Review Article | Published:

Vitamin effects on the immune system: vitamins A and D take centre stage

Nature Reviews Immunology volume 8, pages 685698 (2008) | Download Citation



Vitamins are essential constituents of our diet that have long been known to influence the immune system. Vitamins A and D have received particular attention in recent years as these vitamins have been shown to have an unexpected and crucial effect on the immune response. We present and discuss our current understanding of the essential roles of vitamins in modulating a broad range of immune processes, such as lymphocyte activation and proliferation, T-helper-cell differentiation, tissue-specific lymphocyte homing, the production of specific antibody isotypes and regulation of the immune response. Finally, we discuss the clinical potential of vitamin A and D metabolites for modulating tissue-specific immune responses and for preventing and/or treating inflammation and autoimmunity.

Key points

  • The metabolites of vitamins A and D, retinoic acid and 1,25(OH)2VD3, respectively, bind to nuclear receptors and exert potent and specific immunomodulatory effects.

  • The vitamin D metabolite 1,25(OH)2VD3 inhibits T-helper 1 (TH1)- and enhances TH2-cell responses. It also decreases TH17-cell differentiation, with reciprocal upregulation of forkhead box protein 3 (FOXP3)+ regulatory T (TReg) cells and T regulatory type 1 (TR1) cells.

  • 1,25(OH)2VD3 also inhibits the proliferation of B cells and their differentiation into antibody-secreting cells. Part of this effect might be indirect by decreasing T-cell help.

  • 1,25(OH)2VD3 modulates dendritic cell (DC) function by impairing their maturation and enhancing their capacity to generate TR1 cells. By contrast, 1,25(OH)2VD3 enhances the bactericidal capacity of macrophages.

  • The vitamin A metabolite retinoic acid induces TH2-cell responses. It also inhibits TH17-cell differentiation and, reciprocally, potentiates TReg-cell development.

  • Retinoic acid is synthesized by gut-associated DCs and induces the expression of gut-homing receptors α4β7-integrin and CC-chemokine receptor 9 (CCR9) by lymphocytes following activation. Conversely, retinoic acid blocks the upregulation of skin-homing receptors. Retinoic acid is also involved in the differentiation of IgA-secreting B cells in the gut.

  • Given its potent immunomodulatory properties, 1,25(OH)2VD3 analogues are currently being tested in autoimmune diseases and as adjuvants for immunosuppressive therapy in transplantation.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Challenges and opportunities in the translation of the science of vitamins. Am. J. Clin. Nutr. 85, 325S–327S (2007).

  2. 2.

    , , , & Influence of vitamin C on the metabolism of arachidonic acid and the development of aortic lesions during experimental atherosclerosis in rabbits. Biomed. Biochim. Acta 43, S273–S276 (1984).

  3. 3.

    et al. Effect of vitamins A and E on ischemia-reperfusion damage in rabbit heart. Mol. Cell. Biochem. 145, 45–51 (1995).

  4. 4.

    et al. Intra-arterial vitamin C prevents endothelial dysfunction caused by ischemia-reperfusion. Atherosclerosis 197, 383–391 (2008).

  5. 5.

    Vitamin D deficiency. N. Engl. J. Med. 357, 266–281 (2007).

  6. 6.

    et al. DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27. Nature Immunol. 8, 285–293 (2007). This paper reports that 1,25(OH)2VD3 is synthesized by dermal DCs and induces CCR10 expression by human T cells, presumably increasing their epidermotropism.

  7. 7.

    & Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J. Steroid. Biochem. Mol. Biol. 97, 93–101 (2005).

  8. 8.

    , , , & Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J. Immunol. 179, 1634–1647 (2007).

  9. 9.

    , , , & Regulation of 25-hydroxyvitamin D3–1α-hydroxylase and production of 1α, 25-dihydroxyvitamin D3 by human dendritic cells. Blood 102, 3314–3316 (2003).

  10. 10.

    , , & Mouse vitamin D-24-hydroxylase: molecular cloning, tissue distribution, and transcriptional regulation by 1α, 25-dihydroxyvitamin D3. Endocrinology 138, 2233–2240 (1997).

  11. 11.

    & Overview of retinoid metabolism and function. J. Neurobiol. 66, 606–630 (2006).

  12. 12.

    , , & Delivery of retinoid-based therapies to target tissues. Biochemistry 46, 4449–4458 (2007).

  13. 13.

    , , & Design of selective nuclear receptor modulators: RAR and RXR as a case study. Nature Rev. Drug Discov. 6, 811–820 (2007).

  14. 14.

    , , & Metabolism of vitamin A and its active metabolite all-trans-retinoic acid in small intestinal enterocytes. J. Pharmacol. Exp. Ther. 295, 979–985 (2000).

