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Molecular mechanisms underlying the regulation and functional plasticity of FOXP3+ regulatory T cells

Genes & Immunity volume 13, pages 1–13 (2012)Cite this article

Abstract

CD4+ CD25+ regulatory T (Treg) cells engage in the maintenance of immunological self-tolerance and homeostasis by limiting aberrant or excessive inflammation. The transcription factor forkhead box P3 (FOXP3) is critical for the development and function of Treg cells. The differentiation of the Treg cell lineage is not terminal, as developmental and functional plasticity occur through the sensing of inflammatory signals in the periphery. Here, we review the recent progress in our understanding of the molecular mechanisms underlying the regulation and functional plasticity of CD4+ CD25+ FOXP3+ Treg cells, through the perturbation of FOXP3 and its complex at a transcriptional, translational and post-translational level.

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References

  1. Hori S, Nomura T, Sakaguchi S . Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299: 1057–1061.

    Article  CAS  PubMed  Google Scholar 

  2. Ziegler SF . FOXP3: of mice and men. Annu Rev Immunol 2006; 24: 209–226.

    Article  CAS  PubMed  Google Scholar 

  3. Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 2001; 27: 68–73.

    Article  CAS  PubMed  Google Scholar 

  4. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001; 27: 20–21.

    Article  CAS  PubMed  Google Scholar 

  5. Littman DR, Rudensky A . Th17 and regulatory T cells in mediating and restraining inflammation. Cell 2010; 140: 845–858.

    Article  CAS  PubMed  Google Scholar 

  6. Zou W . Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006; 6: 295–307.

    Article  CAS  PubMed  Google Scholar 

  7. Workman CJ, Szymczak-Workman AL, Collison LW, Pillai MR, Vignali DA . The development and function of regulatory T cells. Cell Mol Life Sci 2009; 66: 2603–2622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Manrique SZ, Correa MA, Hoelzinger DB, Dominguez AL, Mirza N, Lin HH et al. Foxp3-positive macrophages display immunosuppressive properties and promote tumor growth. J Exp Med 2011; 208: 1485–1499.

    Article  CAS  PubMed  Google Scholar 

  9. Sundin M, D’Arcy P, Johansson CC, Barrett AJ, Lonnies H, Sundberg B et al. Multipotent mesenchymal stromal cells express FoxP3: a marker for the immunosuppressive capacity? J Immunother 2011; 34: 336–342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Monteiro M, Almeida CF, Caridade M, Ribot JC, Duarte J, Agua-Doce A et al. Identification of regulatory Foxp3+ invariant NKT cells induced by TGF-beta. J Immunol 2010; 185: 2157–2163.

    Article  CAS  PubMed  Google Scholar 

  11. Campbell DJ, Koch MA . Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev 2011; 11: 119–130.

    CAS  Google Scholar 

  12. Zheng SG, Wang JH, Gray JD, Soucier H, Horwitz DA . Natural and induced CD4+CD25+ cells educate CD4+CD25− cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10. J Immunol 2004; 172: 5213–5221.

    Article  CAS  PubMed  Google Scholar 

  13. McKarns SC, Kaminski NE . TGF-beta 1 differentially regulates IL-2 expression and [3H]-thymidine incorporation in CD3 epsilon mAb- and CD28 mAb-activated splenocytes and thymocytes. Immunopharmacology 2000; 48: 101–115.

    Article  CAS  PubMed  Google Scholar 

  14. Zheng SG, Gray JD, Ohtsuka K, Yamagiwa S, Horwitz DA . Generation ex vivo of TGF-beta-producing regulatory T cells from CD4+CD25− precursors. J Immunol 2002; 169: 4183–4189.

    Article  CAS  PubMed  Google Scholar 

  15. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003; 198: 1875–1886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006; 441: 231–234.

    Article  CAS  PubMed  Google Scholar 

  18. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 2007; 8: 967–974.

    Article  CAS  PubMed  Google Scholar 

  19. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B . TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006; 24: 179–189.

    Article  CAS  PubMed  Google Scholar 

  20. 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 

  21. Voo KS, Wang YH, Santori FR, Boggiano C, Arima K, Bover L et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci USA 2009; 106: 4793–4798.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hovhannisyan Z, Treatman J, Littman DR, Mayer L . Characterization of interleukin-17-producing regulatory T cells in inflamed intestinal mucosa from patients with inflammatory bowel diseases. Gastroenterology 2011; 140: 957–965.

    Article  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang J, Ioan-Facsinay A, van der Voort EI, Huizinga TW, Toes RE . Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol 2007; 37: 129–138.

