Molecular Medicine

, Volume 18, Issue 1, pp 95–110 | Cite as

Influence of Dietary Components on Regulatory T Cells

  • Shohreh Issazadeh-Navikas
  • Roman Teimer
  • Robert Bockermann
Invited Review Article


Common dietary components including vitamins A and D, omega-3 and probiotics are now widely accepted to be essential to protect against many diseases with an inflammatory nature. On the other hand, high-fat diets are documented to exert multiple deleterious effects, including fatty liver diseases. Here we discuss the effect of dietary components on regulatory T cell (Treg) homeostasis, a central element of the immune system to prevent chronic tissue inflammation. Accordingly, evidence on the impact of dietary components on diseases in which Tregs play an influential role will be discussed. We will review chronic tissue-specific autoimmune and inflammatory conditions such as inflammatory bowel disease, type 1 diabetes mellitus, multiple sclerosis, rheumatoid arthritis and allergies among chronic diseases where dietary factors could have a direct influence via modulation of Tregs homeostasis and functions.



This work was supported by grants from the Lundbeck Foundation in Denmark, the Novo Nordisk Foundation and the Danish Research Council-Medicine.


  1. 1.
    Maloy KJ, Powrie F. (2001) Regulatory T cells in the control of immune pathology. Nat. Immunol. 2:816–22.PubMedCrossRefGoogle Scholar
  2. 2.
    Ziegler SF. (2006) FOXP3: of mice and men. Annu. Rev. Immunol. 24:209–26.PubMedCrossRefGoogle Scholar
  3. 3.
    Chen W, Konkel JE. 2010. TGF-beta and ‘adaptive’ Foxp3(+) regulatory T cells. J. Mol. Cell. Biol. 2:30–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Collison LW, et al. (2007) The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 450:566–9.CrossRefGoogle Scholar
  5. 5.
    Collison LW, et al. (2010) IL-35-mediated induction of a potent regulatory T cell population. Nat. Immunol. 11:1093–101.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Kim CH. (2006) Migration and function of FoxP3+ regulatory T cells in the hematolymphoid system. Exp. Hematol. 34:1033–40.PubMedCrossRefGoogle Scholar
  7. 7.
    Bennett CL, et al. (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27:20–1.PubMedCrossRefGoogle Scholar
  8. 8.
    Brunkow ME, et al. (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27:68–73.PubMedCrossRefGoogle Scholar
  9. 9.
    Curiel TJ. (2007) Tregs and rethinking cancer immunotherapy. J. Clin. Invest. 117:1167–74.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Sakaguchi S. (2000) Regulatory T cells: key controllers of immunologic self-tolerance. Cell. 101:455–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Curotto de Lafaille MA, Lafaille JJ. (2009) Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity. 30:626–35.PubMedCrossRefGoogle Scholar
  12. 12.
    Liu Y, Teige I, Birnir B, Issazadeh-Navikas S. (2006) Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE. Nat. Med. 12:518–25.PubMedCrossRefGoogle Scholar
  13. 13.
    Weiner HL, da Cunha AP, Quintana F, Wu H. (2011) Oral tolerance. Immunol. Rev. 241:241–59.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Liu Y, Teige I, Ericsson I, Navikas V, Issazadeh-Navikas S. (2010) Suppression of EAE by oral tolerance is independent of endogenous IFN-beta whereas treatment with recombinant IFN-beta ameliorates EAE. Immunol. Cell. Biol. 88:468–76.PubMedCrossRefGoogle Scholar
  15. 15.
    Food and Agriculture Organization of the United Nations [FAO]; WHO. (2001) Health and Nutritional Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria: Report of a Joint FAO/WHO Expert Consultation on Evaluation of Health and Nutritional Properties of Probiotics in Food Including Powder Milk with Live Lactic Acid Bacteria: Amerian Córdoba Park Hotel, Córdoba, Argentina: 1–4 October 2001 [PDF on the Internet]. [Rome]: FAO; [Geneva]: WHO; [cited 2012 Jan 19]. Available from:
  16. 16.
    Sartor RB. (2004) Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology. 126:1620–33.PubMedCrossRefGoogle Scholar
  17. 17.