  15. 15.

    et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21, 527–538 (2004). This paper reports for the first time that retinoic acid is necessary and sufficient to induce gut-homing receptors on T cells. It is also shown that gut-associated DCs can metabolize dietary vitamin A into retinoic acid, which explains their capacity to imprint gut-homing lymphocytes.

  16. 16.

    et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β- and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007). This paper shows that CD103+ DCs from mesenteric lymph nodes induce TReg cells by a mechanism involving TGFβ and retinoic acid.

  17. 17.

    et al. International union of pharmacology. LXIII. Retinoid X receptors. Pharmacol. Rev. 58, 760–772 (2006).

  18. 18.

    et al. 1α,25-dihydroxyvitamin D3 transrepresses retinoic acid transcriptional activity via vitamin D receptor in myeloid cells. Mol. Endocrinol. 18, 2685–2699 (2004).

  19. 19.

    , , , & Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. Cell 129, 723–733 (2007). This paper demonstrates that the intracellular ratio between cellular retinoic acid binding protein (CRABP) and fatty acid binding protein (FABP) determines whether retinoic acid acts through RAR or PPARβ nuclear receptors, which translates as distinct functional outcomes.

  20. 20.

    , , & 1α,25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J. Clin. Invest. 74, 657–661 (1984).

  21. 21.

    , & Inhibition of T lymphocyte mitogenesis by 1,25-dihydroxyvitamin D3 (calcitriol). J. Clin. Invest. 74, 1451–1455 (1984). References 20 and 21 are among the first reports to clearly demonstrate that 1,25(OH)2VD3 can exert a powerful immunomodulatory effect on T and B cells ex vivo.

  22. 22.

    et al. 1,25-dihydroxyvitamin D3 suppresses human T helper/inducer lymphocyte activity in vitro. J. Immunol. 134, 3032–3035 (1985).

  23. 23.

    , & Differential effects of 1,25-dihydroxyvitamin D3 on human lymphocytes and monocyte/macrophages: inhibition of interleukin-2 and augmentation of interleukin-1 production. Cell. Immunol. 98, 311–322 (1986).

  24. 24.

    , , & 1α,25-dihydroxyvitamin D3 inhibits γ-interferon synthesis by normal human peripheral blood lymphocytes. Proc. Natl Acad. Sci. USA 84, 3385–3389 (1987).

  25. 25.

    , , & Comparison of the effects of 1,25-dihydroxyvitamin D3 on T lymphocyte subpopulations. Eur. J. Immunol. 17, 563–566 (1987).

  26. 26.

    , & 1,25-dihydroxyvitamin D3 enhances the generation of nonspecific suppressor cells while inhibiting the induction of cytotoxic cells in a human MLR. Cell. Immunol. 140, 400–409 (1992).

  27. 27.

    , & Transcriptional repression of the interleukin-2 gene by vitamin D3: direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor. Mol. Cell. Biol. 15, 5789–5799 (1995).

  28. 28.

    & Vitamin D3: a transcriptional modulator of the interferon-γ gene. Eur. J. Immunol. 28, 3017–3030 (1998).

  29. 29.

    , , , & 1,25-dihydroxyvitamin D3 regulates proliferation of activated T-lymphocyte subsets. Life Sci. 37, 95–101 (1985).

  30. 30.

    & Inhibition of human T lymphocyte proliferation and cytokine production by 1,25-dihydroxyvitamin D3. Differential effects on CD45RA+ and CD45R0+ cells. Autoimmunity 14, 37–43 (1992).

  31. 31.

    , & Expression of 1,25-dihydroxyvitamin D3 receptor in the immune system. Arch. Biochem. Biophys. 374, 334–338 (2000).

  32. 32.

    et al. Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-κB downregulation in transcriptional repression of the p40 gene. J. Clin. Invest. 101, 252–262 (1998).

  33. 33.

    & 1α, 25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J. Immunol. 164, 2405–2411 (2000).

  34. 34.

    et al. Treatment of experimental autoimmune prostatitis in nonobese diabetic mice by the vitamin D receptor agonist elocalcitol. J. Immunol. 177, 8504–8511 (2006).

  35. 35.

    , , , & Immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a T helper (Th) 1/Th17 to a Th2 and regulatory T cell profile. J. Pharmacol. Exp. Ther. 324, 23–33 (2008).

  36. 36.

    et al. Topically applied 1,25-dihydroxyvitamin D3 enhances the suppressive activity of CD4+CD25+ cells in the draining lymph nodes. J. Immunol. 179, 6273–6283 (2007).

  37. 37.

    et al. Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3. Blood 106, 3490–3497 (2005).

  38. 38.