    Article  CAS  PubMed  Google Scholar 

  25. Allan SE, Passerini L, Bacchetta R, Crellin N, Dai M, Orban PC et al. The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J Clin Invest 2005; 115: 3276–3284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Allan SE, Crome SQ, Crellin NK, Passerini L, Steiner TS, Bacchetta R et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol 2007; 19: 345–354.

    Article  CAS  PubMed  Google Scholar 

  27. Walker MR, Kasprowicz DJ, Gersuk VH, Benard A, Van Landeghen M, Buckner JH et al. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25− T cells. J Clin Invest 2003; 112: 1437–1443.

    Article  CAS  PubMed  Google Scholar 

  28. Gavin MA, Torgerson TR, Houston E, DeRoos P, Ho WY, Stray-Pedersen A et al. Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc Natl Acad Sci USA 2006; 103: 6659–6664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tran DQ, Ramsey H, Shevach EM . Induction of FOXP3 expression in naive human CD4+FOXP3T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype. Blood 2007; 110: 2983–2990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pillai V, Ortega SB, Wang CK, Karandikar NJ . Transient regulatory T-cells: a state attained by all activated human T-cells. Clin Immunol 2007; 123: 18–29.

    Article  CAS  PubMed  Google Scholar 

  31. Oldenhove G, Bouladoux N, Wohlfert EA, Hall JA, Chou D, Dos Santos L et al. Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 2009; 31: 772–786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rubtsov YP, Niec RE, Josefowicz S, Li L, Darce J, Mathis D et al. Stability of the regulatory T cell lineage in vivo. Science 2010; 329: 1667–1671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhou X, Bailey-Bucktrout SL, Jeker LT, Penaranda C, Martinez-Llordella M, Ashby M et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 2009; 10: 1000–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Duarte JH, Zelenay S, Bergman ML, Martins AC, Demengeot J . Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. Eur J Immunol 2009; 39: 948–955.

    Article  CAS  PubMed  Google Scholar 

  35. Addey C, White M, Dou L, Coe D, Dyson J, Chai JG . Functional plasticity of antigen-specific regulatory T cells in context of tumor. J Immunol 2011; 186: 4557–4564.

    Article  CAS  PubMed  Google Scholar 

  36. Tsuji M, Komatsu N, Kawamoto S, Suzuki K, Kanagawa O, Honjo T et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science 2009; 323: 1488–1492.

    Article  CAS  PubMed  Google Scholar 

  37. O’Connor RA, Leech MD, Suffner J, Hammerling GJ, Anderton SM . Myelin-reactive, TGF-beta-induced regulatory T cells can be programmed to develop Th1-like effector function but remain less proinflammatory than myelin-reactive Th1 effectors and can suppress pathogenic T cell clonal expansion in vivo. J Immunol 2010; 185: 7235–7243.

    Article  PubMed  CAS  Google Scholar 

  38. Esposito M, Ruffini F, Bergami A, Garzetti L, Borsellino G, Battistini L et al. IL-17- and IFN-gamma-secreting Foxp3+ T cells infiltrate the target tissue in experimental autoimmunity. J Immunol 2010; 185: 7467–7473.

    Article  CAS  PubMed  Google Scholar 

  39. Deknuydt F, Bioley G, Valmori D, Ayyoub M . IL-1beta and IL-2 convert human Treg into T(H)17 cells. Clin Immunol 2009; 131: 298–307.

    Article  CAS  PubMed  Google Scholar 

  40. Dominguez-Villar M, Baecher-Allan CM, Hafler DA . Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. Nat Med 2011; 17: 673–675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Williams LM, Rudensky AY . Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 2007; 8: 277–284.

    Article  CAS  PubMed  Google Scholar 

  42. Hippen KL, Merkel SC, Schirm DK, Nelson C, Tennis NC, Riley JL et al. Generation and large-scale expansion of human inducible regulatory T cells that suppress graft-versus-host disease. Am J Transplant 2011; 11: 1148–1157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hippen KL, Merkel SC, Schirm DK, Sieben CM, Sumstad D, Kadidlo DM et al. Massive ex vivo expansion of human natural regulatory T cells (T(regs)) with minimal loss of in vivo functional activity. Sci Transl Med 2011; 3: 83ra41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood 2011; 117: 1061–1070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Komatsu N, Mariotti-Ferrandiz ME, Wang Y, Malissen B, Waldmann H, Hori S . Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci USA 2009; 106: 1903–1908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang Y, Souabni A, Flavell RA, Wan YY . An intrinsic mechanism predisposes Foxp3-expressing regulatory T cells to Th2 conversion in vivo. J Immunol 2010; 185: 5983–5992.

