61:192–98 [Google Scholar]
  2. Moore T. 2.  1930. Vitamin A and carotene: the absence of the liver oil vitamin A from carotene. VI. The conversion of carotene to vitamin A in vivo. Biochem. J. 24:692–702 [Google Scholar]
  3. Karrer P, Morf R, Schöpp K. 3.  1931. Zur Kenntnis des Vitamins-A aus Fischtranen. Helv. Chim. Acta 14:1036–40 [Google Scholar]
  4. Holmes HN, Corbet RE. 4.  1937. The isolation of crystalline Vitamin A1. J. Am. Chem. Soc. 59:2042–47 [Google Scholar]
  5. Semba RD. 5.  1999. Vitamin A as “anti-infective” therapy, 1920–1940. J. Nutr. 129:783–91 [Google Scholar]
  6. 6. World Health Organ. Dep. Nutr. Health Dev 2015. Micronutrient Deficiencies: Vitamin A Deficiency. Geneva: World Health Organ http://www.who.int/nutrition/topics/vad/en/
  7. Harrison EH. 7.  2012. Mechanisms involved in the intestinal absorption of dietary vitamin A and provitamin A carotenoids. Biochim. Biophys. Acta 1821:70–77 [Google Scholar]
  8. Kawaguchi R. 8.  2007. A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A. Science 315:820–25 [Google Scholar]
  9. Theodosiou M, Laudet V, Schubert M. 9.  2010. From carrot to clinic: an overview of the retinoic acid signaling pathway. Cell. Mol. Life Sci. 67:1423–45 [Google Scholar]
  10. Kumar S, Sandell LL, Trainor PA, Koentgen F, Duester G. 10.  2012. Alcohol and aldehyde dehydrogenases: retinoid metabolic effects in mouse knockout models. Biochim. Biophys. Acta 1821:198–205 [Google Scholar]
  11. Dong D, Ruuska SE, Levinthal DJ, Noy N. 11.  1999. Distinct roles for cellular retinoic acid-binding proteins I and II in regulating signaling by retinoic acid. J. Biol. Chem. 274:23695–98 [Google Scholar]
  12. Thatcher JE, Isoherranen N. 12.  2009. The role of CYP26 enzymes in retinoic acid clearance. Expert Opin. Drug Metab. Toxicol. 5:875–86 [Google Scholar]
  13. Rochette-Egly C, Germain P. 13.  2009. Dynamic and combinatorial control of gene expression by nuclear retinoic acid receptors (RARs). Nuclear Recept. Signal. 7:e005 [Google Scholar]
  14. Al Tanoury Z, Piskunov A, Rochette-Egly C. 14.  2013. Vitamin A and retinoid signaling: genomic and nongenomic effects. J. Lipid Res. 54:1761–75 [Google Scholar]
  15. Heyman RA, Mangelsdorf DJ, Dyck JA, Stein RB, Eichele G. 15.  et al. 1992. 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 68:397–406 [Google Scholar]
  16. Wolf G. 16.  2006. Is 9-cis-retinoic acid the endogenous ligand for the retinoic acid-X receptor?. Nutr. Rev. 64:532–38 [Google Scholar]
  17. Georgiadi A, Kersten S. 17.  2012. Mechanisms of gene regulation by fatty acids. Adv. Nutr. 3:127–34 [Google Scholar]
  18. Germain P, Iyer J, Zechel C, Gronemeyer H. 18.  2002. Co-regulator recruitment and the mechanism of retinoic acid receptor synergy. Nature 415:187–92 [Google Scholar]
  19. Poon MM, Chen L. 19.  2008. Retinoic acid-gated sequence-specific translational control by RARα. PNAS 105:20303–8 [Google Scholar]
  20. Shaw N, Elholm M, Noy N. 20.  2003. Retinoic acid is a high affinity selective ligand for the peroxisome proliferator-activated receptor beta/delta. J. Biol. Chem. 278:41589–92 [Google Scholar]
  21. Schug TT, Berry DC, Shaw NS, Travis SN, Noy N. 21.  2007. Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. Cell 129:723–33 [Google Scholar]
  22. Despouy G, Bastie J-N, Deshaies S, Balitrand N, Mazharian A. 22.  et al. 2003. Cyclin D3 is a cofactor of retinoic acid receptors, modulating their activity in the presence of cellular retinoic acid-binding protein II. J. Biol. Chem. 278:6355–62 [Google Scholar]
  23. Gaillard E, Bruck N, Brelivet Y, Bour G, Lalevée S. 23.  et al. 2006. Phosphorylation by PKA potentiates retinoic acid receptor alpha activity by means of increasing interaction with and phosphorylation by cyclin H/cdk7. PNAS 103:9548–53 [Google Scholar]
  24. Bruck N, Vitoux D, Ferry C, Duong V, Bauer A. 24.  et al. 2009. A coordinated phosphorylation cascade initiated by p38MAPK/MSK1 directs RARα to target promoters. EMBO J. 28:34–47 [Google Scholar]
