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The role of nuclear receptors in regulation of Th17/Treg biology and its implications for diseases

Cellular & Molecular Immunology volume 12, pages 533–542 (2015)Cite this article

Abstract

Nuclear receptors play an essential role in cellular environmental sensing, differentiation, development, homeostasis, and metabolism and are thus highly conserved across multiple species. The anti-inflammatory role of nuclear receptors in immune cells has recently gained recognition. Nuclear receptors play critical roles in both myeloid and lymphoid cells, particularly in helper CD4+ T-cell type 17 (Th17) and regulatory T cells (Treg). Th17 and Treg have a major impact on cellular fate through their interactions with cytokine signaling pathways. Recent studies have emphasized the interactions between nuclear receptors and the known cytokine signals and how these interactions affect the expression and function of master transcription factors in Th17 and Treg subsets. This review will focus on the most recent discoveries concerning the roles of nuclear receptors in regulating the Th17/Treg cell-fate determination.

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References

  1. Murphy KM, Reiner SL . The lineage decisions of helper T cells. Nat Rev Immunol 2002; 2: 933–944.

    CAS  PubMed  Google Scholar 

  2. Breitfeld D, Ohl L, Kremmer E, Ellwart J, Sallusto F, Lipp M et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J Exp Med 2000; 192: 1545–1552.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Schmitt E, Klein M, Bopp T . Th9 cells, new players in adaptive immunity. Trends Immunol 2014; 35: 61–68.

    CAS  PubMed  Google Scholar 

  4. Bettelli E, Oukka M, Kuchroo VK . T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol 2007; 8: 345–350.

    CAS  PubMed  Google Scholar 

  5. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441: 235–238.

    Article  CAS  PubMed  Google Scholar 

  6. Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM . 2006 Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 2006; 24: 677–688.

    CAS  PubMed  Google Scholar 

  7. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 2006; 126: 1121–1133.

    CAS  PubMed  Google Scholar 

  8. Romagnani S . Human Th17 cells. Arthritis Res Ther 2008; 10: 206 .

    PubMed  PubMed Central  Google Scholar 

  9. Han L, Yang J, Wang X, Li D, Lv L, Li B . Th17 cells in autoimmune diseases. Front Med 2015; 9: 10–19.

    PubMed  Google Scholar 

  10. Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 2008; 28: 29–39.

    CAS  PubMed  Google Scholar 

  11. Harris TJ, Grosso JF, Yen HR, Xin H, Kortylewski M, Albesiano E et al. Cutting edge: an in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. J Immunol 2007; 179: 4313–4317.

    CAS  PubMed  Google Scholar 

  12. Villarino AV, Gallo E, Abbas AK . STAT1-activating cytokines limit Th17 responses through both T-bet-dependent and -independent mechanisms. J Immunol 2010; 185: 6461–6471.

    CAS  PubMed  Google Scholar 

  13. Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 2007; 26: 371–381.

    CAS  PubMed  Google Scholar 

  14. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y et al. Control of TH17/Treg balance by hypoxia-inducible factor 1. Cell; 146: 772–784.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. D’Cruz LM, Klein L . Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat Immunol 2005; 6: 1152–1159.

    PubMed  Google Scholar 

  16. Rudensky AY . Regulatory T cells and Foxp3. Immunol Rev 2011; 241: 260–268.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Curotto de Lafaille MA, Lafaille JJ . Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 2009; 30: 626–635.

    CAS  PubMed  Google Scholar 

  18. Shevach EM . Mechanisms of Foxp3+ T regulatory cell-mediated suppression. Immunity 2009; 30: 636–645.

    CAS  PubMed  Google Scholar 

  19. Xiao S, Jin H, Korn T, Liu SM, Oukka M, Lim B et al. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-β-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol 2008; 181: 2277–2284.

    CAS  PubMed  Google Scholar 

  20. Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA . IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J Immunol 2007; 178: 280–290.

    CAS  PubMed  Google Scholar 

  21. van Loosdregt J, Fleskens V, Fu J, Brenkman AB, Bekker CP, Pals CE et al. Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity. Immunity 2013; 39: 259–271.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Chen Z, Barbi J, Bu S, Yang HY, Li Z, Gao Y et al. The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity 2013; 39: 272–285.