    Article  CAS  PubMed  Google Scholar 

  47. Hoffmann P, Boeld TJ, Eder R, Huehn J, Floess S, Wieczorek G et al. Loss of FOXP3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation. Eur J Immunol 2009; 39: 1088–1097.

    Article  CAS  PubMed  Google Scholar 

  48. Koenen HJ, Smeets RL, Vink PM, van Rijssen E, Boots AM, Joosten I . Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 2008; 112: 2340–2352.

    Article  CAS  PubMed  Google Scholar 

  49. Zorn E, Nelson EA, Mohseni M, Porcheray F, Kim H, Litsa D et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 2006; 108: 1571–1579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Li L, Kim J, Boussiotis VA . IL-1beta-mediated signals preferentially drive conversion of regulatory T cells but not conventional T cells into IL-17-producing cells. J Immunol 2010; 185: 4148–4153.

    Article  CAS  PubMed  Google Scholar 

  51. Pasare C, Medzhitov R . Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2003; 299: 1033–1036.

    Article  CAS  PubMed  Google Scholar 

  52. Xu L, Kitani A, Fuss I, Strober W . Cutting edge: regulatory T cells induce CD4+CD25-Foxp3- T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta. J Immunol 2007; 178: 6725–6729.

    Article  CAS  PubMed  Google Scholar 

  53. Zheng SG, Wang J, Horwitz DA . Cutting edge: Foxp3+CD4+CD25+ regulatory T cells induced by IL-2 and TGF-beta are resistant to Th17 conversion by IL-6. J Immunol 2008; 180: 7112–7116.

    Article  CAS  PubMed  Google Scholar 

  54. Lu L, Zhou X, Wang J, Zheng SG, Horwitz DA . Characterization of protective human CD4CD25 FOXP3 regulatory T cells generated with IL-2, TGF-beta and retinoic acid. PLoS One 2010; 5: e15150.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. 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.

    Article  CAS  PubMed  Google Scholar 

  56. 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-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol 2008; 181: 2277–2284.

    Article  CAS  PubMed  Google Scholar 

  57. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sharma MD, Hou DY, Baban B, Koni PA, He Y, Chandler PR et al. Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity 2010; 33: 942–954.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Chaudhry A, Rudra D, Treuting P, Samstein RM, Liang Y, Kas A et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 2009; 326: 986–991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Chaudhry A, Samstein RM, Treuting P, Liang Y, Pils MC, Heinrich JM et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 2011; 34: 566–578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kimura A, Naka T, Kishimoto T . IL-6-dependent and -independent pathways in the development of interleukin 17-producing T helper cells. Proc Natl Acad Sci USA 2007; 104: 12099–12104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ . The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 2009; 10: 595–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zheng Y, Chaudhry A, Kas A, deRoos P, Kim JM, Chu TT et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 2009; 458: 351–356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med 2011; 17: 983–988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF et al. Foxp3(+) follicular regulatory T cells control the germinal center response. Nat Med 2011; 17: 975–982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Feng T, Cao AT, Weaver CT, Elson CO, Cong Y . Interleukin-12 converts Foxp3+ regulatory T cells to interferon-gamma-producing Foxp3+ T cells that inhibit colitis. Gastroenterology 2011; 140: 2031–2043.

    Article  CAS  PubMed  Google Scholar 

  67. Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, Hanada T et al. Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 2010; 142: 914–929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Mantel PY, Ouaked N, Ruckert B, Karagiannidis C, Welz R, Blaser K et al. Molecular mechanisms underlying FOXP3 induction in human T cells. J Immunol 2006; 176: 3593–3602.

    Article  CAS  PubMed  Google Scholar 

  69. Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY . Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 2010; 463: 808–812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kim HP, Leonard WJ . CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med 2007; 204: 1543–1551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Tone Y, Furuuchi K, Kojima Y, Tykocinski ML, Greene MI, Tone M . Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat Immunol 2008; 9: 194–202.

    Article  CAS  PubMed  Google Scholar 

  72. Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 2007; 5: e38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Baron U, Floess S, Wieczorek G, Baumann K, Grutzkau A, Dong J et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur J Immunol 2007; 37: 2378–2389.

    Article  CAS  PubMed  Google Scholar 

  74. Liu J, Lluis A, Illi S, Layland L, Olek S, von Mutius E et al. T regulatory cells in cord blood—FOXP3 demethylation as reliable quantitative marker. PLoS One 2010; 5: e13267.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Janson PC, Winerdal ME, Marits P, Thorn M, Ohlsson R, Winqvist O . FOXP3 promoter demethylation reveals the committed Treg population in humans. PLoS One 2008; 3: e1612.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Polansky JK, Kretschmer K, Freyer J, Floess S, Garbe A, Baron U et al. DNA methylation controls Foxp3 gene expression. Eur J Immunol 2008; 38: 1654–1663.