  25. Rochette-Egly C, Adam S, Rossignol M, Egly JM, Chambon P. 25.  1997. Stimulation of RARα activation function AF-1 through binding to the general transcription factor TFIIH and phosphorylation by CDK7. Cell 90:97–107 [Google Scholar]
  26. Schule R, Rangarajan P, Yang N, Kliewer S, Ransone LJ. 26.  et al. 1991. Retinoic acid is a negative regulator of AP-1-responsive genes. PNAS 88:6092–96 [Google Scholar]
  27. Karamouzis MV, Papavassiliou AG. 27.  2005. Retinoid receptor cross-talk in respiratory epithelium cancer chemoprevention. Trends Mol. Med. 11:10–16 [Google Scholar]
  28. Maruya M, Suzuki K, Fujimoto H, Miyajima M, Kanagawa O. 28.  et al. 2011. Vitamin A-dependent transcriptional activation of the nuclear factor of activated T cells c1 (NFATc1) is critical for the development and survival of B1 cells. PNAS 108:722–27 [Google Scholar]
  29. Ohoka Y, Yokota A, Takeuchi H, Maeda N, Iwata M. 29.  2011. Retinoic acid-induced CCR9 expression requires transient TCR stimulation and cooperativity between NFATc2 and the retinoic acid receptor/retinoid X receptor complex. J. Immunol. 186:733–44 [Google Scholar]
  30. Austenaa LM, Carlsen H, Ertesvag A, Alexander G, Blomhoff HK, Blomhoff R. 30.  2004. Vitamin A status significantly alters nuclear factor-κB activity assessed by in vivo imaging. FASEB J. 18:1255–57 [Google Scholar]
  31. Austenaa LM, Carlsen H, Hollung K, Blomhoff HK, Blomhoff R. 31.  2009. Retinoic acid dampens LPS-induced NF-κB activity: results from human monoblasts and in vivo imaging of NF-κB reporter mice. J. Nutr. Biochem. 20:726–34 [Google Scholar]
  32. Nervi C, Grignani F. 32.  2014. RARs and microRNAs. Subcell. Biochem. 70:151–79 [Google Scholar]
  33. Pobezinsky LA, Etzensperger R, Jeurling S, Alag A, Kadakia T. 33.  et al. 2015. Let-7 microRNAs target the lineage-specific transcription factor PLZF to regulate terminal NKT cell differentiation and effector function. Nat. Immunol. 16:517–24 [Google Scholar]
  34. Zeng C, Xu Y, Xu L, Yu X, Cheng J. 34.  et al. 2014. Inhibition of long non-coding RNA NEAT1 impairs myeloid differentiation in acute promyelocytic leukemia cells. BMC Cancer 14:693 [Google Scholar]
  35. Tani H, Mizutani R, Salam KA, Tano K, Ijiri K. 35.  et al. 2012. Genome-wide determination of RNA stability reveals hundreds of short-lived noncoding transcripts in mammals. Genome Res. 22:947–56 [Google Scholar]
  36. Kour S, Rath PC. 36.  2016. All-trans retinoic acid induces expression of a novel intergenic long noncoding RNA in adult rat primary hippocampal neurons. J. Mol. Neurosci. 58266–76
  37. Lu TC, Wang Z, Feng X, Chuang P, Fang W. 37.  et al. 2008. Retinoic acid utilizes CREB and USF1 in a transcriptional feed-forward loop in order to stimulate MKP1 expression in human immunodeficiency virus-infected podocytes. Mol. Cell. Biol. 28:5785–94 [Google Scholar]
  38. Piskunov A, Rochette-Egly C. 38.  2012. A retinoic acid receptor RARα pool present in membrane lipid rafts forms complexes with G protein αQ to activate p38MAPK. Oncogene 31:3333–45 [Google Scholar]
  39. Radominska-Pandya A, Chen G, Czernik PJ, Little JM, Samokyszyn VM. 39.  et al. 2000. Direct interaction of all-trans-retinoic acid with protein kinase C (PKC): implications for PKC signaling and cancer therapy. J. Biol. Chem. 275:22324–30 [Google Scholar]
  40. Donini CF, Di Zazzo E, Zuchegna C, Di Domenico M, D’Inzeo S. 40.  et al. 2012. The p85α regulatory subunit of PI3K mediates cAMP-PKA and retinoic acid biological effects on MCF7 cell growth and migration. Int. J. Oncol. 40:1627–35 [Google Scholar]
  41. Cantrell DA. 41.  2001. Phosphoinositide 3-kinase signalling pathways. J. Cell Sci. 114:1439–45 [Google Scholar]
  42. Dey N, De PK, Wang M, Zhang H, Dobrota EA. 42.  et al. 2007. CSK controls retinoic acid receptor (RAR) signaling: A RAR-c-SRC signaling axis is required for neuritogenic differentiation. Mol. Cell. Biol. 27:4179–97 [Google Scholar]
  43. Hall JA, Cannons JL, Grainger JR, Dos Santos LM, Hand TW. 43.  et al. 2011. Essential role for retinoic acid in the promotion of CD4+ T cell effector responses via retinoic acid receptor alpha. Immunity 34:435–47 [Google Scholar]