    Sartor RB. (2006) Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat. Clin. Pract. Gastroenterol. Hepatol. 3:390–407.PubMedCrossRefGoogle Scholar
  18. 18.
    Taurog JD, et al. (1994) The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J. Exp. Med. 180:2359–64.PubMedCrossRefGoogle Scholar
  19. 19.
    Waidmann M, et al. (2003) Bacteroides vulgatus protects against Escherichia coli-induced colitis in gnotobiotic interleukin-2-deficient mice. Gastroenterology. 125:162–77.PubMedCrossRefGoogle Scholar
  20. 20.
    Kwon HK, et al. (2010) Generation of regulatory dendritic cells and CD4+Foxp3+ T cells by probiotics administration suppresses immune disorders. Proc. Natl. Acad. Sci. U. S. A. 107:2159–64.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Siddiqui KR, Powrie F. (2008) CD103+ GALT DCs promote Foxp3+ regulatory T cells. Mucosal Immunol. 1 Suppl 1:S34–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Izcue A, Coombes JL, Powrie F. (2006) Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol. Rev. 212:256–71.PubMedCrossRefGoogle Scholar
  23. 23.
    Ivanov II, et al. (2008) Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell. Host Microbe. 4:337–49.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Rad R, et al. (2006) CD25+/Foxp3+ T cells regulate gastric inflammation and Helicobacter pylori colonization in vivo. Gastroenterology. 131:525–37.CrossRefGoogle Scholar
  25. 25.
    O’Mahony C, et al. (2008) Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-kappaB activation. PLoS Pathog. 4:e1000112.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    So JS, et al. (2008) Lactobacillus casei potentiates induction of oral tolerance in experimental arthritis. Mol. Immunol. 46:172–80.PubMedCrossRefGoogle Scholar
  27. 27.
    So JS, et al. (2008) Lactobacillus casei suppresses experimental arthritis by down-regulating T helper 1 effector functions. Mol. Immunol. 45:2690–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Kato I, Endo-Tanaka K, Yokokura T. (1998) Suppressive effects of the oral administration of Lactobacillus casei on type II collagen-induced arthritis in DBA/1 mice. Life Sci. 63:635–44.PubMedCrossRefGoogle Scholar
  29. 29.
    Hacini-Rachinel F, et al. (2009) Oral probiotic control skin inflammation by acting on both effector and regulatory T cells. PLoS One. 4:e4903.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Maassen CB, Claassen E. (2008) Strain-dependent effects of probiotic lactobacilli on EAE autoimmunity. Vaccine. 26:2056–7.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Ochoa-Reparaz J, et al. (2010) Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression. J. Immunol. 185:4101–8.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Ochoa-Reparaz J, Mielcarz DW, Haque-Begum S, Kasper LH. (2010) Induction of a regulatory B cell population in experimental allergic encephalomyelitis by alteration of the gut commensal microflora. Gut Microbes. 1:103–8.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Kobayashi T, et al. (2010) Oral administration of probiotic bacteria, Lactobacillus casei and Bifidobacterium breve, does not exacerbate neurological symptoms in experimental autoimmune encephalomyelitis. Immunopharmacol. Immunotoxicol. 32:116–24.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Ezendam J, van Loveren H. (2008) Lactobacillus casei Shirota administered during lactation increases the duration of autoimmunity in rats and enhances lung inflammation in mice. Br. J. Nutr. 99:83–90.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Baken KA, et al. (2006) Evaluation of immunomodulation by Lactobacillus casei Shirota: immune function, autoimmunity and gene expression. Int. J. Food Microbiol. 112:8–18.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Rachmilewitz D, et al. (2004) Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology. 126:520–8.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Karimi K, Inman MD, Bienenstock J, Forsythe P. (2009) Lactobacillus reuteri-induced regulatory T cells protect against an allergic airway response in mice. Am. J. Respir. Crit. Care Med. 179:186–93.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Petrof EO, et al. (2004) Probiotics inhibit nuclear factor-kappaB and induce heat shock proteins in colonic epithelial cells through proteasome inhibition. Gastroenterology. 127:1474–87.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Petrof EO, et al. (2009) Bacteria-free solution derived from Lactobacillus plantarum inhibits multiple NF-kappaB pathways and inhibits proteasome function. Inflamm. Bowel Dis. 15:1537–47.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Cong Y, et al. (2005) Generation of antigen-specific, Foxp3-expressing CD4+ regulatory T cells by inhibition of APC proteosome function. J. Immunol. 174:2787–95.PubMedCrossRefGoogle Scholar
  41. 41.