    Article  CAS  PubMed  Google Scholar 

  77. Mouly E, Chemin K, Nguyen HV, Chopin M, Mesnard L, Leite-de-Moraes M et al. The Ets-1 transcription factor controls the development and function of natural regulatory T cells. J Exp Med 2010; 207: 2113–2125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Polansky JK, Schreiber L, Thelemann C, Ludwig L, Kruger M, Baumgrass R et al. Methylation matters: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells. J Mol Med (Berl) 2010; 88: 1029–1040.

    Article  CAS  Google Scholar 

  79. Lal G, Zhang N, van der Touw W, Ding Y, Ju W, Bottinger EP et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol 2009; 182: 259–273.

    Article  CAS  PubMed  Google Scholar 

  80. Liu B, Tahk S, Yee KM, Fan G, Shuai K . The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression. Science 2010; 330: 521–525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Liu G, Yang K, Burns S, Shrestha S, Chi H . The S1P(1)-mTOR axis directs the reciprocal differentiation of T(H)1 and T(reg) cells. Nat Immunol 2010; 11: 1047–1056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Liu G, Burns S, Huang G, Boyd K, Proia RL, Flavell RA et al. The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR. Nat Immunol 2009; 10: 769–777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Xu L, Kitani A, Stuelten C, McGrady G, Fuss I, Strober W . Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I. Immunity 2010; 33: 313–325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Maruyama T, Li J, Vaque JP, Konkel JE, Wang W, Zhang B et al. Control of the differentiation of regulatory T cells and T(H)17 cells by the DNA-binding inhibitor Id3. Nat Immunol 2010; 12: 86–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Harada Y, Elly C, Ying G, Paik JH, DePinho RA, Liu YC . Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells. J Exp Med 2010; 207: 1381–1391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ouyang W, Beckett O, Ma Q, Paik JH, DePinho RA, Li MO . Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nat Immunol 2010; 11: 618–627.

    Article  CAS  PubMed  Google Scholar 

  87. Kerdiles YM, Stone EL, Beisner DR, McGargill MA, Ch’en IL, Stockmann C et al. Foxo transcription factors control regulatory T cell development and function. Immunity 2010; 33: 890–904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Peng DJ, Zeng M, Muromoto R, Matsuda T, Shimoda K, Subramaniam M et al. Noncanonical K27-linked polyubiquitination of TIEG1 regulates Foxp3 expression and tumor growth. J Immunol 2011; 186: 5638–5647.

    Article  CAS  PubMed  Google Scholar 

  89. Mantel PY, Kuipers H, Boyman O, Rhyner C, Ouaked N, Ruckert B et al. GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells. PLoS Biol 2007; 5: e329.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Takaki H, Ichiyama K, Koga K, Chinen T, Takaesu G, Sugiyama Y et al. STAT6 Inhibits TGF-beta1-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor. J Biol Chem 2008; 283: 14955–14962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wang Y, Su MA, Wan YY . An Essential Role of the Transcription Factor GATA-3 for the Function of Regulatory T Cells. Immunity 2011; 35: 337–348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Egawa T, Tillman RE, Naoe Y, Taniuchi I, Littman DR . The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells. J Exp Med 2007; 204: 1945–1957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Klunker S, Chong MM, Mantel PY, Palomares O, Bassin C, Ziegler M et al. Transcription factors RUNX1 and RUNX3 in the induction and suppressive function of Foxp3+ inducible regulatory T cells. J Exp Med 2009; 206: 2701–2715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Rudra D, Egawa T, Chong MM, Treuting P, Littman DR, Rudensky AY . Runx-CBFbeta complexes control expression of the transcription factor Foxp3 in regulatory T cells. Nat Immunol 2009; 10: 1170–1177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ruan Q, Kameswaran V, Tone Y, Li L, Liou HC, Greene MI et al. Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome. Immunity 2009; 31: 932–940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Long M, Park SG, Strickland I, Hayden MS, Ghosh S . Nuclear factor-kappaB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity 2009; 31: 921–931.

    Article  CAS  PubMed  Google Scholar 

  97. Son JS, Sahoo A, Chae CS, Hwang JS, Park ZY, Im SH . JunB and c-Rel cooperatively enhance Foxp3 expression during induced regulatory T cell differentiation. Biochem Biophys Res Commun 2011; 407: 141–147.