    CAS  PubMed  Google Scholar 

  23. Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 2008; 453: 236–240.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Ichiyama K, Yoshida H, Wakabayashi Y, Chinen T, Saeki K, Nakaya M et al. Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat. J Biol Chem 2008; 283: 17003–17008.

    CAS  PubMed  Google Scholar 

  25. Heller JJ, Qiu J, Zhou L . Nuclear receptors take center stage in Th17 cell-mediated autoimmunity. J Clin Invest 2011; 121: 519–521.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Klotz L, Knolle P . Nuclear receptors: TH17 cell control from within. FEBS Lett 2011; 585: 3764–3769.

    CAS  PubMed  Google Scholar 

  27. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schütz G, Umesono K et al. The nuclear receptor superfamily: the second decade. Cell 1995; 83: 835–839.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Khan S, Lingrel JB . Thematic minireview series on nuclear receptors in biology and diseases. J Biol Chem 2010; 285: 38741–38742.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Daynes RA, Jones DC . Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol 2002; 2: 748–759.

    CAS  PubMed  Google Scholar 

  30. Mangelsdorf DJ, Evans RM . The RXR heterodimers and orphan receptors. Cell 1995; 83: 841–850.

    CAS  PubMed  Google Scholar 

  31. Schupp M, Lazar MA . Endogenous ligands for nuclear receptors: digging deeper. J Biol Chem 2010; 285: 40409–40415.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Rosenfeld MG, Glass CK . Coregulator codes of transcriptional regulation by nuclear receptors. J Biol Chem 2001; 276: 36865–36868.

    CAS  PubMed  Google Scholar 

  33. Jetten AM, Kurebayashi S, Ueda E . The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes. Prog Nucleic Acid Res Mol Biol 2001; 69: 205–247.

    CAS  PubMed  Google Scholar 

  34. Manel N, Unutmaz D, Littman DR The differentiation of human T(H)-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγT. Nat Immunol 2008; 9: 641–649.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M et al. IL-21 and TGF-[bgr] are required for differentiation of human TH17 cells. Nature 2008; 454: 350–352.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Huh JR, Leung MWL, Huang P, Ryan DA, Krout MR, Malapaka RRV et al. Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing ROR[ggr]t activity. Nature 2011; 472: 486–490.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Solt LA, Kumar N, Nuhant P, Wang Y, Lauer JL, Liu J et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 2011; 472: 491–494.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Burgler S, Mantel PY, Bassin C, Ouaked N, Akdis CA, Schmidt-Weber CB RORC2 is involved in T cell polarization through interaction with the FOXP3 promoter. J Immunol 2010; 184: 6161–6169.

    CAS  PubMed  Google Scholar 

  39. Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 2008; 29: 44–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Gianni M, Li Calzi M, Terao M, Guiso G, Caccia S, Barbui T et al. AM580, a stable benzoic derivative of retinoic acid, has powerful and selective cyto-differentiating effects on acute promyelocytic leukemia cells. Blood 1996; 87: 1520–1531.

    CAS  PubMed  Google Scholar 

  41. Chambon P . A decade of molecular biology of retinoic acid receptors. Faseb J 1996; 10: 940–954.

    CAS  PubMed  Google Scholar 

  42. Zhou X, Kong N, Wang J, Fan H, Zou H, Horwitz D et al. Cutting edge: all-trans retinoic acid sustains the stability and function of natural regulatory T cells in an inflammatory milieu. J Immunol 2010; 185: 2675–2679.

    CAS  PubMed  Google Scholar 

  43. Golovina TN, Mikheeva T, Brusko TM, Blazar BR, Bluestone JA, Riley JL . Retinoic acid and rapamycin differentially affect and synergistically promote the ex vivo expansion of natural human T regulatory cells. PLoS ONE 2011; 6: e15868 .

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Takeuchi H, Yokota-Nakatsuma A, Ohoka Y, Kagechika H, Kato C, Song SY et al. Retinoid X receptor agonists modulate Foxp3(+) regulatory T cell and Th17 cell differentiation with differential dependence on retinoic acid receptor activation. J Immunol 2013; 191: 3725–3733.

