Skip to main content
SpringerLink
Log in

Regulatory T-Cell Differentiation and Their Function in Immune Regulation

  • Chapter
  • First Online:
T Helper Cell Differentiation and Their Function

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 841))

Abstract

Regulatory T-cells (Treg) represent a subset of CD4+ T-cells characterized by high suppressive capacity, which can be generated in the thymus or induced in the periphery. The deleterious phenotype of the Scurfy mouse, which develops an X-linked lymphoproliferative disease resulting from defective T-cell tolerance, clearly demonstrates the importance of Treg cells for the maintenance of immune homeostasis. Although significant progress has been achieved, much information regarding the development, characteristics and function of Treg cells remain lacking. This chapter highlights the most recent discoveries in the field of Treg biology, focusing on the development and role of this cell subset in the maintenance of immune balance.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Adeegbe D, Matsutani T et al (2010) CD4(+) CD25(+) Foxp3(+) T regulatory cells with limited TCR diversity in control of autoimmunity. J Immunol 184(1):56–66

    PubMed Central  CAS  PubMed  Google Scholar 

  2. Akdis CA, Blaser K (2001) Mechanisms of interleukin-10-mediated immune suppression. Immunology 103(2):131–136

    PubMed Central  CAS  PubMed  Google Scholar 

  3. Allan SE, Crome SQ et al (2007) Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol 19(4):345–354

    CAS  PubMed  Google Scholar 

  4. Apostolou I, von Boehmer H (2004) In vivo instruction of suppressor commitment in naive T cells. J Exp Med 199(10):1401–1408

    PubMed Central  CAS  PubMed  Google Scholar 

  5. Arpaia NC, Campbell et al. (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 7480:451–455

    Google Scholar 

  6. Atarashi K, Tanoue T et al (2011) Induction of colonic regulatory T-cells by indigenous Clostridium species. Science 331(6015):337–341

    PubMed Central  CAS  PubMed  Google Scholar 

  7. Atarashi K, Tanoue T et al (2013) Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500(7461):232–236

    CAS  PubMed  Google Scholar 

  8. Bacchetta R, Lucarelli B et al (2014) Immunological Outcome in haploidentical-HSC transplanted patients treated with IL-10-anergized donor T Cells. Front Immunol 5:16

    PubMed Central  PubMed  Google Scholar 

  9. Bagavant H, Tung KS (2005) Failure of CD25+ T-cells from lupus-prone mice to suppress lupus glomerulonephritis and sialoadenitis. J Immunol 175(2):944–950

    CAS  PubMed  Google Scholar 

  10. Banerjee A, Vasanthakumar A et al (2013) Modulating T regulatory cells in cancer: how close are we? Immunol Cell Biol 91(5):340–349

    CAS  PubMed  Google Scholar 

  11. Barath S, Aleksza M et al (2007) Measurement of natural (CD4+ CD25high) and inducible (CD4+ IL-10+) regulatory T-cells in patients with systemic lupus erythematosus. Lupus 16(7):489–496

    CAS  PubMed  Google Scholar 

  12. Barnes MJ, Krebs P et al (2009) Commitment to the regulatory T cell lineage requires CARMA1 in the thymus but not in the periphery. PLoS Biol 7(3):e51

    PubMed  Google Scholar 

  13. Baron U, Floess S et al (2007) DNA demethylation in the human FOXP3 locus discriminates regulatory T-cells from activated FOXP3(+) conventional T cells. Eur J Immunol 37(9):2378–2389

    CAS  PubMed  Google Scholar 

  14. Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2):215–233

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Battaglia M, Stabilini A et al (2006) Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T-cells of both healthy subjects and type 1 diabetic patients. J Immunol 177(12):8338–8347

    CAS  PubMed  Google Scholar 

  16. Bazhin AV, Kahnert S et al (2010) Distinct metabolism of cyclic adenosine monophosphate in regulatory and helper CD4+ T cells. Mol Immunol 47(4):678–684

    CAS  PubMed  Google Scholar 

  17. Bedner P, Niessen H et al (2006) Selective permeability of different connexin channels to the second messenger cyclic AMP. J Biol Chem 281(10):6673–6681

    CAS  PubMed  Google Scholar 

  18. Beebe AM, Cua DJ et al (2002) The role of interleukin-10 in autoimmune disease: systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Cytokine Growth Factor Rev 13(4–5):403–412

    CAS  PubMed  Google Scholar 

  19. Bennett CL, Christie J et al (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27(1):20–21

    CAS  PubMed  Google Scholar 

  20. Bettelli E, Das MP et al (1998) IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4-deficient and transgenic mice. J Immunol 161(7):3299–3306

    CAS  PubMed  Google Scholar 

  21. Bilate AM, Lafaille JJ (2012) Induced CD4+Foxp3+ regulatory T-cells in immune tolerance. Annu Rev Immunol 30:733–758

    CAS  PubMed  Google Scholar 

  22. Bodor J, Feigenbaum L et al (2001) Suppression of T-cell responsiveness by inducible cAMP early repressor (ICER). J Leukoc Biol 69(6):1053–1059

    CAS  PubMed  Google Scholar 

  23. Bopp T, Becker C et al (2007) Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med 204(6):1303–1310

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Brunstein CG, Miller JS et al (2011) Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood 117(3):1061–1070

    PubMed Central  CAS  PubMed  Google Scholar 

  25. Brusko T, Wasserfall C et al (2007) No alterations in the frequency of FOXP3+ regulatory T-cells in type 1 diabetes. Diabetes 56(3):604–612

    CAS  PubMed  Google Scholar 

  26. Burzyn D, Benoist C et al (2013) Regulatory T-cells in nonlymphoid tissues. Nat Immunol 14(10):1007–1013

    CAS  PubMed  Google Scholar 

  27. Burzyn D, Kuswanto W et al (2013) A special population of regulatory T-cells potentiates muscle repair. Cell 155(6):1282–1295