  44. Ghyselinck NB, Dupe V, Dierich A, Messaddeq N, Garnier JM. 44.  et al. 1997. Role of the retinoic acid receptor β (RARβ) during mouse development. Int. J. Dev. Biol. 41:425–47 [Google Scholar]
  45. Sitnik KM, Kotarsky K, White AJ, Jenkinson WE, Anderson G, Agace WW. 45.  2012. Mesenchymal cells regulate retinoic acid receptor-dependent cortical thymic epithelial cell homeostasis. J. Immunol. 188:4801–9 [Google Scholar]
  46. Szondy Z, Reichert U, Bernardon JM, Michel S, Toth R. 46.  et al. 1997. Induction of apoptosis by retinoids and retinoic acid receptor gamma-selective compounds in mouse thymocytes through a novel apoptosis pathway. Mol. Pharmacol. 51:972–82 [Google Scholar]
  47. Toth K, Sarang Z, Scholtz B, Brazda P, Ghyselinck N. 47.  et al. 2011. Retinoids enhance glucocorticoid-induced apoptosis of T cells by facilitating glucocorticoid receptor-mediated transcription. Cell Death Differ. 18:783–92 [Google Scholar]
  48. Szegezdi E, Kiss I, Simon A, Blasko B, Reichert U. 48.  et al. 2003. Ligation of retinoic acid receptor alpha regulates negative selection of thymocytes by inhibiting both DNA binding of nur77 and synthesis of bim. J. Immunol. 170:3577–84 [Google Scholar]
  49. Yang Y, Vacchio MS, Ashwell JD. 49.  1993. 9-cis-retinoic acid inhibits activation-driven T-cell apoptosis: implications for retinoid X receptor involvement in thymocyte development. PNAS 90:6170–74 [Google Scholar]
  50. van de Pavert SA, Ferreira M, Domingues RG, Ribeiro H, Molenaar R. 50.  et al. 2014. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508:123–27 [Google Scholar]
  51. Lee YS, Jeong WI. 51.  2012. Retinoic acids and hepatic stellate cells in liver disease. J. Gastroenterol. Hepatol. 27:75–79 [Google Scholar]
  52. Ichikawa S, Mucida D, Tyznik AJ, Kronenberg M, Cheroutre H. 52.  2011. Hepatic stellate cells function as regulatory bystanders. J. Immunol. 186:5549–55 [Google Scholar]
  53. Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM. 53.  et al. 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. 204:1757–64 [Google Scholar]
  54. Jaensson-Gyllenback E, Kotarsky K, Zapata F, Persson EK, Gundersen TE. 54.  et al. 2011. Bile retinoids imprint intestinal CD103+ dendritic cells with the ability to generate gut-tropic T cells. Mucosal. Immunol. 4:438–47 [Google Scholar]
  55. Hammerschmidt SI, Ahrendt M, Bode U, Wahl B, Kremmer E. 55.  et al. 2008. Stromal mesenteric lymph node cells are essential for the generation of gut-homing T cells in vivo. J. Exp. Med. 205:2483–90 [Google Scholar]
  56. Vicente-Suarez I, Larange A, Reardon C, Matho M, Feau S. 56.  et al. 2015. Unique lamina propria stromal cells imprint the functional phenotype of mucosal dendritic cells. Mucosal. Immunol. 8:141–51 [Google Scholar]
  57. Molenaar R, Greuter M, van der Marel AP, Roozendaal R, Martin SF. 57.  et al. 2009. Lymph node stromal cells support dendritic cell-induced gut-homing of T cells. J. Immunol. 183:6395–402 [Google Scholar]
  58. Elgueta R, Sepulveda FE, Vilches F, Vargas L, Mora JR. 58.  et al. 2008. Imprinting of CCR9 on CD4 T cells requires IL-4 signaling on mesenteric lymph node dendritic cells. J. Immunol. 180:6501–7 [Google Scholar]
  59. Huang G, Wang Y, Chi H. 59.  2013. Control of T cell fates and immune tolerance by p38α signaling in mucosal CD103+ dendritic cells. J. Immunol. 191:650–59 [Google Scholar]
  60. Lee SW, Park Y, Eun SY, Madireddi S, Cheroutre H, Croft M. 60.  2012. Cutting edge: 4-1BB controls regulatory activity in dendritic cells through promoting optimal expression of retinal dehydrogenase. J. Immunol. 189:2697–701 [Google Scholar]
  61. Manicassamy S, Reizis B, Ravindran R, Nakaya H, Salazar-Gonzalez RM. 61.  et al. 2010. Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science 329:849–53 [Google Scholar]
  62. Manicassamy S, Ravindran R, Deng J, Oluoch H, Denning TL. 62.  et al. 2009. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nat. Med. 15:401–9 [Google Scholar]