    , , , & The role of monocytes and T cells in 1,25-dihydroxyvitamin D3 mediated inhibition of B cell function in vitro. Immunopharmacology 21, 121–128 (1991).

  39. 39.

    et al. 1,25-dihydroxyvitamin D3 induces CCR10 expression in terminally differentiating human B cells. J. Immunol. 180, 2786–2795 (2008).

  40. 40.

    et al. 1,25 dihydroxyvitamin-D3 regulation of immunoglobulin production in peripheral blood mononuclear cells of patients with systemic lupus erythematosus. J. Autoimmun. 2, 861–867 (1989).

  41. 41.

    et al. Dendritic cell modulation by 1α, 25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc. Natl Acad. Sci. USA 98, 6800–6805 (2001).

  42. 42.

    , , , & 1α,25-dihydroxyvitamin D3 (calcitriol) stimulates proliferation of human circulating monocytes in vitro. FEBS Lett. 185, 9–13 (1985).

  43. 43.

    et al. In vitro and in vivo analysis of the immune system of vitamin D receptor knockout mice. J. Bone Miner. Res. 16, 2057–2065 (2001).

  44. 44.

    & Effects of retinoic acid on the immune system: stimulation of T killer cell induction. Eur. J. Immunol. 8, 23–29 (1978).

  45. 45.

    , , & Retinoic acid stimulates the cell cycle machinery in normal T cells: involvement of retinoic acid receptor-mediated IL-2 secretion. J. Immunol. 169, 5555–5563 (2002).

  46. 46.

    , & Characterization of a helper T lymphocyte defect in vitamin A-deficient mice. J. Immunol. 142, 388–393 (1989).

  47. 47.

    et al. Vitamin A is a key regulator for cell growth, cytokine production, and differentiation in normal B cells. J. Biol. Chem. 267, 23988–23992 (1992).

  48. 48.

    , , & The effects of retinoic acid on immunoglobulin synthesis: role of interleukin 6. J. Clin. Immunol. 16, 171–179 (1996).

  49. 49.

    , , & Vitamin A potentiates CpG-mediated memory B-cell proliferation and differentiation: involvement of early activation of p38MAPK. Blood 109, 3865–3872 (2007).

  50. 50.

    , & In vitro induction of mucosa-type dendritic cells by all-trans retinoic acid. J. Immunol. 179, 3504–3514 (2007). This paper shows that DCs can efficiently store retinoic acid, which can be 'released' during lymphocyte activation.

  51. 51.

    et al. RAR-, not RXR, ligands inhibit cell activation and prevent apoptosis in B-lymphocytes. J. Cell. Physiol. 175, 68–77 (1998).

  52. 52.

    , , , & Intracellular signaling by 14-hydroxy-4, 14-retro-retinol. Science 254, 1654–1656 (1991).

  53. 53.

    et al. Retro-retinoids in regulated cell growth and death. J. Exp. Med. 184, 549–555 (1996).

  54. 54.

    et al. 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 (2007).

  55. 55.

    et al. Retinoids regulate survival and antigen presentation by immature dendritic cells. J. Exp. Med. 198, 623–634 (2003). This paper shows that retinoic acid can also act on DCs, modulating their antigen-presenting capacity.

  56. 56.

    , , & Aberrant T-cell function in vitro and impaired T-cell dependent antibody response in vivo in vitamin A-deficient rats. Immunology 80, 581–586 (1993).

  57. 57.

    , & Retinoic acids exert direct effects on T cells to suppress Th1 development and enhance Th2 development via retinoic acid receptors. Int. Immunol. 15, 1017–1025 (2003).

  58. 58.

    et al. Vitamin A prevents the decline in immunoglobulin A and Th2 cytokine levels in small intestinal mucosa of protein-malnourished mice. J. Nutr. 129, 934–941 (1999).

  59. 59.

    & Retinoic acid promotes the development of Th2-like human myelin basic protein-reactive T cells. Cell. Immunol. 215, 54–60 (2002).

  60. 60.

    et al. Direct and indirect effects of retinoic acid on human Th2 cytokine and chemokine expression by human T lymphocytes. BMC Immunol. 7, 27 (2006).

  61. 61.

    , & Vitamin A deficiency decreases and high dietary vitamin A increases disease severity in the mouse model of asthma. J. Immunol. 180, 1834–1842 (2008).

  62. 62.

    , , & 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, 3736–3739 (2002).

  63. 63.

    Regulatory T cells and infection: a dangerous necessity. Nature Rev. Immunol. 7, 875–888 (2007).

  64. 64.

    et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007). This paper shows that retinoic acid enhances TReg-cell differentiation while blocking differentiation towards TH17 cells.

  65. 65.

    , , & 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, 1775–1774 (2007). This paper shows that retinoic acid enhances TReg-cell differentiation and imprints TReg cells with gut tropism.