    Smits HH, et al. (2005) Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin. J. Allergy Clin. Immunol. 115:1260–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Foligne B, et al. (2007) A key role of dendritic cells in probiotic functionality. PLoS One. 2:e313.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Rahman MK, et al. (2010) The pathogen recognition receptor NOD2 regulates human FOXP3+ T cell survival. J. Immunol. 184:7247–56.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Penack O, et al. (2009) NOD2 regulates hematopoietic cell function during graft-versushost disease. J. Exp. Med. 206:2101–10.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Petnicki-Ocwieja T, et al. (2009) Nod2 is required for the regulation of commensal microbiota in the intestine. Proc. Natl. Acad. Sci. U. S. A. 106:15813–8.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Fernandez EM, et al. (2011) Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide. Gut. 60:1050–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Rachmilewitz D, et al. (2002) Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis. Gastroenterology. 122:1428–41.PubMedCrossRefGoogle Scholar
  48. 48.
    Bleich A, et al. (2009) CpG motifs of bacterial DNA exert protective effects in mouse models of IBD by antigen-independent tolerance induction. Gastroenterology. 136:278–87.PubMedCrossRefGoogle Scholar
  49. 49.
    Bilsborough J, George TC, Norment A, Viney JL. (2003) Mucosal CD8alpha+ DC, with a plasmacytoid phenotype, induce differentiation and support function of T cells with regulatory properties. Immunology. 108:481–92.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Zarek PE, et al. (2008) A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood. 111:251–9.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Mandapathil M, et al. (2010) Generation and accumulation of immunosuppressive adenosine by human CD4+CD25highFOXP3+ regulatory T cells. J. Biol. Chem. 285:7176–86.PubMedCrossRefGoogle Scholar
  52. 52.
    Atarashi K, et al. (2008) ATP drives lamina propria T(H)17 cell differentiation. Nature. 455:808–12.PubMedCrossRefGoogle Scholar
  53. 53.
    Salmi M, Jalkanen S. (2001) Human leukocyte subpopulations from inflamed gut bind to joint vasculature using distinct sets of adhesion molecules. J. Immunol. 166:4650–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Moran JP, Walter J, Tannock GW, Tonkonogy SL, Sartor RB. (2009) Bifidobacterium animalis causes extensive duodenitis and mild colonic inflammation in monoassociated interleukin-10-deficient mice. Inflamm. Bowel Dis. 15:1022–31.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Leach MW, Davidson NJ, Fort MM, Powrie F, Rennick DM. (1999) The role of IL-10 in inflammatory bowel disease: “of mice and men.” Toxicol. Pathol. 27:123–33.PubMedCrossRefGoogle Scholar
  56. 56.
    Lee JS, Paek NS, Kwon OS, Hahm KB. (2010) Anti-inflammatory actions of probiotics through activating suppressor of cytokine signaling (SOCS) expression and signaling in Helicobacter pylori infection: a novel mechanism. J. Gastroenterol. Hepatol. 25:194–202.PubMedCrossRefGoogle Scholar
  57. 57.
    Pillemer BB, Xu H, Oriss TB, Qi Z, Ray A. (2007) Deficient SOCS3 expression in CD4+CD25+FoxP3+ regulatory T cells and SOCS3-mediated suppression of Treg function. Eur. J. Immunol. 37:2082–9.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Schmidt EG, Claesson MH, Jensen SS, Ravn P, Kristensen NN. (2010) Antigen-presenting cells exposed to Lactobacillus acidophilus NCFM, Bifidobacterium bifidum BI-98, and BI-504 reduce regulatory T cell activity. Inflamm. Bowel Dis. 16:390–400.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Ertelt JM, et al. (2009) Selective priming and expansion of antigen-specific Foxp3- CD4+ T cells during Listeria monocytogenes infection. J. Immunol. 182:3032–8.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Kandulski A, et al. (2008) Naturally occurring regulatory T cells (CD4+, CD25high, FOXP3+) in the antrum and cardia are associated with higher H. pylori colonization and increased gene expression of TGF-beta1. Helicobacter. 13:295–303.PubMedCrossRefGoogle Scholar
  61. 61.