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Cebula A, Seweryn M et al (2013) Thymus-derived regulatory T-cells contribute to tolerance to commensal microbiota. Nature 497(7448):258–262

    PubMed Central  CAS  PubMed  Google Scholar 

  29. Chambers CA, Kuhns MS et al (2001) CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 19:565–594

    CAS  PubMed  Google Scholar 

  30. Chatila TA, Blaeser F et al (2000) JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest 106(12):R75–R81

    PubMed Central  CAS  PubMed  Google Scholar 

  31. Chaudhry A, Rudra D et al (2009) CD4+ regulatory T-cells control TH17 responses in a Stat3-dependent manner. Science 326(5955):986–991

    CAS  PubMed  Google Scholar 

  32. Chen W, Jin W et al (2003) 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 198(12):1875–1886

    PubMed Central  CAS  PubMed  Google Scholar 

  33. Cho JH, Gregersen PK (2011) Genomics and the multifactorial nature of human autoimmune disease. N Engl J Med 365(17):1612–1623

    CAS  PubMed  Google Scholar 

  34. Chong MM, Rasmussen JP et al (2008) The RNAseIII enzyme Drosha is critical in T-cells for preventing lethal inflammatory disease. J Exp Med 205(9):2005–2017

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Chung Y, Tanaka S et al (2011) Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med 17(8):983–988

    PubMed Central  CAS  PubMed  Google Scholar 

  36. Cipolletta D, Feuerer M et al (2012) PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486(7404):549–553

    PubMed Central  CAS  PubMed  Google Scholar 

  37. Collison LW, Workman CJ et al (2007) The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450(7169):566–569

    CAS  PubMed  Google Scholar 

  38. Collison LW, Chaturvedi V et al (2010) IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol 11(12):1093–1101

    PubMed Central  CAS  PubMed  Google Scholar 

  39. Crispin JC, Liossis SN et al (2010) Pathogenesis of human systemic lupus erythematosus: recent advances. Trends Mol Med 16(2):47–57

    PubMed Central  CAS  PubMed  Google Scholar 

  40. Curiel TJ, Coukos G et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10(9):942–949

    CAS  PubMed  Google Scholar 

  41. Curotto de Lafaille MA, Lino AC et al (2004) CD25− T cells generate CD25+Foxp3+ regulatory T cells by peripheral expansion. J Immunol 173(12):7259–7268

    CAS  PubMed  Google Scholar 

  42. Curotto de Lafaille MA, Kutchukhidze N et al (2008) Adaptive Foxp3+ regulatory T cell-dependent and -independent control of allergic inflammation. Immunity 29(1):114–126

    CAS  PubMed  Google Scholar 

  43. Curti A, Pandolfi S et al (2007) Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25− into CD25+ T regulatory cells. Blood 109(7):2871–2877

    CAS  PubMed  Google Scholar 

  44. Datto MB, Frederick JP et al (1999) Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction. Mol Cell Biol 19(4):2495–2504

    PubMed Central  CAS  PubMed  Google Scholar 

  45. Deaglio S, Dwyer KM et al (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204(6):1257–1265

    PubMed Central  CAS  PubMed  Google Scholar 

  46. Demir L, Yigit S et al (2013) Predictive and prognostic factors in locally advanced breast cancer: effect of intratumoral FOXP3+ Tregs. Clin Exp Metastasis 30(8):1047–1062

    CAS  PubMed  Google Scholar 

  47. Di Ianni M, Falzetti F et al (2011) Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood 117(14):3921–3928

    PubMed  Google Scholar 

  48. Duhen T, Duhen R et al (2012) Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells. Blood 119(19):4430–4440

    PubMed Central  CAS  PubMed  Google Scholar 

  49. Elkord E (2009) Frequency of human T regulatory cells in peripheral blood is significantly reduced by cryopreservation. J Immunol Methods 347(1–2):87–90

    CAS  PubMed  Google Scholar 

  50. Etemire E, Krull M et al (2013) Transiently reduced PI3 K/Akt activity drives the development of regulatory function in antigen-stimulated Naive T-cells. PLoS ONE 8(7):e68378

    PubMed Central  CAS  PubMed  Google Scholar 

  51. Fallarino F, Grohmann U et al (2006) The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol 176(11):6752–6761

    CAS  PubMed  Google Scholar 

  52. Fantini MC, Becker C et al (2004) Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25− T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 172(9):5149–5153

    CAS  PubMed  Google Scholar 

  53. Feuerer M, Herrero L et al (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15(8):930–939

    PubMed Central  CAS  PubMed  Google Scholar 

  54. Feuerer M, Hill JA et al (2009) Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nat Immunol 10(7):689–695

    CAS  PubMed  Google Scholar 

  55. Floess S, Freyer J et al (2007) Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 5(2):e38

    PubMed Central  PubMed  Google Scholar 

  56. Fohse L, Suffner J et al (2011) High TCR diversity ensures optimal function and homeostasis of Foxp3+ regulatory T cells. Eur J Immunol 41(11):3101–3113

    PubMed  Google Scholar 

  57. Fontenot JD, Gavin MA et al (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4(4):330–336

    CAS  PubMed  Google Scholar 

  58. Fontenot JD, Rasmussen JP et al (2005) A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6(11):1142–1151

    CAS  PubMed  Google Scholar 

  59. Friedlander MR, Lizano E et al (2014) Evidence for the biogenesis of more than 1,000 novel human microRNAs. Genome Biol 15(4):R57

    PubMed Central  PubMed  Google Scholar 

  60. Furtado GC, Curotto de Lafaille MA et al (2002) Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J Exp Med 196(6):851–857