  63. Zhu B, Buttrick T, Bassil R, Zhu C, Olah M. 63.  et al. 2013. IL-4 and retinoic acid synergistically induce regulatory dendritic cells expressing Aldh1a2. J. Immunol. 191:3139–51 [Google Scholar]
  64. Stock A, Booth S, Cerundolo V. 64.  2011. Prostaglandin E2 suppresses the differentiation of retinoic acid-producing dendritic cells in mice and humans. J. Exp. Med. 208:761–73 [Google Scholar]
  65. Mortha A, Chudnovskiy A, Hashimoto D, Bogunovic M, Spencer SP. 65.  et al. 2014. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343:1249288 [Google Scholar]
  66. Broadhurst MJ, Leung JM, Lim KC, Girgis NM, Gundra UM. 66.  et al. 2012. Upregulation of retinal dehydrogenase 2 in alternatively activated macrophages during retinoid-dependent type-2 immunity to helminth infection in mice. PLOS Pathog. 8:e1002883 [Google Scholar]
  67. Lampen A, Meyer S, Arnhold T, Nau H. 67.  2000. Metabolism of vitamin A and its active metabolite all-trans-retinoic acid in small intestinal enterocytes. J. Pharmacol. Exp. Ther. 295:979–85 [Google Scholar]
  68. Galvin KC, Dyck L, Marshall NA, Stefanska AM, Walsh KP. 68.  et al. 2013. Blocking retinoic acid receptor-alpha enhances the efficacy of a dendritic cell vaccine against tumours by suppressing the induction of regulatory T cells. Cancer Immunol. Immunother. 62:1273–82 [Google Scholar]
  69. Zhan XX, Liu Y, Yang JF, Wang GY, Mu L. 69.  et al. 2013. All-trans-retinoic acid ameliorates experimental allergic encephalomyelitis by affecting dendritic cell and monocyte development. Immunology 138:333–45 [Google Scholar]
  70. Martin JC, Beriou G, Heslan M, Chauvin C, Utriainen L. 70.  et al. 2014. Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid. Mucosal. Immunol. 7:101–13 [Google Scholar]
  71. Huber S, Gagliani N, Zenewicz LA, Huber FJ, Bosurgi L. 71.  et al. 2012. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491:259–63 [Google Scholar]
  72. Geissmann F, Revy P, Brousse N, Lepelletier Y, Folli C. 72.  et al. 2003. Retinoids regulate survival and antigen presentation by immature dendritic cells. J. Exp. Med. 198:623–34 [Google Scholar]
  73. DePaolo RW, Abadie V, Tang F, Fehlner-Peach H, Hall JA. 73.  et al. 2011. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471:220–24 [Google Scholar]
  74. Szatmari I, Pap A, Ruhl R, Ma JX, Illarionov PA. 74.  et al. 2006. PPARγ controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J. Exp. Med. 203:2351–62 [Google Scholar]
  75. Mehta K, McQueen T, Tucker S, Pandita R, Aggarwal BB. 75.  1994. Inhibition by all-trans-retinoic acid of tumor necrosis factor and nitric oxide production by peritoneal macrophages. J. Leukoc. Biol. 55:336–42 [Google Scholar]
  76. Na SY, Kang BY, Chung SW, Han SJ, Ma X. 76.  et al. 1999. Retinoids inhibit interleukin-12 production in macrophages through physical associations of retinoid X receptor and NFκB. J. Biol. Chem. 274:7674–80 [Google Scholar]
  77. Wang X, Allen C, Ballow M. 77.  2007. Retinoic acid enhances the production of IL-10 while reducing the synthesis of IL-12 and TNF-alpha from LPS-stimulated monocytes/macrophages. J. Clin. Immunol. 27:193–200 [Google Scholar]
  78. Kim BH, Kang KS, Lee YS. 78.  2004. Effect of retinoids on LPS-induced COX-2 expression and COX-2 associated PGE2 release from mouse peritoneal macrophages and TNF-α release from rat peripheral blood mononuclear cells. Toxicol. Lett. 150:191–201 [Google Scholar]
  79. Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B. 79.  2007. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat. Immunol. 8:1086–94 [Google Scholar]
  80. Dzhagalov I, Chambon P, He YW. 80.  2007. Regulation of CD8+ T lymphocyte effector function and macrophage inflammatory cytokine production by retinoic acid receptor gamma. J. Immunol. 178:2113–21 [Google Scholar]
  81. Johansson-Lindbom B, Svensson M, Wurbel MA, Malissen B, Marquez G, Agace W. 81.  2003. Selective generation of gut tropic T cells in gut-associated lymphoid tissue (GALT): requirement for GALT dendritic cells and adjuvant. J. Exp. Med. 198:963–69 [Google Scholar]