    DeLuca HF. (2004) Overview of general physiologic features and functions of vitamin D. Am. J. Clin. Nutr. 80:1689S–96S.PubMedCrossRefGoogle Scholar
  62. 62.
    Belkaid Y, Oldenhove G. (2008) Tuning microenvironments: induction of regulatory T cells by dendritic cells. Immunity. 29:362–71.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Matheu V, Back O, Mondoc E, Issazadeh-Navikas S. (2003) Dual effects of vitamin D-induced alteration of TH1/TH2 cytokine expression: enhancing IgE production and decreasing airway eosinophilia in murine allergic airway disease. J. Allergy Clin. Immunol. 112:585–92.PubMedCrossRefGoogle Scholar
  64. 64.
    Matheu V, et al. (2009) Impact on allergic immune response after treatment with vitamin A. Nutr. Metab. 6:44.CrossRefGoogle Scholar
  65. 65.
    Penniston KL, Tanumihardjo SA. (2006) The acute and chronic toxic effects of vitamin A. Am. J. Clin. Nutr. 83:191–201.PubMedCrossRefGoogle Scholar
  66. 66.
    Cantorna MT, Nashold FE, Hayes CE. (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.PubMedGoogle Scholar
  67. 67.
    Stephensen CB, et al. (2002) Vitamin A enhances in vitro Th2 development via retinoid X receptor pathway. J. Immunol. 168:4495–503.PubMedCrossRefGoogle Scholar
  68. 68.
    Kang SG, et al. (2007) Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells. J. Immunol. 179:3724–33.PubMedCrossRefGoogle Scholar
  69. 69.
    Mucida D, et al. (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science. 317:256–60.PubMedCrossRefGoogle Scholar
  70. 70.
    Elias KM, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Korn T, et al. (2007) Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat. Med. 13:423–31.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Racke MK, et al. (1995) Retinoid treatment of experimental allergic encephalomyelitis: IL-4 production correlates with improved disease course. J. Immunol. 154:450–8.PubMedGoogle Scholar
  73. 73.
    Massacesi L, et al. (1991) Immunosuppressive activity of 13-cis-retinoic acid and prevention of experimental autoimmune encephalomyelitis in rats. J. Clin. Invest. 88:1331–7.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Massacesi L, et al. (1987) Suppression of experimental allergic encephalomyelitis by retinoic acid. J. Neurol. Sci. 80:55–64.PubMedCrossRefGoogle Scholar
  75. 75.
    Xiao S, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Hall JA, Grainger JR, Spencer SP, Belkaid Y. (2011) The role of retinoic acid in tolerance and immunity. Immunity. 35:13–22.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Manicassamy S, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    White JH. (2011) Vitamin D metabolism and signaling in the immune system. Rev. Endocr. Metab. Disord. 2011, Aug 16. [Epub ahead of print].Google Scholar
  79. 79.
    Vieth R. (2004) Why the optimal requirement for vitamin D3 is probably much higher than what is officially recommended for adults. J. Steroid. Biochem. Mol. Biol. 89–90:575–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Ghoreishi M, et al. (2009) Expansion of antigen-specific regulatory T cells with the topical vitamin D analog calcipotriol. J. Immunol. 182:6071–8.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Ghoreishi M, Dutz JP. (2006) Tolerance induction by transcutaneous immunization through ultraviolet-irradiated skin is transferable through CD4+CD25+ T regulatory cells and is dependent on host-derived IL-10. J. Immunol. 176:2635–44.PubMedCrossRefGoogle Scholar
  82. 82.
    Spach KM, Hayes CE. (2005) Vitamin D3 confers protection from autoimmune encephalomyelitis only in female mice. J. Immunol. 175:4119–26.PubMedCrossRefGoogle Scholar
  83. 83.