    PubMed Central  CAS  PubMed  Google Scholar 

  61. Furusawa Y, Obata Y et al (2013) Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504(7480):446–450

    CAS  PubMed  Google Scholar 

  62. Gagliani N, Magnani CF et al (2013) Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med 19(6):739–746

    CAS  PubMed  Google Scholar 

  63. Gavin MA, Torgerson TR et al (2006) Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc Natl Acad Sci USA 103(17):6659–6664

    PubMed Central  CAS  PubMed  Google Scholar 

  64. Gazzinelli RT, Wysocka M et al (1996) In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-gamma and TNF-alpha. J Immunol 157(2):798–805

    CAS  PubMed  Google Scholar 

  65. Glisic-Milosavljevic S, Waukau J et al (2007) At-risk and recent-onset type 1 diabetic subjects have increased apoptosis in the CD4+CD25+ T-cell fraction. PLoS ONE 2(1):e146

    PubMed Central  PubMed  Google Scholar 

  66. Gobert M, Treilleux I et al (2009) Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res 69(5):2000–2009

    CAS  PubMed  Google Scholar 

  67. Goerner M, Gooley T et al (2002) Morbidity and mortality of chronic GVHD after hematopoietic stem cell transplantation from HLA-identical siblings for patients with aplastic or refractory anemias. Biol Blood Marrow Transplant 8(1):47–56

    CAS  PubMed  Google Scholar 

  68. Gottschalk RA, Corse E et al (2010) TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo. J Exp Med 207(8):1701–1711

    PubMed Central  CAS  PubMed  Google Scholar 

  69. Govindaraj C, Scalzo-Inguanti K et al (2013) Impaired Th1 immunity in ovarian cancer patients is mediated by TNFR2+ Tregs within the tumor microenvironment. Clin Immunol 149(1):97–110

    CAS  PubMed  Google Scholar 

  70. Grohmann U, Fallarino F et al (2003) Tolerance, DCs and tryptophan: much ado about IDO. Trends Immunol 24(5):242–248

    CAS  PubMed  Google Scholar 

  71. Grohmann U, Volpi C et al (2007) Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nat Med 13(5):579–586

    CAS  PubMed  Google Scholar 

  72. Groux H, O’Garra A et al (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389(6652):737–742

    CAS  PubMed  Google Scholar 

  73. Guo H, Ingolia NT et al (2010) Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466(7308):835–840

    PubMed Central  CAS  PubMed  Google Scholar 

  74. Gupta S, Manicassamy S et al (2008) Differential requirement of PKC-theta in the development and function of natural regulatory T cells. Mol Immunol 46(2):213–224

    PubMed Central  CAS  PubMed  Google Scholar 

  75. Hata H, Sakaguchi N et al (2004) Distinct contribution of IL-6, TNF-alpha, IL-1, and IL-10 to T cell-mediated spontaneous autoimmune arthritis in mice. J Clin Invest 114(4):582–588

    PubMed Central  CAS  PubMed  Google Scholar 

  76. Hayashi T, Hasegawa K et al (2005) Elimination of CD4(+)CD25(+) T cell accelerates the development of glomerulonephritis during the preactive phase in autoimmune-prone female NZB × NZW F mice. Int J Exp Pathol 86(5):289–296

    PubMed Central  CAS  PubMed  Google Scholar 

  77. Herman AE, Freeman GJ et al (2004) CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J Exp Med 199(11):1479–1489

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Hindley JP, Ferreira C et al (2011) Analysis of the T-cell receptor repertoires of tumor-infiltrating conventional and regulatory T cells reveals no evidence for conversion in carcinogen-induced tumors. Cancer Res 71(3):736–746

    PubMed Central  CAS  PubMed  Google Scholar 

  79. Hinterberger M, Aichinger M et al (2010) Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance. Nat Immunol 11(6):512–519

    CAS  PubMed  Google Scholar 

  80. Hoffmann P, Boeld TJ et al (2006) Isolation of CD4+CD25+ regulatory T cells for clinical trials. Biol Blood Marrow Transplant 12(3):267–274

    CAS  PubMed  Google Scholar 

  81. Hori S, Haury M et al (2002) Specificity requirements for selection and effector functions of CD25+4+ regulatory T cells in anti-myelin basic protein T cell receptor transgenic mice. Proc Natl Acad Sci USA 99(12):8213–8218

    PubMed Central  CAS  PubMed  Google Scholar 

  82. Hori S, Nomura T et al (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061

    CAS  PubMed  Google Scholar 

  83. Hsieh CS, Liang Y et al (2004) Recognition of the peripheral self by naturally arising CD25+CD4+ T cell receptors. Immunity 21(2):267–277

    CAS  PubMed  Google Scholar 

  84. Hsu WT, Suen JL et al (2006) The role of CD4CD25 T cells in autoantibody production in murine lupus. Clin Exp Immunol 145(3):513–519

    PubMed Central  CAS  PubMed  Google Scholar 

  85. Hsu LY, Tan YX et al (2009) A hypomorphic allele of ZAP-70 reveals a distinct thymic threshold for autoimmune disease versus autoimmune reactivity. J Exp Med 206(11):2527–2541

    PubMed Central  CAS  PubMed  Google Scholar 

  86. Hung T, Wang Y et al (2011) Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat Genet 43(7):621–629

    PubMed Central  CAS  PubMed  Google Scholar 

  87. Isomura I, Palmer S et al (2009) c-Rel is required for the development of thymic Foxp3+CD4 regulatory T cells. J Exp Med 206(13):3001–3014

    PubMed Central  CAS  PubMed  Google Scholar 

  88. Itoh M, Takahashi T et al (1999) Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol 162(9):5317–5326

    CAS  PubMed  Google Scholar 

  89. Jailwala P, Waukau J et al (2009) Apoptosis of CD4+CD25(high) T cells in type 1 diabetes may be partially mediated by IL-2 deprivation. PLoS ONE 4(8):e6527