  82. Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL. 82.  et al. 2003. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature 424:88–93 [Google Scholar]
  83. Stagg AJ, Kamm MA, Knight SC. 83.  2002. Intestinal dendritic cells increase T cell expression of α4β7 integrin. Eur. J. Immunol. 32:1445–54 [Google Scholar]
  84. Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY. 84.  2004. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21:527–38 [Google Scholar]
  85. DeNucci CC, Pagan AJ, Mitchell JS, Shimizu Y. 85.  2010. Control of α4β7 integrin expression and CD4 T cell homing by the β1 integrin subunit. J. Immunol. 184:2458–67 [Google Scholar]
  86. Mucida D, Park Y, Kim G, Turovskaya O, Scott I. 86.  et al. 2007. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317:256–60 [Google Scholar]
  87. Kang SG, Wang C, Matsumoto S, Kim CH. 87.  2009. High and low vitamin A therapies induce distinct FoxP3+ T-cell subsets and effectively control intestinal inflammation. Gastroenterology 137:1391–402e1–6 [Google Scholar]
  88. Zhou X, Kong N, Wang J, Fan H, Zou H. 88.  et al. 2010. Cutting edge: All-trans retinoic acid sustains the stability and function of natural regulatory T cells in an inflammatory milieu. J. Immunol. 185:2675–79 [Google Scholar]
  89. Van YH, Lee WH, Ortiz S, Lee MH, Qin HJ, Liu CP. 89.  2009. All-trans retinoic acid inhibits type 1 diabetes by T regulatory (Treg)-dependent suppression of interferon-gamma-producing T-cells without affecting Th17 cells. Diabetes 58:146–55 [Google Scholar]
  90. Maynard CL, Hatton RD, Helms WS, Oliver JR, Stephensen CB, Weaver CT. 90.  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. 206:343–57 [Google Scholar]
  91. Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ. 91.  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. 204:1765–74 [Google Scholar]
  92. Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M. 92.  et al. 2007. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204:1775–85 [Google Scholar]
  93. Xiao S, Jin H, Korn T, Liu SM, Oukka M. 93.  et al. 2008. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J. Immunol. 181:2277–84 [Google Scholar]
  94. La P, Morgan TA, Sykes SM, Mao H, Schnepp RW. 94.  et al. 2003. Fusion proteins of retinoid receptors antagonize TGF-beta-induced growth inhibition of lung epithelial cells. Oncogene 22:198–210 [Google Scholar]
  95. Lu L, Ma J, Li Z, Lan Q, Chen M. 95.  et al. 2011. All-trans retinoic acid promotes TGF-β-induced Tregs via histone modification but not DNA demethylation on Foxp3 gene locus. PLOS ONE 6:e24590 [Google Scholar]
  96. Nolting J, Daniel C, Reuter S, Stuelten C, Li P. 96.  et al. 2009. Retinoic acid can enhance conversion of naive into regulatory T cells independently of secreted cytokines. J. Exp. Med. 206:2131–39 [Google Scholar]
  97. Lu L, Lan Q, Li Z, Zhou X, Gu J. 97.  et al. 2014. Critical role of all-trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions. PNAS 111:E3432–40 [Google Scholar]
  98. Takahashi H, Kanno T, Nakayamada S, Hirahara K, Sciume G. 98.  et al. 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. 13:587–95 [Google Scholar]
  99. Hill JA, Hall JA, Sun CM, Cai Q, Ghyselinck N. 99.  et al. 2008. Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi cells. Immunity 29:758–70 [Google Scholar]
  100. Bai A, Lu N, Guo Y, Liu Z, Chen J, Peng Z. 100.  2009. All-trans retinoic acid down-regulates inflammatory responses by shifting the Treg/Th17 profile in human ulcerative and murine colitis. J. Leukoc. Biol. 86:959–69 [Google Scholar]
  101. Klemann C, Raveney BJ, Klemann AK, Ozawa T, von Horsten S. 101.  et al. 2009. Synthetic retinoid AM80 inhibits Th17 cells and ameliorates experimental autoimmune encephalomyelitis. Am. J. Pathol. 174:2234–45 [Google Scholar]
  102. Kwok SK, Park MK, Cho ML, Oh HJ, Park EM. 102.  et al. 2012. Retinoic acid attenuates rheumatoid inflammation in mice. J. Immunol. 189:1062–71 [Google Scholar]
  103. Elias KM, Laurence A, Davidson TS, Stephens G, Kanno Y. 103.  et al. 2008. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood 111:1013–20 [Google Scholar]