    Horst RL, Reinhardt TA, Ramberg CF, Koszewski NJ, Napoli JL. (1986) 24-Hydroxylation of 1,25-dihydroxyergocalciferol: an unambiguous deactivation process. J. Biol. Chem. 261:9250–6.PubMedGoogle Scholar
  84. 84.
    Nashold FE, Spach KM, Spanier JA, Hayes CE. (2009) Estrogen controls vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis by controlling vitamin D3 metabolism and receptor expression. J. Immunol. 183:3672–81.PubMedCrossRefGoogle Scholar
  85. 85.
    Jeffery LE, et al. (2009) 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J. Immunol. 183:5458–67.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Driver JP, Foreman O, Mathieu C, van Etten E, Serreze DV. (2008) Comparative therapeutic effects of orally administered 1,25-dihydroxyvitamin D(3) and 1alpha-hydroxyvitamin D(3) on type-1 diabetes in non-obese diabetic mice fed a normal-calcaemic diet. Clin. Exp. Immunol. 151:76–85.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Gregori S, Giarratana N, Smiroldo S, Uskokovic M, Adorini L. (2002) A 1alpha,25-dihydroxyvitamin D(3) analog enhances regulatory T-cells and arrests autoimmune diabetes in NOD mice. Diabetes. 51:1367–74.PubMedCrossRefGoogle Scholar
  88. 88.
    Barrat FJ, et al. (2002) 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. 195:603–16.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Vieira PL, et al. (2004) IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J. Immunol. 172:5986–93.PubMedCrossRefGoogle Scholar
  90. 90.
    Daniel C, Sartory NA, Zahn N, Radeke HH, Stein JM. (2008) 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.PubMedCrossRefGoogle Scholar
  91. 91.
    Gorman S, Judge MA, Burchell JT, Turner DJ, Hart PH. (2010) 1,25-dihydroxyvitamin D3 enhances the ability of transferred CD4+ CD25+ cells to modulate T helper type 2-driven asthmatic responses. Immunology. 130:181–92.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Hewison M, et al. (2007) Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease. J. Steroid. Biochem. Mol. Biol. 103:316–21.PubMedCrossRefGoogle Scholar
  93. 93.
    Sigmundsdottir H, et al. (2007) DCs metabolize sunlight-induced vitamin D3 to ‘program’ T cell attraction to the epidermal chemokine CCL27. Nat. Immunol. 8:285–93.PubMedCrossRefGoogle Scholar
  94. 94.
    Correale J, Ysrraelit MC, Gaitan MI. (2009) Immunomodulatory effects of vitamin D in multiple sclerosis. Brain. 132:1146–60.PubMedCrossRefGoogle Scholar
  95. 95.
    Meehan TF, DeLuca HF. (2002) The vitamin D receptor is necessary for 1alpha,25-dihydroxyvitamin D(3) to suppress experimental autoimmune encephalomyelitis in mice. Arch. Biochem. Biophys. 408:200–4.PubMedCrossRefGoogle Scholar
  96. 96.
    Smolders J, et al. (2009) Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis. PLoS One. 4:e6635.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. (2006) Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 296:2832–8.CrossRefGoogle Scholar
  98. 98.
    Zhou X, et al. (2009) Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 10:1000–7.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Green PH, Cellier C. (2007) Celiac disease. N. Engl. J. Med. 357:1731–43.PubMedCrossRefGoogle Scholar
  100. 100.
    Frisullo G, et al. (2009) Increased CD4+CD25+Foxp3+ T cells in peripheral blood of celiac disease patients: correlation with dietary treatment. Hum. Immunol. 70:430–5.PubMedCrossRefGoogle Scholar
  101. 101.
    Funda DP, Kaas A, Bock T, Tlaskalova-Hogenova H, Buschard K. (1999) Gluten-free diet prevents diabetes in NOD mice. Diabetes Metab. Res. Rev. 15:323–7.PubMedCrossRefGoogle Scholar
  102. 102.