    PubMed Central  PubMed  Google Scholar 

  90. Jordan MS, Boesteanu A et al (2001) Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat Immunol 2(4):301–306

    CAS  PubMed  Google Scholar 

  91. Kerdiles YM, Stone EL et al (2010) Foxo transcription factors control regulatory T cell development and function. Immunity 33(6):890–904

    PubMed Central  CAS  PubMed  Google Scholar 

  92. Khalil AM, Guttman M et al (2009) Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci USA 106(28):11667–11672

    PubMed Central  CAS  PubMed  Google Scholar 

  93. Khattri R, Cox T et al (2003) An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4(4):337–342

    CAS  PubMed  Google Scholar 

  94. Kim HP, Leonard WJ (2007) CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med 204(7):1543–1551

    PubMed Central  CAS  PubMed  Google Scholar 

  95. Kim JM, Rasmussen JP et al (2007) Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 8(2):191–197

    CAS  PubMed  Google Scholar 

  96. Kitani A, Fuss I et al (2003) Transforming growth factor (TGF)-beta1-producing regulatory T cells induce Smad-mediated interleukin 10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGF-beta1-mediated fibrosis. J Exp Med 198(8):1179–1188

    PubMed Central  CAS  PubMed  Google Scholar 

  97. Koch MA, Tucker-Heard G et al (2009) The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 10(6):595–602

    PubMed Central  CAS  PubMed  Google Scholar 

  98. Koonpaew S, Shen S et al (2006) LAT-mediated signaling in CD4+CD25+ regulatory T cell development. J Exp Med 203(1):119–129

    PubMed Central  CAS  PubMed  Google Scholar 

  99. Kornete M, Sgouroudis E et al (2012) ICOS-dependent homeostasis and function of Foxp3+ regulatory T cells in islets of nonobese diabetic mice. J Immunol 188(3):1064–1074

    CAS  PubMed  Google Scholar 

  100. Kretschmer K, Apostolou I et al (2005) Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 6(12):1219–1227

    CAS  PubMed  Google Scholar 

  101. Ladoire S, Martin F et al (2011) Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother 60(7):909–918

    CAS  PubMed  Google Scholar 

  102. Lahl K, Loddenkemper C et al (2007) Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med 204(1):57–63

    PubMed Central  CAS  PubMed  Google Scholar 

  103. Lathrop SK, Bloom SM et al (2011) Peripheral education of the immune system by colonic commensal microbiota. Nature 478(7368):250–254

    PubMed Central  CAS  PubMed  Google Scholar 

  104. Laurie KL, Van Driel IR et al (2002) The role of CD4+CD25+ immunoregulatory T cells in the induction of autoimmune gastritis. Immunol Cell Biol 80(6):567–573

    PubMed  Google Scholar 

  105. Leon LR, Kozak W et al (1998) Role of IL-10 in inflammation. Studies using cytokine knockout mice. Ann N Y Acad Sci 856:69–75

    CAS  PubMed  Google Scholar 

  106. Liao G, Nayak S et al (2010) GITR engagement preferentially enhances proliferation of functionally competent CD4+CD25+FoxP3+ regulatory T cells. Int Immunol 22(4):259–270

    PubMed Central  CAS  PubMed  Google Scholar 

  107. Lin SC, Chen KH et al (2007) The quantitative analysis of peripheral blood FOXP3-expressing T cells in systemic lupus erythematosus and rheumatoid arthritis patients. Eur J Clin Invest 37(12):987–996

    CAS  PubMed  Google Scholar 

  108. Lin SZ, Chen KJ et al (2013) Prediction of recurrence and survival in hepatocellular carcinoma based on two Cox models mainly determined by FoxP3+ regulatory T cells. Cancer Prev Res (Phila) 6(6):594–602

    CAS  Google Scholar 

  109. Linterman MA, Pierson W et al (2011) Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med 17(8):975–982

    PubMed Central  CAS  PubMed  Google Scholar 

  110. Lio CW, Dodson LF et al (2010) CD28 facilitates the generation of Foxp3(-) cytokine responsive regulatory T cell precursors. J Immunol 184(11):6007–6013

    PubMed Central  CAS  PubMed  Google Scholar 

  111. Liston A, Lu LF et al (2008) Dicer-dependent microRNA pathway safeguards regulatory T cell function. J Exp Med 205(9):1993–2004

    PubMed Central  CAS  PubMed  Google Scholar 

  112. Liu W, Putnam AL et al (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 203(7):1701–1711

    PubMed Central  CAS  PubMed  Google Scholar 

  113. Liu VC, Wong LY et al (2007) Tumor evasion of the immune system by converting CD4+CD25− T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-beta. J Immunol 178(5):2883–2892

    CAS  PubMed  Google Scholar 

  114. Liu X, Robinson SN et al (2014) FOXP3 is a direct target of miR15a/16 in umbilical cord blood regulatory T cells. Bone Marrow Transplant 49(6):793–799

    CAS  PubMed  Google Scholar 

  115. Loewer S, Cabili MN et al (2010) Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat Genet 42(12):1113–1117

    PubMed Central  CAS  PubMed  Google Scholar 

  116. Lu LF, Thai TH et al (2009) Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity 30(1):80–91

    PubMed Central  CAS  PubMed  Google Scholar 

  117. Lu LF, Boldin MP et al (2010) Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142(6):914–929

    PubMed Central  CAS  PubMed  Google Scholar 

  118. Lu L, Ma J et al (2011) All-trans retinoic acid promotes TGF-beta-induced Tregs via histone modification but not DNA demethylation on Foxp3 gene locus. PLoS ONE 6(9):e24590