  66. 66.

    et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007). This paper demonstrates that lamina propria DCs induce de novo TReg-cell differentiation in a retinoic acid-dependent manner.

  67. 67.

    , , , & Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nature Immunol. 8, 1086–1094 (2007).

  68. 68.

    et al. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nature Immunol. 9, 769–776 (2008).

  69. 69.

    et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

  70. 70.

    , & The differentiation of human TH-17 cells requires transforming growth factor-b and induction of the nuclear receptor RORγt. Nature Immunol. 9, 641–649 (2008). This paper re-assesses the role of TGFβ in human TH17-cell differentiation, showing that, similar to mouse TH17 cells, human TH17 cells also require this cytokine for their differentiation.

  71. 71.

    et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006). This paper demonstrates that the transcription factor RORγt is necessary and sufficient for TH17-cell differentiation.

  72. 72.

    , & The immunoglobulin class switch: beyond “accessibility”. Immunity 6, 217–223 (1997).

  73. 73.

    Homing imprinting and immunomodulation in the gut: role of dendritic cells and retinoids. Inflamm. Bowel Dis. 14, 275–289 (2008).

  74. 74.

    & Freshly isolated Peyer's patch, but not spleen, dendritic cells produce interleukin 10 and induce the differentiation of T helper type 2 cells. J. Exp. Med. 190, 229–239 (1999).

  75. 75.

    et al. CD11b+ Peyer's patch dendritic cells secrete IL-6 and induce IgA secretion from naive B cells. J. Immunol. 171, 3684–3690 (2003).

  76. 76.

    et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314, 1157–1160 (2006). This paper shows that retinoic acid is a mechanistic link between gut-homing imprinting of B cells and differentiation of IgA-secreting cells.

  77. 77.

    et al. Loss of integrin αv β8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449, 361–365 (2007).

  78. 78.

    et al. Intestinal bacteria trigger T cell-independent immunoglobulin A2 class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 26, 812–826 (2007).

  79. 79.

    et al. Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells. Nature 448, 929–933 (2007). This paper shows that iNOS is required for IgA production in all mucosal compartments. It is also reported that gut-associated DCs express iNOS in a TLR-dependent manner.

  80. 80.

    & 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 (1999).

  81. 81.

    et al. Impaired vitamin A-mediated mucosal IgA response in IL-5 receptor-knockout mice. Biochem. Biophys. Res. Commun. 285, 546–549 (2001).

  82. 82.

    et al. The role of interleukin-6 in mucosal IgA antibody responses in vivo. Science 264, 561–563 (1994).

  83. 83.

    , , & Loss of ileal IgA+ plasma cells and of CD4+ lymphocytes in ileal Peyer's patches of vitamin A deficient rats. Clin. Exp. Immunol. 130, 404–408 (2002). This paper shows that vitamin A depletion markedly decreases the number of IgA-antibody-secreting cells in the rat ileum.

  84. 84.

    , & Novel synthetic retinoic acid inhibits rat collagen arthritis and differentially affects serum immunoglobulin subclass levels. FEBS Lett. 378, 153–156 (1996).

  85. 85.

    et al. 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 (2007).

  86. 86.

    et al. Enhancement of the inducible NO synthase activation by retinoic acid is mimicked by RARα agonist in vivo. Am. J. Physiol. Endocrinol. Metab. 283, E525–E535 (2002).

  87. 87.

    , , , & Gut IgA class switch recombination in the absence of CD40 does not occur in the lamina propria and is independent of germinal centers. J. Immunol. 177, 7772–7783 (2006).

  88. 88.

    , , , & Impaired local immune response in vitamin A-deficient rats. Clin. Exp. Immunol. 40, 127–135 (1980).

  89. 89.

    & Differentiation and homing of IgA-secreting cells. Mucosal Immunology 1, 96–109 (2008).

  90. 90.

    & Rapid acquisition of tissue-specific homing phenotypes by CD4+ T cells activated in cutaneous or mucosal lymphoid tissues. J. Exp. Med. 195, 135–141 (2002).

  91. 91.

    et al. In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. Immunity 17, 211–220 (2002).

  92. 92.

    , & Intestinal dendritic cells increase T cell expression of α4β7 integrin. Eur. J. Immunol. 32, 1445–1454 (2002).

  93. 93.

    et al. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature 424, 88–93 (2003).

  94. 94.

    et al. Selective generation of gut tropic T cells in gut-associated lymphoid tissue (GALT): requirement for GALT dendritic cells and adjuvant. J. Exp. Med. 198, 963–969 (2003).

  95. 95.

    et al. Reciprocal and dynamic control of CD8 T cell homing by dendritic cells from skin- and gut-associated lymphoid tissues. J. Exp. Med. 201, 303–316 (2005).