    CAS  PubMed  Google Scholar 

  45. Mucida D, Pino-Lagos K, Kim G, Nowak E, Benson MJ, Kronenberg M et al. Retinoic acid can directly promote TGF-β-mediated Foxp3+ Treg cell conversion of naive T cells. Immunity 2013; 30: 471–472.

    Google Scholar 

  46. Nolting J, Daniel C, Reuter S, Stuelten C, Li P, Sucov H et al. Retinoic acid can enhance conversion of naive into regulatory T cells independently of secreted cytokines. J Exp Med 2009; 206: 2131–2139.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Hill JA, Hall JA, Sun CM, Cai Q, Ghyselinck N, Chambon P et al. Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi cells. Immunity 2008; 29: 758–770.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Schambach F, Schupp M, Lazar MA, Reiner SL . Activation of retinoic acid receptor-alpha favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation. Eur J Immunol 2007; 37: 2396–2399.

    CAS  PubMed  Google Scholar 

  49. Bai A, Lu N, Guo Y, Liu Z, Chen J, Peng Z . All-trans retinoic acid down-regulates inflammatory responses by shifting the Treg/Th17 profile in human ulcerative and murine colitis. J Leukoc Biol 2009; 86: 959–969.

    CAS  PubMed  Google Scholar 

  50. Jafarirad S, Siassi F, Harirchian MH, Sahraian MA, Eshraghian MR, Shokri F et al. The effect of vitamin A supplementation on stimulated T-cell proliferation with myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. J Neurosci Rural Pract 2012; 3: 294–298.

    PubMed  PubMed Central  Google Scholar 

  51. Harrirchian MH, Mohammadzadeh Honarvar N, Koohdani F, Bitarafan S, Siassi F, Jafarirad S et al. The effect of vitamin a supplementation on disease progression, cytokine levels and gene expression in multiple sclerotic patients: study protocol for a randomized controlled trial. Acta Medica Iranica 2014; 52: 94–100.

    CAS  PubMed  Google Scholar 

  52. Fragoso YD, Stoney PN, McCaffery PJ . The evidence for a beneficial role of vitamin A in multiple sclerosis. CNS Drugs 2014; 28: 291–299.

    CAS  PubMed  Google Scholar 

  53. Gebel T, Arand M, Oesch F . Induction of the peroxisome proliferator activated receptor by fenofibrate in rat liver. FEBS Lett 1992; 309: 37–40.

    CAS  PubMed  Google Scholar 

  54. Dreyer C, Keller H, Mahfoudi A, Laudet V, Krey G, Wahli W . Positive regulation of the peroxisomal beta-oxidation pathway by fatty acids through activation of peroxisome proliferator-activated receptors (PPAR). Biol Cell 1993; 77: 67–76.

    CAS  PubMed  Google Scholar 

  55. Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE et al. PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 2012; 486: 549–553.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Klotz L, Burgdorf S, Dani I, Saijo K, Flossdorf J, Hucke S et al. The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. J Exp Med 2009; 206: 2079–2089.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Li B, Reynolds JM, Stout RD, Bernlohr DA, Suttles J . Regulation of Th17 differentiation by epidermal fatty acid-binding protein. J Immunol 2009; 182: 7625–7633.

    CAS  PubMed  Google Scholar 

  58. Wang LH, Yang XY, Zhang X, Huang J, Hou J, Li J et al. Transcriptional inactivation of STAT3 by PPARgamma suppresses IL-6-responsive multiple myeloma cells. Immunity 2004; 20: 205–218.

    CAS  PubMed  Google Scholar 

  59. Wohlfert EA, Nichols FC, Nevius E, Clark RB . Peroxisome proliferator-activated receptor gamma (PPARgamma) and immunoregulation: enhancement of regulatory T cells through PPARgamma-dependent and -independent mechanisms. J Immunol 2007; 178: 4129–4135.

    CAS  PubMed  Google Scholar 

  60. Hontecillas R, Bassaganya-Riera J . Peroxisome proliferator-activated receptor gamma is required for regulatory CD4+ T cell-mediated protection against colitis. J Immunol 2007; 178: 2940–2949.