    Article  CAS  PubMed  Google Scholar 

  98. Soligo M, Camperio C, Caristi S, Scotta C, Del Porto P, Costanzo A et al. CD28 costimulation regulates FOXP3 in a RelA/NF-kappaB-dependent mechanism. Eur J Immunol 2011; 41: 503–513.

    Article  CAS  PubMed  Google Scholar 

  99. Sakaguchi S, Yamaguchi T, Nomura T, Ono M . Regulatory T cells and immune tolerance. Cell 2008; 133: 775–787.

    Article  CAS  PubMed  Google Scholar 

  100. Zheng SG, Wang J, Wang P, Gray JD, Horwitz DA . IL-2 is essential for TGF-beta to convert naive CD4+CD25− cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells. J Immunol 2007; 178: 2018–2027.

    Article  CAS  PubMed  Google Scholar 

  101. Chen Q, Kim YC, Laurence A, Punkosdy GA, Shevach EM . IL-2 controls the stability of Foxp3 expression in TGF-beta-induced Foxp3+ T cells in vivo. J Immunol 2011; 186: 6329–6337.

    Article  CAS  PubMed  Google Scholar 

  102. Yao Z, Kanno Y, Kerenyi M, Stephens G, Durant L, Watford WT et al. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 2007; 109: 4368–4375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 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.

    Article  CAS  PubMed  Google Scholar 

  104. Yang XP, Ghoreschi K, Steward-Tharp SM, Rodriguez-Canales J, Zhu J, Grainger JR et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat Immunol 2011; 12: 247–254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 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.

    Article  CAS  PubMed  Google Scholar 

  106. Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E et al. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 2008; 453: 65–71.

    Article  CAS  PubMed  Google Scholar 

  107. Samon JB, Champhekar A, Minter LM, Telfer JC, Miele L, Fauq A et al. Notch1 and TGFbeta1 cooperatively regulate Foxp3 expression and the maintenance of peripheral regulatory T cells. Blood 2008; 112: 1813–1821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ou-Yang HF, Zhang HW, Wu CG, Zhang P, Zhang J, Li JC et al. Notch signaling regulates the FOXP3 promoter through RBP-J- and Hes1-dependent mechanisms. Mol Cell Biochem 2009; 320: 109–114.

    Article  CAS  PubMed  Google Scholar 

  109. Barbarulo A, Grazioli P, Campese AF, Bellavia D, Di Mario G, Pelullo M et al. Notch3 and canonical NF-kappaB signaling pathways cooperatively regulate Foxp3 transcription. J Immunol 2011; 186: 6199–6206.

    Article  CAS  PubMed  Google Scholar 

  110. Vanvalkenburgh J, Albu DI, Bapanpally C, Casanova S, Califano D, Jones DM et al. Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease. J Exp Med 2011; 208: 2069–2081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Wei G, Wei L, Zhu J, Zang C, Hu-Li J, Yao Z et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 2009; 30: 155–167.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Lau NC, Lim LP, Weinstein EG, Bartel DP . An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 2001; 294: 858–862.

    Article  CAS  PubMed  Google Scholar 

  113. Lee RC, Ambros V . An extensive class of small RNAs in Caenorhabditis elegans. Science 2001; 294: 862–864.

    Article  CAS  PubMed  Google Scholar 

  114. Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T . Identification of novel genes coding for small expressed RNAs. Science 2001; 294: 853–858.

    Article  CAS  PubMed  Google Scholar 

  115. Wightman B, Ha I, Ruvkun G . Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 1993; 75: 855–862.

    Article  CAS  PubMed  Google Scholar 

  116. Lee RC, Feinbaum RL, Ambros V . The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75: 843–854.

    Article  CAS  PubMed  Google Scholar 

  117. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC . Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998; 391: 806–811.

    Article  CAS  PubMed  Google Scholar 

  118. Bartel DP . MicroRNAs: target recognition and regulatory functions. Cell 2009; 136: 215–233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Guo H, Ingolia NT, Weissman JS, Bartel DP . Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 2010; 466: 835–840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Chen CZ, Li L, Lodish HF, Bartel DP . MicroRNAs modulate hematopoietic lineage differentiation. Science 2004; 303: 83–86.

    Article  CAS  PubMed  Google Scholar 

  121. Navarro F, Lieberman J . Small RNAs guide hematopoietic cell differentiation and function. J Immunol 2010; 184: 5939–5947.