    Lefebvre DE, Powell KL, Strom A, Scott FW. (2006) Dietary proteins as environmental modifiers of type 1 diabetes mellitus. Annu. Rev. Nutr. 26:175–202.PubMedCrossRefGoogle Scholar
  103. 103.
    Schmid S, et al. (2004) Delayed exposure to wheat and barley proteins reduces diabetes incidence in non-obese diabetic mice. Clin. Immunol. 111:108–18.PubMedCrossRefGoogle Scholar
  104. 104.
    Ejsing-Duun M, Josephsen J, Aasted B, Buschard K, Hansen AK. (2008) Dietary gluten reduces the number of intestinal regulatory T cells in mice. Scand. J. Immunol. 67:553–9.PubMedCrossRefGoogle Scholar
  105. 105.
    Pop SM, Wong CP, Culton DA, Clarke SH, Tisch R. (2005) Single cell analysis shows decreasing FoxP3 and TGFbeta1 coexpressing CD4+CD25+ regulatory T cells during autoimmune diabetes. J. Exp. Med. 201:1333–46.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Kivling A, et al. (2008) Diverse foxp3 expression in children with type 1 diabetes and celiac disease. Ann. N. Y. Acad. Sci. 1150:273–7.PubMedCrossRefGoogle Scholar
  107. 107.
    Di Marco R, et al. (2004) Exacerbation of protracted-relapsing experimental allergic encephalomyelitis in DA rats by gluten-free diet. APMIS. 112:651–5.PubMedCrossRefGoogle Scholar
  108. 108.
    Du Pre MF, et al. (2011) Tolerance to ingested deamidated gliadin in mice is maintained by splenic, type 1 regulatory T cells. Gastroenterology. 141:610–620, e611–612.PubMedCrossRefGoogle Scholar
  109. 109.
    McNamara RK, et al. (2007) Selective deficits in the omega-3 fatty acid docosahexaenoic acid in the postmortem orbitofrontal cortex of patients with major depressive disorder. Biol. Psychiatry. 62:17–24.PubMedCrossRefGoogle Scholar
  110. 110.
    Serhan CN, Gotlinger K, Hong S, Arita M. (2004) Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their aspirin-triggered endogenous epimers: an overview of their protective roles in catabasis. Prostaglandins Other Lipid Mediat. 73:155–72.PubMedCrossRefGoogle Scholar
  111. 111.
    El-Mesery M, Al-Gayyar M, Salem H, Darweish M, El-Mowafy A. (2009) Chemopreventive and renal protective effects for docosahexaenoic acid (DHA): implications of CRP and lipid peroxides. Cell Div. 4:6.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Kato T, et al. (2002) Influence of omega-3 fatty acids on the growth of human colon carcinoma in nude mice. Cancer Lett. 187:169–77.PubMedCrossRefGoogle Scholar
  113. 113.
    Schonberg SA, et al. (2006) Closely related colon cancer cell lines display different sensitivity to polyunsaturated fatty acids, accumulate different lipid classes and downregulate sterol regulatory element-binding protein 1. FEBS J. 273:2749–65.PubMedCrossRefGoogle Scholar
  114. 114.
    Shaikh IA, Brown I, Schofield AC, Wahle KW, Heys SD. (2008) Docosahexaenoic acid enhances the efficacy of docetaxel in prostate cancer cells by modulation of apoptosis: the role of genes associated with the NF-kappaB pathway. Prostate. 68:1635–46.PubMedCrossRefGoogle Scholar
  115. 115.
    Yessoufou A, Ple A, Moutairou K, Hichami A, Khan NA. (2009) Docosahexainoic acid HA reduces suppressive and migratory functions of CD4+CD25+ regulatory T-cells. J Lipid Res. 50:2377–88.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Shevach EM. (2002) CD4+ CD25+ suppressor T cells: more questions than answers. Nat. Rev. Immunol. 2:389–400.PubMedCrossRefGoogle Scholar
  117. 117.
    Sebastiani S, et al. (2001) Chemokine receptor expression and function in CD4+ T lymphocytes with regulatory activity. J. Immunol. 166:996–1002.PubMedCrossRefGoogle Scholar
  118. 118.