    CAS  PubMed  Google Scholar 

  61. Kanakasabai S, Walline CC, Chakraborty S, Bright JJ . PPARdelta deficient mice develop elevated Th1/Th17 responses and prolonged experimental autoimmune encephalomyelitis. Brain Res 2011; 1376: 101–112.

    CAS  PubMed  Google Scholar 

  62. Dunn SE, Ousman SS, Sobel RA, Zuniga L, Baranzini SE, Youssef S et al. Peroxisome proliferator–activated receptor (PPAR)α expression in T cells mediates gender differences in development of T cell–mediated autoimmunity. J Exp Med 2007; 204: 321–330.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhang MA, Rego D, Moshkova M, Kebir H, Chruscinski A, Nguyen H et al. Peroxisome proliferator-activated receptor (PPAR)α and -γ regulate IFNγ and IL-17A production by human T cells in a sex-specific way. Proc Nat Acad Sci 2012; 109: 9505–9510.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Gocke AR, Hussain RZ, Yang Y, Peng H, Weiner J, Ben LH et al. Transcriptional modulation of the immune response by peroxisome proliferator-activated receptor-{alpha} agonists in autoimmune disease. J Immunol 2009; 182: 4479–4487.

    CAS  PubMed  Google Scholar 

  65. Kanakasabai S, Chearwae W, Walline CC, Iams W, Adams SM, Bright JJ . Peroxisome proliferator-activated receptor delta agonists inhibit T helper type 1 (Th1) and Th17 responses in experimental allergic encephalomyelitis. Immunology 2010; 130: 572–588.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Lei J, Hasegawa H, Matsumoto T, Yasukawa M . Peroxisome proliferator-activated receptor alpha and gamma agonists together with TGF-beta convert human CD4+CD25- T cells into functional Foxp3+ regulatory T cells. J Immunol 2010; 185: 7186–7198.

    CAS  PubMed  Google Scholar 

  67. Dubrac S, Elentner A, Schoonjans K, Auwerx J, Schmuth M . Lack of IL-2 in PPAR-alpha-deficient mice triggers allergic contact dermatitis by affecting regulatory T cells. Eur J Immunol 2011; 41: 1980–1991.

    CAS  PubMed  Google Scholar 

  68. Zuo X, Wu Y, Morris JS, Stimmel JB, Leesnitzer LM, Fischer SM, Lippman SM et al. Oxidative metabolism of linoleic acid modulates PPAR-beta//delta suppression of PPAR-gamma activity. Oncogene 2005; 25: 1225–1241.

    Google Scholar 

  69. Pershadsingh HA, Heneka MT, Saini R, Amin NM, Broeske DJ, Feinstein DL . Effect of pioglitazone treatment in a patient with secondary multiple sclerosis. J Neuroinflammation 2004; 1: 3 .

    PubMed  PubMed Central  Google Scholar 

  70. Hack K, Reilly L, Palmer C, Read KD, Norval S, Kime R et al. Skin-targeted inhibition of PPAR β/δ by selective antagonists to treat PPAR β/δ – mediated psoriasis-like skin disease in vivo. PLoS ONE 2012; 7: e37097 .

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Nguyen LP, Bradfield CA . The search for endogenous activators of the aryl hydrocarbon receptor. Chem Res Toxicol 2008; 21: 102–116.

    CAS  PubMed  Google Scholar 

  72. Poland A, Glover E, Kende AS . Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. J Biol Chem 1976; 251: 4936–4946.

    CAS  PubMed  Google Scholar 

  73. Rannug A, Rannug U, Rosenkranz HS, Winqvist L, Westerholm R, Agurell E et al. Certain photooxidized derivatives of tryptophan bind with very high affinity to the Ah receptor and are likely to be endogenous signal substances. J Biol Chem 1987; 262: 15422–15427.

    CAS  PubMed  Google Scholar 

  74. Oberg M, Bergander L, Hakansson H, Rannug U, Rannug A . Identification of the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole, in cell culture medium, as a factor that controls the background aryl hydrocarbon receptor activity. Toxicol Sci 2005; 85: 935–943.