    Article  CAS  PubMed  Google Scholar 

  122. O’Neill LA, Sheedy FJ, McCoy CE . MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat Rev 2011; 11: 163–175.

    Google Scholar 

  123. O’Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, Chaudhuri AA et al. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity 2010; 33: 607–619.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. O’Connell RM, Rao DS, Chaudhuri AA, Baltimore D . Physiological and pathological roles for microRNAs in the immune system. Nat Rev 2010; 10: 111–122.

    Google Scholar 

  125. Belver L, Papavasiliou FN, Ramiro AR . MicroRNA control of lymphocyte differentiation and function. Curr Opin Immunol 2011; 23: 368–373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Cobb BS, Nesterova TB, Thompson E, Hertweck A, O’Connor E, Godwin J et al. T cell lineage choice and differentiation in the absence of the RNase III enzyme Dicer. J Exp Med 2005; 201: 1367–1373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Cobb BS, Hertweck A, Smith J, O’Connor E, Graf D, Cook T et al. A role for Dicer in immune regulation. J Exp Med 2006; 203: 2519–2527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Koralov SB, Muljo SA, Galler GR, Krek A, Chakraborty T, Kanellopoulou C et al. Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage. Cell 2008; 132: 860–874.

    Article  CAS  PubMed  Google Scholar 

  129. Ventura A, Young AG, Winslow MM, Lintault L, Meissner A, Erkeland SJ et al. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell 2008; 132: 875–886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Muljo SA, Ansel KM, Kanellopoulou C, Livingston DM, Rao A, Rajewsky K . Aberrant T cell differentiation in the absence of Dicer. J Exp Med 2005; 202: 261–269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Chong MM, Rasmussen JP, Rudensky AY, Littman DR . The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. J Exp Med 2008; 205: 2005–2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Liston A, Lu LF, O’Carroll D, Tarakhovsky A, Rudensky AY . Dicer-dependent microRNA pathway safeguards regulatory T cell function. J Exp Med 2008; 205: 1993–2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Zhou X, Jeker LT, Fife BT, Zhu S, Anderson MS, McManus MT et al. Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity. J Exp Med 2008; 205: 1983–1991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Rouas R, Fayyad-Kazan H, El Zein N, Lewalle P, Rothe F, Simion A et al. Human natural Treg microRNA signature: role of microRNA-31 and microRNA-21 in FOXP3 expression. Eur J Immunol 2009; 39: 1608–1618.

    Article  CAS  PubMed  Google Scholar 

  135. Fayyad-Kazan H, Rouas R, Merimi M, El Zein N, Lewalle P, Jebbawi F et al. Valproate treatment of human cord blood CD4-positive effector T cells confers on them the molecular profile (microRNA signature and FOXP3 expression) of natural regulatory CD4-positive cells through inhibition of histone deacetylase. J Biol Chem 2010; 285: 20481–20491.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR et al. Requirement of bic/microRNA-155 for normal immune function. Science 2007; 316: 608–611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y et al. Regulation of the germinal center response by microRNA-155. Science 2007; 316: 604–608.

    Article  CAS  PubMed  Google Scholar 

  138. Marson A, Kretschmer K, Frampton GM, Jacobsen ES, Polansky JK, MacIsaac KD et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 2007; 445: 931–935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Zheng Y, Josefowicz SZ, Kas A, Chu TT, Gavin MA, Rudensky AY . Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 2007; 445: 936–940.

    Article  CAS  PubMed  Google Scholar 

  140. Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, Tanaka K et al. Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity 2009; 30: 80–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, Vigorito E . Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells. J Immunol 2009; 182: 2578–2582.

    Article  CAS  PubMed  Google Scholar 

  142. Yamamoto M, Kondo E, Takeuchi M, Harashima A, Otani T, Tsuji-Takayama K et al. miR-155, a modulator of FOXO3a protein expression, is underexpressed and cannot be upregulated by stimulation of HOZOT, a line of multifunctional treg. PLoS One 2011; 6: e16841.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Huang B, Zhao J, Lei Z, Shen S, Li D, Shen GX et al. miR-142-3p restricts cAMP production in CD4+CD25− T cells and CD4+CD25+ TREG cells by targeting AC9 mRNA. EMBO Rep 2009; 10: 180–185.

    Article  CAS  PubMed  Google Scholar 

  144. Bopp T, Becker C, Klein M, Klein-Hessling S, Palmetshofer A, Serfling E et al. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med 2007; 204: 1303–1310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Bopp T, Dehzad N, Reuter S, Klein M, Ullrich N, Stassen M et al. Inhibition of cAMP degradation improves regulatory T cell-mediated suppression. J Immunol 2009; 182: 4017–4024.