  104. Brown CC, Esterhazy D, Sarde A, London M, Pullabhatla V. 104.  et al. 2015. Retinoic acid is essential for Th1 cell lineage stability and prevents transition to a Th17 cell program. Immunity 42:499–511 [Google Scholar]
  105. Brustle A, Heink S, Huber M, Rosenplanter C, Stadelmann C. 105.  et al. 2007. The development of inflammatory TH-17 cells requires interferon-regulatory factor 4. Nat. Immunol. 8:958–66 [Google Scholar]
  106. Pino-Lagos K, Guo Y, Brown C, Alexander MP, Elgueta R. 106.  et al. 2011. A retinoic acid-dependent checkpoint in the development of CD4+ T cell-mediated immunity. J. Exp. Med. 208:1767–75 [Google Scholar]
  107. Wang C, Kang SG, HogenEsch H, Love PE, Kim CH. 107.  2010. Retinoic acid determines the precise tissue tropism of inflammatory Th17 cells in the intestine. J. Immunol. 184:5519–26 [Google Scholar]
  108. Chenery A, Burrows K, Antignano F, Underhill TM, Petkovich M, Zaph C. 108.  2013. The retinoic acid-metabolizing enzyme Cyp26b1 regulates CD4 T cell differentiation and function. PLOS ONE 8:e72308 [Google Scholar]
  109. Takeuchi H, Yokota A, Ohoka Y, Iwata M. 109.  2011. Cyp26b1 regulates retinoic acid-dependent signals in T cells and its expression is inhibited by transforming growth factor-beta. PLOS ONE 6:e16089 [Google Scholar]
  110. Bhaumik S, Giffon T, Bolinger D, Kirkman R, Lewis DB. 110.  et al. 2013. Retinoic acid hypersensitivity promotes peripheral tolerance in recent thymic emigrants. J. Immunol. 190:2603–13 [Google Scholar]
  111. Wiedermann U, Hanson LA, Kahu H, Dahlgren UI. 111.  1993. Aberrant T-cell function in vitro and impaired T-cell dependent antibody response in vivo in vitamin A-deficient rats. Immunology 80:581–86 [Google Scholar]
  112. Cantorna MT, Nashold FE, Hayes CE. 112.  1994. In vitamin A deficiency multiple mechanisms establish a regulatory T helper cell imbalance with excess Th1 and insufficient Th2 function. J. Immunol. 152:1515–22 [Google Scholar]
  113. Racke MK, Burnett D, Pak SH, Albert PS, Cannella B. 113.  et al. 1995. Retinoid treatment of experimental allergic encephalomyelitis: IL-4 production correlates with improved disease course. J. Immunol. 154:450–58 [Google Scholar]
  114. Austenaa LMI, Ross AC. 114.  2001. Potentiation of interferon-gamma-stimulated nitric oxide production by retinoic acid in RAW 264.7 cells. J. Leukoc. Biol. 70:121–29 [Google Scholar]
  115. Hoag KA, Nashold FE, Goverman J, Hayes CE. 115.  2002. Retinoic acid enhances the T helper 2 cell development that is essential for robust antibody responses through its action on antigen-presenting cells. J. Nutr. 132:3736–39 [Google Scholar]
  116. Reis BS, Rogoz A, Costa-Pinto FA, Taniuchi I, Mucida D. 116.  2013. Mutual expression of the transcription factors Runx3 and ThPOK regulates intestinal CD4+ T cell immunity. Nat. Immunol. 14:271–80 [Google Scholar]
  117. Reis BS, Hoytema van Konijnenburg DP, Grivennikov SI, Mucida D. 117.  2014. Transcription factor T-bet regulates intraepithelial lymphocyte functional maturation. Immunity 41:244–56 [Google Scholar]
  118. Mucida D, Husain MM, Muroi S, van Wijk F, Shinnakasu R. 118.  et al. 2013. Transcriptional reprogramming of mature CD4+ helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes. Nat. Immunol. 14:281–89 [Google Scholar]
  119. Cheroutre H, Husain MM. 119.  2013. CD4 CTL: living up to the challenge. Semin. Immunol. 25:273–81 [Google Scholar]
  120. Huang Y, Park Y, Wang-Zhu Y, Larange A, Arens R. 120.  et al. 2011. Mucosal memory CD8+ T cells are selected in the periphery by an MHC class I molecule. Nat. Immunol. 12:1086–95 [Google Scholar]
  121. Tan X, Sande JL, Pufnock JS, Blattman JN, Greenberg PD. 121.  2011. Retinoic acid as a vaccine adjuvant enhances CD8+ T cell response and mucosal protection from viral challenge. J. Virol. 85:8316–27 [Google Scholar]
  122. Allie SR, Zhang W, Tsai CY, Noelle RJ, Usherwood EJ. 122.  2013. Critical role for all-trans retinoic acid for optimal effector and effector memory CD8 T cell differentiation. J. Immunol. 190:2178–87 [Google Scholar]