    PubMed  Google Scholar 

  75. Yasui T, Kim EY, Iwata H, Franks DG, Karchner SI, Hahn ME et al. Functional characterization and evolutionary history of two aryl hydrocarbon receptor isoforms (AhR1 and AhR2) from avian species. Toxicol Sci 2007; 99: 101–117.

    CAS  PubMed  Google Scholar 

  76. Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 2008; 453: 106–109.

    CAS  PubMed  Google Scholar 

  77. Veldhoen M, Hirota K, Christensen J, O’Garra A, Stockinger B . Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J Exp Med 2009; 206: 43–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Kimura A, Naka T, Nohara K, Fujii-Kuriyama Y, Kishimoto T . Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells. Proc Nat Acad Sci 2008; 105: 9721–9726.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 2008; 453: 65–71.

    CAS  PubMed  Google Scholar 

  80. Gandhi R, Kumar D, Burns EJ, Nadeau M, Dake B, Laroni A et al. Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3(+) regulatory T cells. Nat Immunol 2010; 11: 846–853.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Pot C . Aryl hydrocarbon receptor controls regulatory CD4+ T cell function. Swiss Med Wkly 2012; 142: w13592 .

    PubMed  Google Scholar 

  82. Nguyen NT, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara K et al. Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci USA 2010;107: 19961–19966.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Quintana FJ, Murugaiyan G, Farez MF, Mitsdoerffer M, Tukpah AM, Burns EJ et al. An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 2010; 107: 20768–20773.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Maxwell MA, Muscat GE . The NR4A subgroup: immediate early response genes with pleiotropic physiological roles. Nucl Recept Signal 2006; 4: e002 .

    PubMed  PubMed Central  Google Scholar 

  85. Kurakula K, Koenis DS, van Tiel CM, de Vries CJ . NR4A nuclear receptors are orphans but not lonesome. Biochim Biophys Acta 2014.

  86. Fassett MS, Jiang W, D’Alise AM, Mathis D, Benoist C . Nuclear receptor Nr4a1 modulates both regulatory T-cell (Treg) differentiation and clonal deletion. Proc Natl Acad Sci USA 2012; 109: 3891–3896.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Raveney BJE, Oki S, Yamamura T . Nuclear receptor NR4A2 orchestrates Th17 cell-mediated autoimmune inflammation via IL-21 signalling. PLoS ONE 2013; 8: e56595 .

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Sekiya T, Kashiwagi I, Inoue N, Morita R, Hori S, Waldmann H et al. The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells. Nat Commun 2011; 2: 269 .

    PubMed  Google Scholar 

  89. Sekiya T, Kashiwagi I, Yoshida R, Fukaya T, Morita R, Kimura A et al. Nr4a receptors are essential for thymic regulatory T cell development and immune homeostasis. Nat Immunol 2013; 14: 230–237.

    CAS  PubMed  Google Scholar 

  90. Kang SW, Kim SH, Lee N, Lee WW, Hwang KA, Shin MS et al. 1,25-Dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region. J Immunol 2012; 188: 5276–5282.

    CAS  PubMed  Google Scholar 

  91. Khoo AL, Joosten I, Michels M, Woestenenk R, Preijers F, He XH et al. 1,25-Dihydroxyvitamin D3 inhibits proliferation but not the suppressive function of regulatory T cells in the absence of antigen-presenting cells. Immunology 2011; 134: 459–468.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Bruce D, Yu S, Ooi JH, Cantorna MT . Converging pathways lead to overproduction of IL-17 in the absence of vitamin D signaling. Int Immunol 2011; 23: 519–528.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Smolders J, Thewissen M, Peelen E, Menheere P, Cohen Tervaert JW, Damoiseaux J et al. Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis. PLoS ONE 2009; 4: e6635 .

    PubMed  PubMed Central  Google Scholar 

  94. Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JPA . Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ 2014; 348 .

  95. Yang L, Weaver V, Smith JP, Bingaman S, Hartman TJ, Cantorna MT . Therapeutic effect of vitamin d supplementation in a pilot study of Crohn’s patients. Clin Transl Gastroenterol 2013; 4: e33 .