    Article  CAS  PubMed  Google Scholar 

  146. Boldin MP, Taganov KD, Rao DS, Yang L, Zhao JL, Kalwani M et al. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med 2011; 208: 1189–1201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. De Santis G, Ferracin M, Biondani A, Caniatti L, Rosaria Tola M, Castellazzi M et al. Altered miRNA expression in T regulatory cells in course of multiple sclerosis. J Neuroimmunol 2010; 226: 165–171.

    Article  CAS  PubMed  Google Scholar 

  148. Hezova R, Slaby O, Faltejskova P, Mikulkova Z, Buresova I, Raja KR et al. microRNA-342, microRNA-191 and microRNA-510 are differentially expressed in T regulatory cells of type 1 diabetic patients. Cell Immunol 2009; 260: 70–74.

    Article  CAS  Google Scholar 

  149. Divekar AA, Dubey S, Gangalum PR, Singh RR . Dicer insufficiency and microRNA-155 overexpression in lupus regulatory T cells: an apparent paradox in the setting of an inflammatory milieu. J Immunol 2010; 186: 924–930.

    Article  PubMed  CAS  Google Scholar 

  150. Cheloufi S, Dos Santos CO, Chong MM, Hannon GJ . A dicer-independent miRNA biogenesis pathway that requires Ago catalysis. Nature 2010; 465: 584–589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Cifuentes D, Xue H, Taylor DW, Patnode H, Mishima Y, Cheloufi S et al. A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity. Science 2010; 328: 1694–1698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Yang JS, Maurin T, Robine N, Rasmussen KD, Jeffrey KL, Chandwani R et al. Conserved vertebrate mir-451 provides a platform for Dicer-independent, Ago2-mediated microRNA biogenesis. Proc Natl Acad Sci USA 2010; 107: 15163–15168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Kuchen S, Resch W, Yamane A, Kuo N, Li Z, Chakraborty T et al. Regulation of microRNA expression and abundance during lymphopoiesis. Immunity 2010; 32: 828–839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Yamane A, Resch W, Kuo N, Kuchen S, Li Z, Sun HW et al. Deep-sequencing identification of the genomic targets of the cytidine deaminase AID and its cofactor RPA in B lymphocytes. Nat Immunol 2010; 12: 62–69.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Li B, Samanta A, Song X, Iacono KT, Brennan P, Chatila TA et al. FOXP3 is a homo-oligomer and a component of a supramolecular regulatory complex disabled in the human XLAAD/IPEX autoimmune disease. Int Immunol 2007; 19: 825–835.

    Article  CAS  PubMed  Google Scholar 

  156. Zhou Z, Song X, Li B, Greene MI . FOXP3 and its partners: structural and biochemical insights into the regulation of FOXP3 activity. Immunol Res 2008; 42: 19–28.

    Article  CAS  PubMed  Google Scholar 

  157. Du J, Huang C, Zhou B, Ziegler SF . Isoform-specific inhibition of ROR alpha-mediated transcriptional activation by human FOXP3. J Immunol 2008; 180: 4785–4792.

    Article  CAS  PubMed  Google Scholar 

  158. de Zoeten EF, Lee I, Wang L, Chen C, Ge G, Wells AD et al. Foxp3 processing by proprotein convertases and control of regulatory T cell function. J Biol Chem 2009; 284: 5709–5716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Hancock WW, Ozkaynak E . Three distinct domains contribute to nuclear transport of murine Foxp3. PLoS One 2009; 4: e7890.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Macian F, Lopez-Rodriguez C, Rao A . Partners in transcription: NFAT and AP-1. Oncogene 2001; 20: 2476–2489.

    Article  CAS  PubMed  Google Scholar 

  161. Rao A, Luo C, Hogan PG . Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 1997; 15: 707–747.

    Article  CAS  PubMed  Google Scholar 

  162. Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan AD, Stroud JC et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 2006; 126: 375–387.

    Article  CAS  PubMed  Google Scholar 

  163. Bandukwala HS, Wu Y, Feurer M, Chen Y, Barbosa B, Ghosh S et al. Structure of a domain-swapped FOXP3 dimer on DNA and its function in regulatory T cells. Immunity 2011; 34: 479–491.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Lopes JE, Torgerson TR, Schubert LA, Anover SD, Ocheltree EL, Ochs HD et al. Analysis of FOXP3 reveals multiple domains required for its function as a transcriptional repressor. J Immunol 2006; 177: 3133–3142.