  123. Guo Y, Pino-Lagos K, Ahonen CA, Bennett KA, Wang J. 123.  et al. 2012. A retinoic acid-rich tumor microenvironment provides clonal survival cues for tumor-specific CD8+ T cells. Cancer Res. 72:5230–39 [Google Scholar]
  124. Motomura K, Ohata M, Satre M, Tsukamoto H. 124.  2001. Destabilization of TNF-alpha mRNA by retinoic acid in hepatic macrophages: implications for alcoholic liver disease. Am. J. Physiol. Endocrinol. Metab. 281:E420–29 [Google Scholar]
  125. Ertesvag A, Austenaa LM, Carlsen H, Blomhoff R, Blomhoff HK. 125.  2009. Retinoic acid inhibits in vivo interleukin-2 gene expression and T-cell activation in mice. Immunology 126:514–22 [Google Scholar]
  126. Guo Y, Lee YC, Brown C, Zhang W, Usherwood E, Noelle RJ. 126.  2014. Dissecting the role of retinoic acid receptor isoforms in the CD8 response to infection. J. Immunol. 192:3336–44 [Google Scholar]
  127. Pasatiempo AMG, Kinoshita M, Taylor CE, Ross AC. 127.  1990. Antibody-production in vitamin A-depleted rats is impaired after immunization with bacterial polysaccharide or protein antigens. FASEB J. 4:2518–27 [Google Scholar]
  128. Ma Y, Ross AC. 128.  2009. Toll-like receptor 3 ligand and retinoic acid enhance germinal center formation and increase the tetanus toxoid vaccine response. Clin. Vaccine Immunol. 16:1476–84 [Google Scholar]
  129. Nikawa T, Ikemoto M, Kano M, Tokuoka K, Hirasaka K. 129.  et al. 2001. Impaired vitamin A-mediated mucosal IgA response in IL-5 receptor-knockout mice. Biochem. Biophys. Res. Commun. 285:546–49 [Google Scholar]
  130. Tokuyama H, Tokuyama Y. 130.  1999. The regulatory effects of all-trans-retinoic acid on isotype switching: retinoic acid induces IgA switch rearrangement in cooperation with IL-5 and inhibits IgG1 switching. Cell Immunol. 192:41–47 [Google Scholar]
  131. Ertesvag A, Aasheim HC, Naderi S, Blomhoff HK. 131.  2007. Vitamin A potentiates CpG-mediated memory B-cell proliferation and differentiation: involvement of early activation of p38MAPK. Blood 109:3865–72 [Google Scholar]
  132. Chen Q, Ross AC. 132.  2007. Retinoic acid promotes mouse splenic B cell surface IgG expression and maturation stimulated by CD40 and IL-4. Cell Immunol. 249:37–45 [Google Scholar]
  133. Guidoboni M, Zancai P, Cariati R, Rizzo S, Dal Col J. 133.  et al. 2005. Retinoic acid inhibits the proliferative response induced by CD40 activation and interleukin-4 in mantle cell lymphoma. Cancer Res. 65:587–95 [Google Scholar]
  134. Naderi S, Blomhoff HK. 134.  1999. Retinoic acid prevents phosphorylation of pRB in normal human B lymphocytes: regulation of cyclin E, cyclin A, and p21Cip1. Blood 94:1348–58 [Google Scholar]
  135. Boller S, Grosschedl R. 135.  2014. The regulatory network of B-cell differentiation: a focused view of early B-cell factor 1 function. Immunol. Rev. 261:102–15 [Google Scholar]
  136. Chen Q, Ross AC. 136.  2005. Vitamin A and immune function: retinoic acid modulates population dynamics in antigen receptor and CD38-stimulated splenic B cells. PNAS 102:14142–49 [Google Scholar]
  137. Chorny A, Puga I, Cerutti A. 137.  2010. Innate signaling networks in mucosal IgA class switching. Adv. Immunol. 107:31–69 [Google Scholar]
  138. Sirisinha S, Darip MD, Moongkarndi P, Ongsakul M, Lamb AJ. 138.  1980. Impaired local immune response in vitamin A-deficient rats. Clin. Exp. Immunol. 40:127–35 [Google Scholar]
  139. Gangopadhyay NN, Moldoveanu Z, Stephensen CB. 139.  1996. Vitamin A deficiency has different effects on immunoglobulin A production and transport during influenza A infection in BALB/c mice. J. Nutr. 126:2960–67 [Google Scholar]
  140. Bjersing JL, Telemo E, Dahlgren U, Hanson LA. 140.  2002. Loss of ileal IgA+ plasma cells and of CD4+ lymphocytes in ileal Peyer's patches of vitamin A deficient rats. Clin. Exp. Immunol. 130:404–8 [Google Scholar]
  141. Mora JR. 141.  2006. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314:1157–60 [Google Scholar]
  142. Uematsu S. 142.  2008. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat. Immunol. 9:769–76 [Google Scholar]