    CAS  PubMed  PubMed Central  Google Scholar 

  96. O’Sullivan M . Vitamin D as a novel therapy in inflammatory bowel disease: new hope or false dawn? Proc Nutr Soc 2015; 74: 5–12.

    PubMed  Google Scholar 

  97. Zhao C, Dahlman-Wright K . Liver X receptor in cholesterol metabolism. J Endocrinol 2010; 204: 233–240.

    CAS  PubMed  Google Scholar 

  98. Bensinger SJ, Bradley MN, Joseph SB, Zelcer N, Janssen EM, Hausner MA et al. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 2008; 134: 97–111.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Cui G, Qin X, Wu L, Zhang Y, Sheng X, Yu Q et al. Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation. J Clin Invest 2011; 121: 658–670.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Vucic E, Calcagno C, Dickson SD, Rudd JH, Hayashi K, Bucerius J et al. Regression of inflammation in atherosclerosis by the LXR agonist R211945: a noninvasive assessment and comparison with atorvastatin. JACC Cardiovasc Imaging 2012; 5: 819–828.

    PubMed  PubMed Central  Google Scholar 

  101. Sodhi RK, Singh N . Liver X receptors: emerging therapeutic targets for Alzheimer’s disease. Pharmacol Res 2013; 72: 45–51.

    CAS  PubMed  Google Scholar 

  102. Wang R, Green DR . Metabolic checkpoints in activated T cells. Nat Immunol 2012; 13: 907–915.

    CAS  PubMed  Google Scholar 

  103. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 2011; 186: 3299–3303.

    CAS  PubMed  Google Scholar 

  104. Michalek RD, Gerriets VA, Nichols AG, Inoue M, Kazmin D, Chang CY et al. Estrogen-related receptor-alpha is a metabolic regulator of effector T-cell activation and differentiation. Proc Natl Acad Sci USA 2011; 108: 18348–18353.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Powell JD, Delgoffe GM . The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity 2010; 33: 301–311.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Barbi J, Pardoll D, Pan F . Metabolic control of the Treg/Th17 axis. Immunol Rev 2013; 252: 52–77.

    PubMed  PubMed Central  Google Scholar 

  107. Nistala K, Moncrieffe H, Newton KR, Varsani H, Hunter P, Wedderburn LR . Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers. Arthritis Rheum 2008; 58: 875–887.

    PubMed  PubMed Central  Google Scholar 

  108. Jamshidian A, Shaygannejad V, Pourazar A, Zarkesh-Esfahani SH, Gharagozloo M . Biased Treg/Th17 balance away from regulatory toward inflammatory phenotype in relapsed multiple sclerosis and its correlation with severity of symptoms. J Neuroimmunol 2013; 262: 106–112.

    CAS  PubMed  Google Scholar 

  109. Nishikawa H, Sakaguchi S . Regulatory T cells in tumor immunity. Int J Cancer 2010; 127: 759–767.

    CAS  PubMed  Google Scholar 

  110. Kaipainen A, Kieran MW, Huang S, Butterfield C, Bielenberg D, Mostoslavsky G et al. PPARα deficiency in inflammatory cells suppresses tumor growth. PLoS ONE 2007; 2: e260 .

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Our research is supported by grants from the Melanoma Research Alliance, the National Institute of Health (RO1AI099300 and RO1AI089830), ‘‘Kelly’s Dream’’ Foundation, the Janey Fund, the Seraph Foundation, and gifts from Bill and Betty Topecer and Dorothy Needle.

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Authors and Affiliations

  1. Immunology and Hematopoiesis Division, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, 21287, MD, USA

    Benjamin V. Park & Fan Pan

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  1. Benjamin V. Park
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  2. Fan Pan
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Correspondence to Fan Pan.

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Park, B., Pan, F. The role of nuclear receptors in regulation of Th17/Treg biology and its implications for diseases. Cell Mol Immunol 12, 533–542 (2015). https://doi.org/10.1038/cmi.2015.21

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  • DOI: https://doi.org/10.1038/cmi.2015.21

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