  96. 96.

    et al. Dendritic cells govern induction and reprogramming of polarized tissue-selective homing receptor patterns of T cells: important roles for soluble factors and tissue microenvironments. Eur. J. Immunol. 35, 1056–1065 (2005).

  97. 97.

    et al. Impaired intestinal localization of mesenteric lymphoblasts associated with vitamin A deficiency and protein-calorie malnutrition. Immunology 45, 1–5 (1982). This paper shows that vitamin A depletion decreases the migration of mesenteric lymph node lymphoblasts to the small bowel (but not the colon).

  98. 98.

    et al. Colonic patches direct the cross-talk between systemic compartments and large intestine independently of innate immunity. J. Immunol. 180, 1609–1618 (2008).

  99. 99.

    et al. Vitamins A and D are potent inhibitors of cutaneous lymphocyte-associated antigen expression. J. Allergy Clin. Immunol. 121, 148–157 (2007). This paper shows that 1,25(OH)2VD3 decreases the expression of ligands for E- and P-selectin, inhibits T-cell homing to the inflamed skin and decreases the expression of gut-homing receptors.

  100. 100.

    & Retinoic acid: an educational “vitamin elixir” for gut-seeking T cells. Immunity 21, 458–460 (2004).

  101. 101.

    Vitamin D and the skin: an ancient friend, revisited. Exp. Dermatol. 16, 618–625 (2007).

  102. 102.

    et al. The α1,3 fucosyltransferase Fuc-TVII controls leukocyte trafficking through an essential role in L-, E-, and P-selectin ligand biosynthesis. Cell 86, 643–653 (1996).

  103. 103.

    , , & 1,25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking. J. Neurosci. Res. 85, 2480–2490 (2007).

  104. 104.

    et al. A vitamin D analog down-regulates proinflammatory chemokine production by pancreatic islets inhibiting T cell recruitment and type 1 diabetes development. J. Immunol. 173, 2280–2287 (2004).

  105. 105.

    & Vitamin E: inflammation and atherosclerosis. Vitam. Horm. 76, 519–549 (2007).

  106. 106.

    , & The effect of α-tocopherol on monocyte proatherogenic activity. J. Nutr. 131, 389S–394S (2001).

  107. 107.

    & α-tocopherol decreases interleukin-1 β release from activated human monocytes by inhibition of 5-lipoxygenase. Arterioscler. Thromb. Vasc. Biol. 19, 1125–1133 (1999).

  108. 108.

    & Cellular, molecular and clinical aspects of vitamin E on atherosclerosis prevention. Mol. Aspects Med. 28, 538–590 (2007).

  109. 109.

    et al. Antioxidants inhibit the expression of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 induced by oxidized LDL on human umbilical vein endothelial cells. Free Radic. Biol. Med. 22, 117–127 (1997).

  110. 110.

    et al. α-tocopherol protects against expression of adhesion molecules on neutrophils and endothelial cells. Biofactors 7, 15–19 (1998).

  111. 111.

    , , & Vitamin C and E suppress mitogen-stimulated peripheral blood mononuclear cells in vitro. Int. Arch. Allergy Immunol. 142, 127–132 (2007).

  112. 112.

    et al. Vitamin E inhibits CD95 ligand expression and protects T cells from activation-induced cell death. J. Clin. Invest. 110, 681–690 (2002).

  113. 113.

    , , , & Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice. Nature Med. 4, 1189–1192 (1998).

  114. 114.

    et al. A novel vitamin E derivative (TMG) protects against gastric mucosal damage induced by ischemia and reperfusion in rats. Dig. Dis. Sci. 48, 54–58 (2003).

  115. 115.

    et al. Neuroprotective effects of L-carnitine and vitamin E alone or in combination against ischemia-reperfusion injury in rats. J. Surg. Res. 131, 124–130 (2006).

  116. 116.

    et al. Increased atherosclerosis in hyperlipidemic mice deficient in α -tocopherol transfer protein and vitamin E. Proc. Natl Acad. Sci. USA 97, 13830–13834 (2000).

  117. 117.

    et al. The effects of iloprost and vitamin C on kidney as a remote organ after ischemia/reperfusion of lower extremities. J. Surg. Res. 140, 20–26 (2007).

  118. 118.

    , & Vitamin C prevents cigarette smoke-induced leukocyte aggregation and adhesion to endothelium in vivo. Proc. Natl Acad. Sci. USA 91, 7688–7692 (1994).

  119. 119.

    , , , & Protection from oxidized LDL-induced leukocyte adhesion to microvascular and macrovascular endothelium in vivo by vitamin C but not by vitamin E. Circulation 91, 1525–1532 (1995).