  143. Feng T, Cong Y, Qin H, Benveniste EN, Elson CO. 143.  2010. Generation of mucosal dendritic cells from bone marrow reveals a critical role of retinoic acid. J. Immunol. 185:5915–25 [Google Scholar]
  144. Zou F, Liu Y, Liu L, Wu K, Wei W. 144.  et al. 2007. Retinoic acid activates human inducible nitric oxide synthase gene through binding of RARα/RXRα heterodimer to a novel retinoic acid response element in the promoter. Biochem. Biophys. Res. Commun. 355:494–500 [Google Scholar]
  145. Seguin-Devaux C, Devaux Y, Latger-Cannard V, Grosjean S, Rochette-Egly C. 145.  et al. 2002. Enhancement of the inducible NO synthase activation by retinoic acid is mimicked by RARα agonist in vivo. Am. J. Physiol. Endocrinol. Metab. 283:E525–35 [Google Scholar]
  146. Tezuka H, Abe Y, Iwata M, Takeuchi H, Ishikawa H. 146.  et al. 2007. Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells. Nature 448:929–33 [Google Scholar]
  147. Mora JR, von Andrian UH. 147.  2008. Differentiation and homing of IgA-secreting cells. Mucosal. Immunol. 1:96–109 [Google Scholar]
  148. Kimata H, Fujimoto M. 148.  1994. Vasoactive intestinal peptide specifically induces human IgA1 and IgA2 production. Eur. J. Immunol. 24:2262–65 [Google Scholar]
  149. Waschek JA, Muller JM, Duan DS, Sadee W. 149.  1989. Retinoic acid enhances VIP receptor expression and responsiveness in human neuroblastoma cell, SH-SY5Y. FEBS Lett. 250:611–14 [Google Scholar]
  150. Sarkar J, Gangopadhyay NN, Moldoveanu Z, Mestecky J, Stephensen CB. 150.  1998. Vitamin A is required for regulation of polymeric immunoglobulin receptor (plgR) expression by interleukin-4 and interferon-gamma in a human intestinal epithelial cell line. J. Nutr. 128:1063–69 [Google Scholar]
  151. Gangopadhyay IH, Moldoveanu Z, Stephensen CB. 151.  1996. Vitamin A deficiency has different effects on immunoglobulin A production and transport during influenza A infection in BALB/c mice. J. Nutr. 126:2960–67 [Google Scholar]
  152. Worm M, Krah JM, Manz RA, Henz BM. 152.  1998. Retinoic acid inhibits CD40+ interleukin-4-mediated IgE production in vitro. Blood 92:1713–20 [Google Scholar]
  153. Ruiter B, Patil SU, Shreffler WG. 153.  2015. Vitamins A and D have antagonistic effects on expression of effector cytokines and gut-homing integrin in human innate lymphoid cells. Clin. Exp. Allergy 45:1214–25 [Google Scholar]
  154. Kim MH, Taparowsky EJ, Kim CH. 154.  2015. Retinoic acid differentially regulates the migration of innate lymphoid cell subsets to the gut. Immunity 43:107–19 [Google Scholar]
  155. McCarthy NE, Bashir Z, Vossenkamper A, Hedin CR, Giles EM. 155.  et al. 2013. Proinflammatory Vδ2+ T cells populate the human intestinal mucosa and enhance IFN-gamma production by colonic αβ T cells. J. Immunol. 191:2752–63 [Google Scholar]
  156. Gao B, Radaeva S, Park O. 156.  2009. Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases. J. Leukoc. Biol. 86:513–28 [Google Scholar]
  157. Ahmad SM, Haskell MJ, Raqib R, Stephensen CB. 157.  2009. Markers of innate immune function are associated with vitamin A stores in men. J. Nutr. 139:377–85 [Google Scholar]
  158. Chang HK, Hou WS. 158.  2015. Retinoic acid modulates interferon-γ production by hepatic natural killer T cells via phosphatase 2A and the extracellular signal-regulated kinase pathway. J. Interferon Cytokine Res. 35:200–12 [Google Scholar]
  159. Maricic I, Sheng H, Marrero I, Seki E, Kisseleva T. 159.  et al. 2015. Inhibition of type I NKT cells by retinoids or following sulfatide-mediated activation of type II NKT cells attenuates alcoholic liver disease. Hepatology 61:1357–69 [Google Scholar]
  160. Spencer SP, Wilhelm C, Yang Q, Hall JA, Bouladoux N. 160.  et al. 2014. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 343:432–37 [Google Scholar]
  161. Mielke LA, Jones SA, Raverdeau M, Higgs R, Stefanska A. 161.  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. 210:1117–24 [Google Scholar]

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