    Article  CAS  PubMed  Google Scholar 

  165. Chae WJ, Henegariu O, Lee SK, Bothwell AL . The mutant leucine-zipper domain impairs both dimerization and suppressive function of Foxp3 in T cells. Proc Natl Acad Sci USA 2006; 103: 9631–9636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Djuretic IM, Cruz-Guilloty F, Rao A . Regulation of gene expression in peripheral T cells by Runx transcription factors. Adv Immunol 2009; 104: 1–23.

    Article  CAS  PubMed  Google Scholar 

  167. Ono M, Yaguchi H, Ohkura N, Kitabayashi I, Nagamura Y, Nomura T et al. Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 2007; 446: 685–689.

    Article  CAS  PubMed  Google Scholar 

  168. Pan F, Yu H, Dang EV, Barbi J, Pan X, Grosso JF et al. Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells. Science 2009; 325: 1142–1146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Loizou L, Andersen KG, Betz AG . Foxp3 interacts with c-Rel to mediate NF-kappaB repression. PLoS One 2011; 6: e18670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Tang Y, Zhao W, Chen Y, Zhao Y, Gu W . Acetylation is indispensable for p53 activation. Cell 2008; 133: 612–626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Sykes SM, Mellert HS, Holbert MA, Li K, Marmorstein R, Lane WS et al. Acetylation of the p53 DNA-binding domain regulates apoptosis induction. Mol Cell 2006; 24: 841–851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Xia ZP, Sun L, Chen X, Pineda G, Jiang X, Adhikari A et al. Direct activation of protein kinases by unanchored polyubiquitin chains. Nature 2009; 461: 114–119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Bode AM, Dong Z . Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer 2004; 4: 793–805.

    Article  CAS  PubMed  Google Scholar 

  174. Li B, Samanta A, Song X, Iacono KT, Bembas K, Tao R et al. FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proc Natl Acad Sci USA 2007; 104: 4571–4576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Tao R, de Zoeten EF, Ozkaynak E, Chen C, Wang L, Porrett PM et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med 2007; 13: 1299–1307.

    Article  CAS  PubMed  Google Scholar 

  176. van Loosdregt J, Vercoulen Y, Guichelaar T, Gent YY, Beekman JM, van Beekum O et al. Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization. Blood 2009; 115: 965–974.

    Article  PubMed  CAS  Google Scholar 

  177. Beier UH, Wang L, Bhatti TR, Liu Y, Han R, Ge G et al. Sirtuin-1 targeting promotes Foxp3+ T-regulatory cell function and prolongs allograft survival. Mol Cell Biol 2011; 31: 1022–1029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. van Loosdregt J, Brunen D, Fleskens V, Pals CE, Lam EW, Coffer PJ . Rapid temporal control of Foxp3 protein degradation by sirtuin-1. PLoS One 2011; 6: e19047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Chen C, Rowell EA, Thomas RM, Hancock WW, Wells AD . Transcriptional regulation by Foxp3 is associated with direct promoter occupancy and modulation of histone acetylation. J Biol Chem 2006; 281: 36828–36834.

    Article  CAS  PubMed  Google Scholar 

  180. Samanta A, Li B, Song X, Bembas K, Zhang G, Katsumata M et al. TGF-beta and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3. Proc Natl Acad Sci USA 2008; 105: 14023–14027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The research is supported by the National Science Foundation of China (NSFC) 30972702, SMCST09JC1416100; Shanghai Pasteur Foundation; Shanghai ‘Rising Star’ program 10QA1407900; China-Germany PPP program; Novo Nordisk-Chinese Academy of Sciences Foundation; and the Chinese Academy of Sciences (CAS) network lab program. BL is a recipient of CAS ‘100-talent’ program. AT is a recipient of CAS ‘International Young Scientist Fellowship’ and supported by NSFC 31050110129. We gratefully acknowledge the support of the Sanofi-Aventis-Shanghai Institutes for Biological Sciences scholarship program. We apologize to any authors whose publications in the field have not been fully cited due to space limitations. We thank members in the Institut Pasteur of Shanghai for their critical comments and helpful discussions.

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  1. Unit of Molecular Immunology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    Y Gao, F Lin, J Su, Z Gao, Y Li, J Yang, Z Deng, A Tsun & B Li

  2. Department of Surgery, Shanghai Public Health Center, Fudan University, Shanghai, China

    J Su & B Liu

  3. S,

    Z Gao

  4. c,

    Z Gao

  5. hool of Life Sciences, Fudan University, Shanghai, China

    Z Gao

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Gao, Y., Lin, F., Su, J. et al. Molecular mechanisms underlying the regulation and functional plasticity of FOXP3+ regulatory T cells. Genes Immun 13, 1–13 (2012). https://doi.org/10.1038/gene.2011.77

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