  120. 120.

    et al. Antioxidant activity of vitamin B6 delays homocysteine-induced atherosclerosis in rats. Br. J. Nutr. 95, 1088–1093 (2006).

  121. 121.

    , & Atherosclerosis and oxidant stress: the end of the road for antioxidant vitamin treatment? Cardiovasc. Drugs Ther. 21, 195–210 (2007).

  122. 122.

    , , & Supplementation of atherogenic diet with B vitamins does not prevent atherosclerosis or vascular dysfunction in monkeys. Circulation 103, 1006–1011 (2001).

  123. 123.

    et al. Lower levels of plasma 25-hydroxyvitamin D among young adults at diagnosis of autoimmune type 1 diabetes compared with control subjects: results from the nationwide Diabetes Incidence Study in Sweden (DISS). Diabetologia 49, 2847–2852 (2006).

  124. 124.

    et al. Vitamin D3 metabolism in patients with rheumatic diseases: low serum levels of 25-hydroxyvitamin D3 in patients with systemic lupus erythematosus. Clin. Rheumatol. 14, 397–400 (1995).

  125. 125.

    , , , & Vitamin D in rheumatoid arthritis. Autoimmun. Rev. 7, 59–64 (2007).

  126. 126.

    , , & 1,25-dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine inflammatory bowel disease. J. Nutr. 130, 2648–2652 (2000).

  127. 127.

    , , & Vitamin D and diabetes. Diabetologia 48, 1247–1257 (2005).

  128. 128.

    , , , & Lymphocyte subpopulations in children with vitamin D deficient rickets. Acta Paediatr. Jpn. 37, 500–502 (1995).

  129. 129.

    et al. Prevention of immunological disorders in MRL/l mice by a new synthetic analogue of vitamin D3, 22-oxa-1α,25-dihydroxyvitamin D3. J. Nutr. Sci. Vitaminol. (Tokyo) 36, 21–31 (1990).

  130. 130.

    , & 1,25-dihydroxyvitamin D3 attenuates the expression of experimental murine lupus of MRL/l mice. Autoimmunity 12, 143–148 (1992).

  131. 131.

    & 1,25-dihydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis. J. Clin. Invest. 87, 1103–1107 (1991).

  132. 132.

    , , & IL-10 signaling is essential for 1,25-dihydroxyvitamin D3-mediated inhibition of experimental autoimmune encephalomyelitis. J. Immunol. 177, 6030–6037 (2006).

  133. 133.

    et al. In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J. Exp. Med. 195, 603–616 (2002).

  134. 134.

    , & 1,25-dihydroxycholecalciferol inhibits the progression of arthritis in murine models of human arthritis. J. Nutr. 128, 68–72 (1998).

  135. 135.

    , , & Effect of calcitriol on the production of T-cell-derived cytokines in psoriasis. Br. J. Dermatol. 136, 536–541 (1997).

  136. 136.

    , & Topical paricalcitol (19-nor-1α, 25-dihydroxyvitamin D2) is a novel, safe and effective treatment for plaque psoriasis: a pilot study. Br. J. Dermatol. 151, 190–195 (2004).

  137. 137.

    et al. Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc. Natl Acad. Sci. USA 103, 11736–11741 (2006).

  138. 138.

    et al. Prolongation of the survival of murine cardiac allografts by the vitamin D3 analogue 1,25-dihydroxy-δ16-cholecalciferol. Transplantation 54, 762–763 (1992).

  139. 139.

    , & Inhibition of acute and chronic allograft rejection in mouse models by BXL-628, a nonhypercalcemic vitamin D receptor agonist. Transplantation 80, 81–87 (2005).

  140. 140.

    , , & Effect of 1,25-dihydroxyvitamin D3 on preventing allograft from acute rejection following rat orthotopic liver transplantation. World J. Gastroenterol. 9, 1067–1071 (2003).

  141. 141.

    et al. Regulatory T cells induced by 1α, 25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J. Immunol. 167, 1945–1953 (2001).

  142. 142.

    , , & MC1288, a vitamin D analog, prevents acute graft-versus-host disease in rat bone marrow transplantation. Bone Marrow Transplant. 27, 863–867 (2001).

  143. 143.

    et al. Prevention of chronic allograft nephropathy with vitamin D. Transpl. Int. 18, 1175–1186 (2005).

  144. 144.

    et al. Vitamin D receptor gene polymorphism associates with graft-versus-host disease and survival in HLA-matched sibling allogeneic bone marrow transplantation. Bone Marrow Transplant. 30, 223–228 (2002).

  145. 145.

    , , , & Potential effects of 1,25-dihydroxyvitamin D3 in renal transplant recipients. Transplant. Proc. 37, 3109–3111 (2005).