    PubMed Central  CAS  PubMed  Google Scholar 

  119. Lyssuk EY, Torgashina AV et al (2007) Reduced number and function of CD4+CD25 high FoxP3+ regulatory T cells in patients with systemic lupus erythematosus. Adv Exp Med Biol 601:113–119

    PubMed  Google Scholar 

  120. Macfarlane GT, Macfarlane S (1997) Human colonic microbiota: ecology, physiology and metabolic potential of intestinal bacteria. Scand J Gastroenterol Suppl 222:3–9

    CAS  PubMed  Google Scholar 

  121. Makita S, Kanai T et al (2007) Intestinal lamina propria retaining CD4+CD25+ regulatory T cells is a suppressive site of intestinal inflammation. J Immunol 178(8):4937–4946

    CAS  PubMed  Google Scholar 

  122. Mantel PY, Ouaked N et al (2006) Molecular mechanisms underlying FOXP3 induction in human T cells. J Immunol 176(6):3593–3602

    CAS  PubMed  Google Scholar 

  123. Marek-Trzonkowska N, Mysliwiec M et al (2012) Administration of CD4+CD25 high CD127- regulatory T cells preserves beta-cell function in type 1 diabetes in children. Diabetes Care 35(9):1817–1820

    PubMed Central  PubMed  Google Scholar 

  124. Marks SD, Tullus K (2012) Autoantibodies in systemic lupus erythematosus. Pediatr Nephrol 27(10):1855–1868

    PubMed  Google Scholar 

  125. Marson A, Kretschmer K et al (2007) Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445(7130):931–935

    PubMed Central  CAS  PubMed  Google Scholar 

  126. McHugh RS, Whitters MJ et al (2002) CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16(2):311–323

    CAS  PubMed  Google Scholar 

  127. Mestecky J, McGhee JR (1987) Immunoglobulin A (IgA): molecular and cellular interactions involved in IgA biosynthesis and immune response. Adv Immunol 40:153–245

    CAS  PubMed  Google Scholar 

  128. Miyara M, Amoura Z et al (2005) Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol 175(12):8392–8400

    CAS  PubMed  Google Scholar 

  129. Miyara M, Yoshioka Y et al (2009) Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30(6):899–911

    CAS  PubMed  Google Scholar 

  130. Mucida D, Kutchukhidze N et al (2005) Oral tolerance in the absence of naturally occurring Tregs. J Clin Invest 115(7):1923–1933

    PubMed Central  CAS  PubMed  Google Scholar 

  131. Nakamura K, Kitani A et al (2001) Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 194(5):629–644

    PubMed Central  CAS  PubMed  Google Scholar 

  132. Nakamura K, Kitani A et al (2004) TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol 172(2):834–842

    CAS  PubMed  Google Scholar 

  133. Nelson BH, Willerford DM (1998) Biology of the interleukin-2 receptor. Adv Immunol 70:1–81

    CAS  PubMed  Google Scholar 

  134. Nguyen LT, Jacobs J et al (2007) Where FoxP3-dependent regulatory T cells impinge on the development of inflammatory arthritis. Arthritis Rheum 56(2):509–520

    CAS  PubMed  Google Scholar 

  135. Ohkura N, Hamaguchi M et al (2012) T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 37(5):785–799

    CAS  PubMed  Google Scholar 

  136. Olivares-Villagomez D, Wang Y et al (1998) Regulatory CD4(+) T cells expressing endogenous T cell receptor chains protect myelin basic protein-specific transgenic mice from spontaneous autoimmune encephalomyelitis. J Exp Med 188(10):1883–1894

    PubMed Central  CAS  PubMed  Google Scholar 

  137. Onishi Y, Fehervari Z et al (2008) Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc Natl Acad Sci USA 105(29):10113–10118

    PubMed Central  CAS  PubMed  Google Scholar 

  138. Onizuka S, Tawara I et al (1999) Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 59(13):3128–3133

    CAS  PubMed  Google Scholar 

  139. Ostman S, Rask C et al (2006) Impaired regulatory T cell function in germ-free mice. Eur J Immunol 36(9):2336–2346

    PubMed  Google Scholar 

  140. Ouyang W, Beckett O et al (2010) Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nat Immunol 11(7):618–627

    CAS  PubMed  Google Scholar 

  141. Ouyang W, Liao W et al (2012) Novel Foxo1-dependent transcriptional programs control T(reg) cell function. Nature 491(7425):554–559

    PubMed Central  CAS  PubMed  Google Scholar 

  142. Pacholczyk R, Kern J (2008) The T-cell receptor repertoire of regulatory T cells. Immunology 125(4):450–458

    PubMed Central  CAS  PubMed  Google Scholar 

  143. Pacholczyk R, Ignatowicz H et al (2006) Origin and T cell receptor diversity of Foxp3+CD4+CD25+ T cells. Immunity 25(2):249–259

    CAS  PubMed  Google Scholar 

  144. Pandiyan P, Zheng L et al (2007) CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol 8(12):1353–1362

    CAS  PubMed  Google Scholar 

  145. Pandiyan P, Conti HR et al (2011) CD4(+)CD25(+)Foxp3(+) regulatory T cells promote Th17 cells in vitro and enhance host resistance in mouse Candida albicans Th17 cell infection model. Immunity 34(3):422–434

    PubMed Central  CAS  PubMed  Google Scholar 

  146. Papiernik M (2001) Natural CD4+CD25+ regulatory T cells. Their role in the control of superantigen responses. Immunol Rev 182:180–189

    CAS  PubMed  Google Scholar 

  147. Park HJ, Kusnadi A et al (2012) Tumor-infiltrating regulatory T cells delineated by upregulation of PD-1 and inhibitory receptors. Cell Immunol 278(1–2):76–83