    Kong W, Yen JH, Ganea D. (2011) Docosahexaenoic acid prevents dendritic cell maturation, inhibits antigen-specific Th1/Th17 differentiation and suppresses experimental autoimmune encephalomyelitis. Brain Behave. Immun. 25:872–82.CrossRefGoogle Scholar
  119. 119.
    Tran DQ, Ramsey H, Shevach EM. (2007) Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype. Blood. 110:2983–90.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Chang KM. (2005) Regulatory T cells and the liver: a new piece of the puzzle. Hepatology. 41:700–2.PubMedCrossRefGoogle Scholar
  121. 121.
    Winer S, et al. (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15:921–9.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Ma X, et al. (2007) A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury. Hepatology. 46:1519–29.PubMedCrossRefGoogle Scholar
  123. 123.
    Hildeman DA, et al. (1999) Reactive oxygen species regulate activation-induced T cell apoptosis. Immunity. 10:735–44.PubMedCrossRefGoogle Scholar
  124. 124.
    Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ. (1993) Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 75:241–51.PubMedCrossRefGoogle Scholar
  125. 125.
    Laurent A, et al. (2004) Pivotal role of superoxide anion and beneficial effect of antioxidant molecules in murine steatohepatitis. Hepatology. 39:1277–85.PubMedCrossRefGoogle Scholar
  126. 126.
    Roselli M, et al. (2009) Prevention of TNBS-induced colitis by different Lactobacillus and Bifidobacterium strains is associated with an expansion of gammadeltaT and regulatory T cells of intestinal intraepithelial lymphocytes. Inflamm. Bowel Dis. 15:1526–36.PubMedCrossRefGoogle Scholar
  127. 127.
    Di Giacinto C, Marinaro M, Sanchez M, Strober W, Boirivant M. (2005) Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells. J. Immunol. 174:3237–46.PubMedCrossRefGoogle Scholar
  128. 128.
    Pronio A, et al. (2008) Probiotic administration in patients with ileal pouch-anal anastomosis for ulcerative colitis is associated with expansion of mucosal regulatory cells. Inflamm. Bowel Dis. 14:662–8.PubMedCrossRefGoogle Scholar
  129. 129.
    Sheil B, et al. (2004) Is the mucosal route of administration essential for probiotic function? Subcutaneous administration is associated with attenuation of murine colitis and arthritis. Gut. 53:694–700.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Baharav E, Mor F, Halpern M, Weinberger A. (2004) Lactobacillus GG bacteria ameliorate arthritis in Lewis rats. J. Nutr. 134:1964–9.PubMedCrossRefGoogle Scholar
  131. 131.
    Lavasani S, et al. (2010) A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL-10 producing regulatory T cells. PLoS One. 5:e9009.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Feleszko W, et al. (2007) Probiotic-induced suppression of allergic sensitization and airway inflammation is associated with an increase of T regulatory-dependent mechanisms in a murine model of asthma. Clin. Exp. Allergy. 37:498–505.PubMedCrossRefGoogle Scholar
  133. 133.
    Sun CM, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Coombes JL, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Royal W 3rd, Mia Y, Li H, Naunton K. (2009) Peripheral blood regulatory T cell measurements correlate with serum vitamin D levels in patients with multiple sclerosis. J. Neuroimmunol. 213:135–41.PubMedCrossRefGoogle Scholar
  136. 136.
    Unger WW, Laban S, Kleijwegt FS, van der Slik AR, Roep BO. (2009) Induction of Treg by monocyte-derived DC modulated by vitamin D(3) or dexamethasone: differential role for PDL1. Eur. J. Immunol. 39:3147–59.PubMedCrossRefGoogle Scholar
  137. 137.
    Cipolletta D, Kolodin D, Benoist C, Mathis D. (2011) Tissular Tregs: a unique population of adipose-tissue-resident Foxp3+CD4+ T cells that impacts organismal metabolism. Semin. Immunol. 23:431–7.PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  • Shohreh Issazadeh-Navikas
    • 1
  • Roman Teimer
    • 1
  • Robert Bockermann
    • 1
  1. 1.Biotech Research and Innovation CentreUniversity of Copenhagen, Copenhagen BiocenterCopenhagen NDenmark

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