  146. 146.

    et al. Are plasma 1,25-dihydroxyvitamin D3 concentrations appropriate after successful kidney transplantation? Nephrol. Dial. Transplant. 13 (Suppl. 3), 91–93 (1998).

  147. 147.

    & Failure of successful renal transplant to produce appropriate levels of 1,25-dihydroxyvitamin D. Osteoporos. Int. 18, 363–368 (2007).

  148. 148.

    et al. 1,25-dihydroxyvitamin D3 prolongs graft survival without compromising host resistance to infection or bone mineral density. Transplantation 66, 828–831 (1998).

  149. 149.

    et al. Effects of long-term administration of vitamin D3 analogs to mice. J. Endocrinol. 165, 163–172 (2000).

  150. 150.

    , , & Increased mortality in children with mild vitamin A deficiency. Lancet 2, 585–588 (1983). References 149 and 150 provide epidemiological evidence that indicate a role for vitamin A in preventing child mortality in developing countries.

  151. 151.

    et al. Impact of vitamin A supplementation on childhood mortality. A randomised controlled community trial. Lancet 1, 1169–1173 (1986).

  152. 152.

    et al. Effect of periodic vitamin A supplementation on mortality and morbidity of human immunodeficiency virus-infected children in Uganda: a controlled clinical trial. Nutrition 21, 25–31 (2005).

  153. 153.

    et al. Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course. J. Immunol. 154, 450–458 (1995).

  154. 154.

    et al. The effect of Am-80, one of retinoids derivatives on experimental allergic encephalomyelitis in rats. Life Sci. 67, 1869–1879 (2000).

  155. 155.

    , & Inflammation and collagenase production in rats with adjuvant arthritis reduced with 13-cis-retinoic acid. Science 221, 756–758 (1983).

  156. 156.

    et al. Effect of Am-80, a synthetic derivative of retinoid, on experimental arthritis in mice. Pharmacology 58, 101–112 (1999).

  157. 157.

    et al. Therapeutic effect of all-trans-retinoic acid (at-RA) on an autoimmune nephritis experimental model: role of the VLA-4 integrin. BMC Nephrol. 8, 3 (2007).

  158. 158.

    Update on retinoid therapy of psoriasis in: an update on the use of retinoids in dermatology. Dermatol. Ther. 19, 252–263 (2006).

  159. 159.

    et al. Oral alitretinoin (9-cis-retinoic acid) therapy for chronic hand dermatitis in patients refractory to standard therapy: results of a randomized, double-blind, placebo-controlled, multicenter trial. Arch. Dermatol. 140, 1453–1459 (2004).

  160. 160.

    et al. Effect of Am-80, a retinoid derivative, on 2, 4-dinitrofluorobenzene-induced contact dermatitis in mice. Pharmacology 60, 208–214 (2000).

  161. 161.

    , & Vitamin A deficiency diminishes the salivary immunoglobulin A response and enhances the serum immunoglobulin G. response to influenza A virus infection in BALB/c mice. J. Nutr. 126, 94–102 (1996).

  162. 162.

    et al. Induction of organ-selective CD4+ regulatory T cell homing. Eur. J. Immunol. 37, 978–989 (2007).

  163. 163.

    et al. Anhydroretinol: a naturally occurring inhibitor of lymphocyte physiology. J. Exp. Med. 178, 675–680 (1993).

Download references


We thank S. Davis for editorial assistance and E. Villablanca for critical reading of this manuscript. J.R.M. is grateful to I. Ramos for constant support. J.R.M. is supported by grants from the Crohn's & Colitis Foundation of America, the Cancer Research Institute, the Howard M. Goodman Fellowship and the Center for the Study of IBD (DK 43351). M.I. is supported by the Grants-in-Aid from Japan Society for the Promotion of Science and the Ministry of Education, Culture, Sports, Science and Technology, the Naito Foundation and the Uehara Memorial Foundation. U.H.v.A. is supported by National Institutes of Health grants AI061663, AI069259, AI072252, HL56949 and AR42689.

Author information


  1. Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

    • J. Rodrigo Mora
  2. Laboratory of Biodefense Research, Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Kagawa, 769-2193, Japan.

    • Makoto Iwata
  3. Immune Disease Institute & Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Ulrich H. von Andrian


  1. Search for J. Rodrigo Mora in:

  2. Search for Makoto Iwata in:

  3. Search for Ulrich H. von Andrian in:

Corresponding authors

Correspondence to J. Rodrigo Mora or Ulrich H. von Andrian.

Supplementary information

PDF files

  1. 1.

    Supplementary information S1 (table)

    Overview of vitamins and the immune system.


Stellate cells

(Also known as Ito cells). Types of pericytes found in the hepatic perisinusoidal space that are the main reservoirs of retinol in the liver.