    CAS  PubMed  Google Scholar 

  148. Patterson SJ, Han JM et al (2011) Cutting edge: PHLPP regulates the development, function, and molecular signaling pathways of regulatory T cells. J Immunol 186(10):5533–5537

    PubMed Central  CAS  PubMed  Google Scholar 

  149. Patton DT, Garden OA et al (2006) Cutting edge: the phosphoinositide 3-kinase p110 delta is critical for the function of CD4+CD25+Foxp3+ regulatory T cells. J Immunol 177(10):6598–6602

    CAS  PubMed  Google Scholar 

  150. Peters JH, Preijers FW et al (2008) Clinical grade Treg: GMP isolation, improvement of purity by CD127 Depletion, Treg expansion, and Treg cryopreservation. PLoS ONE 3(9):e3161

    PubMed Central  PubMed  Google Scholar 

  151. Putnam AL, Vendrame F et al (2005) CD4+CD25 high regulatory T cells in human autoimmune diabetes. J Autoimmun 24(1):55–62

    CAS  PubMed  Google Scholar 

  152. Qiao YQ, Huang ML et al (2013) LncRNA DQ786243 affects Treg related CREB and Foxp3 expression in Crohn’s disease. J Biomed Sci 20:87

    PubMed Central  PubMed  Google Scholar 

  153. Qin J, Li R et al (2010) A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464(7285):59–65

    PubMed Central  CAS  PubMed  Google Scholar 

  154. Racke MK, Burnett D et al (1995) Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course. J Immunol 154(1):450–458

    CAS  PubMed  Google Scholar 

  155. Rao S, Gerondakis S et al (2003) c-Rel is required for chromatin remodeling across the IL-2 gene promoter. J Immunol 170(7):3724–3731

    CAS  PubMed  Google Scholar 

  156. Read S, Greenwald R et al (2006) Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J Immunol 177(7):4376–4383

    CAS  PubMed  Google Scholar 

  157. Ronchetti S, Zollo O et al (2004) GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T lymphocyte subpopulations. Eur J Immunol 34(3):613–622

    CAS  PubMed  Google Scholar 

  158. Rouas R, Fayyad-Kazan H et al (2009) Human natural Treg microRNA signature: role of microRNA-31 and microRNA-21 in FOXP3 expression. Eur J Immunol 39(6):1608–1618

    CAS  PubMed  Google Scholar 

  159. Ruan Q, Kameswaran V et al (2009) Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome. Immunity 31(6):932–940

    PubMed Central  CAS  PubMed  Google Scholar 

  160. Rubtsov YP, Rasmussen JP et al (2008) Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28(4):546–558

    CAS  PubMed  Google Scholar 

  161. Rudra D, deRoos P et al (2012) Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nat Immunol 13(10):1010–1019

    PubMed Central  CAS  PubMed  Google Scholar 

  162. Sadlack B, Kuhn R et al (1994) Development and proliferation of lymphocytes in mice deficient for both interleukins-2 and -4. Eur J Immunol 24(1):281–284

    CAS  PubMed  Google Scholar 

  163. Sadlack B, Lohler J et al (1995) Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur J Immunol 25(11):3053–3059

    CAS  PubMed  Google Scholar 

  164. Salomon B, Lenschow DJ et al (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12(4):431–440

    CAS  PubMed  Google Scholar 

  165. Samstein RM, Arvey A et al (2012) Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 151(1):153–166

    PubMed Central  CAS  PubMed  Google Scholar 

  166. Samstein RM, Josefowicz SZ et al (2012) Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell 150(1):29–38

    PubMed Central  CAS  PubMed  Google Scholar 

  167. Saoudi A, Seddon B et al (1996) The physiological role of regulatory T cells in the prevention of autoimmunity: the function of the thymus in the generation of the regulatory T cell subset. Immunol Rev 149:195–216

    CAS  PubMed  Google Scholar 

  168. Sather BD, Treuting P et al (2007) Altering the distribution of Foxp3(+) regulatory T cells results in tissue-specific inflammatory disease. J Exp Med 204(6):1335–1347

    PubMed Central  CAS  PubMed  Google Scholar 

  169. Sattui S, de la Flor C et al (2012) Cryopreservation modulates the detection of regulatory T cell markers. Cytometry B Clin Cytom 82(1):54–58

    PubMed  Google Scholar 

  170. Savage PA, Malchow S et al (2013) Basic principles of tumor-associated regulatory T cell biology. Trends Immunol 34(1):33–40

    PubMed Central  CAS  PubMed  Google Scholar 

  171. Scalapino KJ, Tang Q et al (2006) Suppression of disease in New Zealand Black/New Zealand White lupus-prone mice by adoptive transfer of ex vivo expanded regulatory T cells. J Immunol 177(3):1451–1459

    CAS  PubMed  Google Scholar 

  172. Schmidl C, Klug M et al (2009) Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity. Genome Res 19(7):1165–1174

    PubMed Central  CAS  PubMed  Google Scholar 

  173. Schmidt AM, Zou T et al (2013) Diacylglycerol kinase zeta limits the generation of natural regulatory T cells. Sci Signal 6(303):ra101

    Google Scholar 

  174. Schmidt-Supprian M, Courtois G et al (2003) Mature T cells depend on signaling through the IKK complex. Immunity 19(3):377–389

    CAS  PubMed  Google Scholar 

  175. Seale AC, de Jong BC et al (2008) Effects of cryopreservation on CD4+CD25+ T cells of HIV-1 infected individuals. J Clin Lab Anal 22(3):153–158

    PubMed  Google Scholar 

  176. Sell K, Barth PJ et al (2012) Localization of FOXP3-positive cells in renal cell carcinoma. Tumour Biol 33(2):507–513

    CAS  PubMed  Google Scholar 

  177. Shevach EM, Stephens GL (2006) The GITR-GITRL interaction: co-stimulation or contrasuppression of regulatory activity? Nat Rev Immunol 6(8):613–618