Intestinal epithelial cells

(IECs). A tight monolayer of cells covering the luminal surface of the intestine. They are specialized in the absorption of nutrients and also serve as a mechanical and immunological barrier with the external environment (the intestinal lumen).

Peyer's patches

Groups of lymphoid nodules present in the small intestine (usually the ileum). They are found massed together on the intestinal wall, opposite the line of attachment of the mesentery. Peyer's patches consist of a dome area, B-cell follicles and interfollicular T-cell areas.

Mesenteric lymph nodes

(MLNs). Lymph nodes located at the base of the mesentery. They collect lymph (including cells and antigens) draining from the intestinal mucosa.

TH17 cells

(T helper 17 cells). A subset of CD4+ T helper cells that produce interleukin-17 (IL-17) and are thought to be important in inflammatory and autoimmune diseases. Their generation involves TGFβ, IL-6, IL-23 or IL-21, IL-1β and the transcription factor RORγt.

TReg cells

(Regulatory T cells). Specialized types of CD4+ T cells that can suppress the effector responses of other immune cells. These cells provide a crucial mechanism for the maintenance of peripheral self-tolerance and are characterized by the expression of the transcription factor forkhead box P3.

Systemic lupus erythematosus

(SLE). An autoimmune disease in which autoantibodies specific for DNA, RNA or proteins associated with nucleic acids form immune complexes. These complexes damage small blood vessels, especially in the kidneys. Patients with SLE generally have abnormal B- and T-cell function as well as rashes, arthritis, kidney disease and central-nervous-system involvement.

Antibody-secreting cells

(ASCs). Cells specialized in secreting immunoglobulins. Although they originate from activated B cells, ASCs lose the expression of surface immunoglobulins and other B-cell markers and upregulate plasma cell markers, such as CD138 in mice or CD27 in humans.

TR1 cells

(T regulatory type 1 cells) A population of regulatory T cells that arises in the periphery after an encounter with antigen in the presence of interleukin-10 (IL-10) and that regulates immune responses through the secretion of IL-10 and transforming growth factor-β. They suppress T-cell responses, downregulate the expression of co-stimulatory molecules and pro-inflammatory cytokines by antigen-presenting cells and favour the production of IgD, IgA and IgG by B cells.

Gut-associated lymphoid tissue

(GALT). Lymphoid structure associated with the intestinal mucosa, including cryptopatches, isolated lymphoid follicles, Peyer's patches and caecal and colonic patches.

Small intestinal lamina propria

Connective tissue between the intestinal epithelium and the intestinal muscularis mucosae layer, which contains various myeloid and lymphoid cells, including macrophages, dendritic cells, T cells and B cells.

Colonic patches

Structures resembling Peyer's patches that are scattered throughout the colon. They have been implicated in the generation of colonic immune responses.

Experimental allergic encephalomyelitis

(EAE). An experimental model of the human disease multiple sclerosis. Autoimmune disease is induced in experimental animals by immunization with myelin or peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.

Type 1 diabetes

A chronic autoimmune disease that is characterized by the T-cell-mediated destruction of β cells (which secrete insulin) in the pancreas. Patients with type 1 diabetes develop hyperglycaemia and can develop diabetes-associated complications in multiple organ systems, owing to a lack of insulin. Diabetes in non-obese diabetic mice is a model of type I diabetes.


A chronic disorder of the arterial wall characterized by endothelial damage that gradually induces deposits of cholesterol, cellular debris, calcium and other substances. These deposits eventually lead to plaque formation and arterial stiffness.

Ischaemia-reperfusion injury

(IRI). Cellular damage caused by the return of blood supply to a tissue after a period of inadequate blood supply. The absence of oxygen and nutrients causes cellular damage, such that restoration of the blood flow results in inflammation.

Rheumatoid arthritis

An immunological disorder that is characterized by symmetrical polyarthritis, often progressing to crippling deformation after years of synovitis. It is associated with systemic immune activation, with the presence of acute-phase reactants in the peripheral blood and with rheumatoid factor (immunoglobulins specific for IgG), which form immune complexes that are deposited in many tissues.

Inflammatory bowel disease

(IBD). A chronic condition of the intestine that is characterized by severe inflammation and mucosal destruction. The most common forms in humans are ulcerative colitis and Crohn's disease, which are believed to be T helper 2 (TH2)- and TH1-type diseases, respectively. However, interleukin-23 and TH17 cells have also recently been shown to be involved in the pathology of IBD.

Graft-versus-host disease

(GVHD). An immune response mounted against the recipient of an allograft by immunocompetent donor T cells that are derived from the graft. Typically, it is seen in the context of allogeneic bone-marrow transplantation.

About this article

Publication history



Further reading