    CAS  PubMed  Google Scholar 

  178. Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113(6):685–700

    CAS  PubMed  Google Scholar 

  179. Shimizu J, Yamazaki S et al (2002) Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3(2):135–142

    CAS  PubMed  Google Scholar 

  180. Siggs OM, Miosge LA et al (2007) Opposing functions of the T cell receptor kinase ZAP-70 in immunity and tolerance differentially titrate in response to nucleotide substitutions. Immunity 27(6):912–926

    PubMed Central  CAS  PubMed  Google Scholar 

  181. Sledzinska A, Hemmers S et al (2013) TGF-beta Signalling Is Required for CD4(+) T Cell Homeostasis But Dispensable for Regulatory T Cell Function. PLoS Biol 11(10):e1001674

    PubMed Central  CAS  PubMed  Google Scholar 

  182. Sobel ES, Brusko TM et al (2011) Defective response of CD4(+) T cells to retinoic acid and TGFbeta in systemic lupus erythematosus. Arthritis Res Ther 13(3):R106

    PubMed Central  CAS  PubMed  Google Scholar 

  183. Somerset DA, Zheng Y et al (2004) Normal human pregnancy is associated with an elevation in the immune suppressive CD25+CD4+ regulatory T-cell subset. Immunology 112(1):38–43

    PubMed Central  CAS  PubMed  Google Scholar 

  184. Stephens GL, McHugh RS et al (2004) Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. J Immunol 173(8):5008–5020

    CAS  PubMed  Google Scholar 

  185. Suen JL, Li HT et al (2009) Altered homeostasis of CD4(+)FoxP3(+) regulatory T-cell subpopulations in systemic lupus erythematosus. Immunology 127(2):196–205

    PubMed Central  CAS  PubMed  Google Scholar 

  186. Suffia IJ, Reckling SK et al (2006) Infected site-restricted Foxp3+ natural regulatory T cells are specific for microbial antigens. J Exp Med 203(3):777–788

    PubMed Central  CAS  PubMed  Google Scholar 

  187. Szymczak-Workman AL, Delgoffe GM et al (2011) Cutting edge: regulatory T cells do not mediate suppression via programmed cell death pathways. J Immunol 187(9):4416–4420

    PubMed Central  CAS  PubMed  Google Scholar 

  188. Tai X, Cowan M et al (2005) CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat Immunol 6(2):152–162

    CAS  PubMed  Google Scholar 

  189. Takahashi T, Tagami T et al (2000) Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192(2):303–310

    PubMed Central  CAS  PubMed  Google Scholar 

  190. Tanchot C, Terme M et al (2013) Tumor-infiltrating regulatory T cells: phenotype, role, mechanism of expansion in situ and clinical significance. Cancer Microenviron 6(2):147–157

    PubMed Central  CAS  PubMed  Google Scholar 

  191. Teles A, Schumacher A et al (2013) Control of uterine microenvironment by foxp3(+) cells facilitates embryo implantation. Front Immunol 4:158

    PubMed Central  PubMed  Google Scholar 

  192. Tivol EA, Borriello F et al (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3(5):541–547

    CAS  PubMed  Google Scholar 

  193. Tran DQ, Ramsey H et al (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(8):2983–2990

    PubMed Central  CAS  PubMed  Google Scholar 

  194. Trzonkowski P, Bieniaszewska M et al (2009) First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127− T regulatory cells. Clin Immunol 133(1):22–26

    CAS  PubMed  Google Scholar 

  195. Turner M, Galloway A et al (2014) Noncoding RNA and its associated proteins as regulatory elements of the immune system. Nat Immunol 15(6):484–491

    CAS  PubMed  Google Scholar 

  196. Valencia X, Yarboro C et al (2007) Deficient CD4+CD25 high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol 178(4):2579–2588

    CAS  PubMed  Google Scholar 

  197. Valzasina B, Piconese S et al (2006) Tumor-induced expansion of regulatory T cells by conversion of CD4+CD25− lymphocytes is thymus and proliferation independent. Cancer Res 66(8):4488–4495

    CAS  PubMed  Google Scholar 

  198. van Santen HM, Benoist C et al (2004) Number of T reg cells that differentiate does not increase upon encounter of agonist ligand on thymic epithelial cells. J Exp Med 200(10):1221–1230

    PubMed Central  PubMed  Google Scholar 

  199. Vargas-Rojas MI, Crispin JC et al (2008) Quantitative and qualitative normal regulatory T cells are not capable of inducing suppression in SLE patients due to T-cell resistance. Lupus 17(4):289–294

    CAS  PubMed  Google Scholar 

  200. Venigalla RK, Tretter T et al (2008) Reduced CD4+,CD25− T cell sensitivity to the suppressive function of CD4+,CD25 high,CD127 -/low regulatory T cells in patients with active systemic lupus erythematosus. Arthritis Rheum 58(7):2120–2130

    PubMed  Google Scholar 

  201. Viguier M, Lemaitre F et al (2004) Foxp3 expressing CD4+CD25 (high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immunol 173(2):1444–1453

    CAS  PubMed  Google Scholar 

  202. Wainwright DA, Dey M et al (2013) Targeting tregs in malignant brain cancer: overcoming IDO. Front Immunol 4:116

    PubMed Central  CAS  PubMed  Google Scholar 

  203. Wan YY, Flavell RA (2005) Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc Natl Acad Sci USA 102(14):5126–5131

    PubMed Central  CAS  PubMed  Google Scholar 

  204. Wan YY, Chi H et al (2006) The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function. Nat Immunol 7(8):851–858

    CAS  PubMed  Google Scholar 

  205. Wang J, Huizinga TW et al (2009) De novo generation and enhanced suppression of human CD4+CD25+ regulatory T cells by retinoic acid. J Immunol 183(6):4119–4126

    CAS  PubMed  Google Scholar 

  206. Wang KC, Yang YW et al (2011) A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 472(7341):120–124

    PubMed Central  CAS  PubMed  Google Scholar 

  207. Wei G, Wei L et al (2009) Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30(1):155–167

    PubMed Central  PubMed  Google Scholar 

  208. Weiss JM, Bilate AM et al (2012) Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J Exp Med 209(10):1723–1742, S1721

    Google Scholar 

  209. Whiteside TL (2012) What are regulatory T cells (Treg) regulating in cancer and why? Semin Cancer Biol 22(4):327–334

    PubMed Central  CAS  PubMed  Google Scholar 

  210. Wildin RS, Freitas A (2005) IPEX and FOXP3: clinical and research perspectives. J Autoimmun 25(Suppl):56–62

    CAS  PubMed  Google Scholar 

  211. Wildin RS, Ramsdell F et al (2001) X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 27(1):18–20

    CAS  PubMed  Google Scholar 

  212. Wing K, Onishi Y et al (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322(5899):271–275

    CAS  PubMed  Google Scholar 

  213. Wong J, Obst R et al (2007) Adaptation of TCR repertoires to self-peptides in regulatory and nonregulatory CD4+ T cells. J Immunol 178(11):7032–7041

    CAS  PubMed  Google Scholar 

  214. Xufre C, Costa M et al (2013) Low frequency of GITR+ T cells in ex vivo and in vitro expanded Treg cells from type 1 diabetic patients. Int Immunol 25(10):563–574

    CAS  PubMed  Google Scholar 

  215. Yadav M, Louvet C et al (2012) Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med 209(10):1713–1722, S1711–1719

    Google Scholar 

  216. Yadav M, Stephan S et al (2013) Peripherally induced tregs—role in immune homeostasis and autoimmunity. Front Immunol 4:232

    PubMed Central  CAS  PubMed  Google Scholar 

  217. Yan B, Ye S et al (2008) Dysfunctional CD4+,CD25+ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-alpha-producing antigen-presenting cells. Arthritis Rheum 58(3):801–812

    CAS  PubMed  Google Scholar 

  218. Yang W, Xu Y (2013) Clinical significance of Treg cell frequency in acute myeloid leukemia. Int J Hematol 98(5):558–562

    CAS  PubMed  Google Scholar 

  219. Yang ZZ, Novak AJ et al (2006) Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. Blood 107(9):3639–3646

    PubMed Central  CAS  PubMed  Google Scholar 

  220. Yates J, Whittington A et al (2008) Natural regulatory T cells: number and function are normal in the majority of patients with lupus nephritis. Clin Exp Immunol 153(1):44–55

    PubMed Central  CAS  PubMed  Google Scholar 

  221. Zhan Y, Funda DP et al (2004) TCR-mediated activation promotes GITR upregulation in T cells and resistance to glucocorticoid-induced death. Int Immunol 16(9):1315–1321

    Google Scholar 

  222. Zhao SS, Li XM et al (2008) Expression of CD4+CD25+CD127(low/-) T cells in patients with systemic lupus erythematosus. Zhonghua Yi Xue Za Zhi 88(7):453–456

    CAS  PubMed  Google Scholar 

  223. Zheng SG, Gray JD et al (2002) Generation ex vivo of TGF-beta-producing regulatory T cells from CD4+CD25− precursors. J Immunol 169(8):4183–4189

    CAS  PubMed  Google Scholar 

  224. Zheng SG, Wang JH et al (2006) TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J Immunol 176(6):3321–3329

    CAS  PubMed  Google Scholar 

  225. Zheng SG, Wang J et al (2007) 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 178(4):2018–2027

    CAS  PubMed  Google Scholar 

  226. Zheng Y, Josefowicz SZ et al (2007) Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445(7130):936–940

    CAS  PubMed  Google Scholar 

  227. Zheng Y, Chaudhry A et al (2009) Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458(7236):351–356

    PubMed Central  CAS  PubMed  Google Scholar 

  228. Zheng Y, Josefowicz S et al (2010) Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463(7282):808–812

    PubMed Central  CAS  PubMed  Google Scholar 

  229. Zhou G, Levitsky HI (2007) Natural regulatory T-cells and de novo-induced regulatory T-cells contribute independently to tumor-specific tolerance. J Immunol 178(4):2155–2162

    CAS  PubMed  Google Scholar 

  230. Zhou X, Bailey-Bucktrout SL et al (2009) Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T-cells in vivo. Nat Immunol 10(9):1000–1007

    PubMed Central  CAS  PubMed  Google Scholar 

  231. Zunino SJ, Storms DH et al (2007) Diets rich in polyphenols and vitamin A inhibit the development of type I autoimmune diabetes in nonobese diabetic mice. J Nutr 137(5):1216–1221

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institute Pasteur of Shanghai, Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200025, China

    Miranda Piccioni, Zuojia Chen, Andy Tsun & Bin Li

  2. New Drug and Cell Line Development, Department of Process Development, Innovent Biologics Inc, Suzhou, 215151, China

    Andy Tsun

Authors
  1. Miranda Piccioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zuojia Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andy Tsun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bin Li .

Editor information

Editors and Affiliations

  1. Institute of Biochemistry and Cell Biology Chinese Academy of Sciences, Shanghai, China

    Bing Sun

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Piccioni, M., Chen, Z., Tsun, A., Li, B. (2014). Regulatory T-Cell Differentiation and Their Function in Immune Regulation. In: Sun, B. (eds) T Helper Cell Differentiation and Their Function. Advances in Experimental Medicine and Biology, vol 841. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9487-9_4

Download citation

Publish with us

Policies and ethics

Search

Navigation