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Phenotypic and Functional Differences Between Human CD4+CD25+ and Type 1 Regulatory T Cells

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CD4+CD25+ Regulatory T Cells: Origin, Function and Therapeutic Potential

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 293))

Abstract

T regulatory (Tr) cells have an essential role in the induction and maintenance of tolerance to both and foreign self-antigens. Many types of T cells with regulatory activity have been described in mice and humans, and those within the CD4+ subset have been extensively characterized. CD4+ Type-1 regulatory T (Tr1) cells produce high levels of IL-10 and mediate IL-10-dependent suppression, whereas the effects of naturally occurring CD4+CD25+ Tr cells appear to be cell-contact-dependent. Tr1 cells arise in the periphery upon encountering antigen in a tolerogenic environment. In contrast, it appears that CD4+CD25+ Tr cells can either arise directly in the thymus or be induced by antigen in the periphery. We have been interested in defining the phenotype and function of different subsets of CD4+ Tr cells present in human peripheral blood, with the ultimate aim of designing therapeutic strategies to harness their immunoregulatory effects. This review will discuss the similarities and differences between human Tr1 and naturally occurring CD4+CD25+ Tr cells, as well as evidence that indicates that they have nonoverlapping, but synergistic roles in immune homeostasis.

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References

  1. Aandahl EM, Michaelsson J, Moretto WJ, Hecht FM, Nixon DF (2004) Human CD4+CD25+ regulatory T cells control T-cell responses to human immunodeficiency virus and cytomegalovirus antigens. J Virol 78:2454–2459

    Article  PubMed  CAS  Google Scholar 

  2. Adorini L, Giarratana N, Penna G (2004) Pharmacological induction of tolerogenic dendritic cells and regulatory T cells. Semin Immunol 16:127–134

    Article  PubMed  CAS  Google Scholar 

  3. Akbari O, DeKruyff RH, Umetsu DT (2001) Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat Immunol 2:725–731

    Article  PubMed  CAS  Google Scholar 

  4. Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH, Berry G, DeKruyff RH, Umetsu DT (2002) Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med 8:1024–1032

    Article  PubMed  CAS  Google Scholar 

  5. Annunziato F, Cosmi L, Liotta F, Lazzeri E, Manetti R, Vanini V, Romagnani P, Maggi E, Romagnani S (2002) Phenotype, localization, mechanism of suppression of CD4(+)CD25(+) human thymocytes. J Exp Med 196:379–387

    Article  PubMed  CAS  Google Scholar 

  6. Azuma T, Takahashi T, Kunisato A, Kitamura T, Hirai H (2003) Human CD4+CD25+ regulatory T cells suppress NKT cell functions. Cancer Res 63:4516–4520

    PubMed  CAS  Google Scholar 

  7. Bacchetta R, Bigler M, Touraine JL, Parkman R, Tovo PA, Abrams J, de Waal Malefyt R, de Vries JE, Roncarolo MG (1994) High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. J Exp Med 179:493–502

    Article  PubMed  CAS  Google Scholar 

  8. Bacchetta R, Sartirana C, Levings MK, Bordignon C, Narula S, Roncarolo MG (2002) Growth and expansion of human T regulatory type 1 cells are independent from TCR activation but require exogenous cytokines. Eur J Immunol 32:2237–2245

    Article  PubMed  CAS  Google Scholar 

  9. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA (2001) CD4+CD25high regulatory cells in human peripheral blood. J Immunol 167:1245–1253

    PubMed  CAS  Google Scholar 

  10. Baecher-Allan C, Viglietta V, Hafler DA (2004) Human CD4+CD25+ regulatory T cells. Semin Immunol 16:89–98

    Article  PubMed  CAS  Google Scholar 

  11. Balandina A, Lecart S, Dartevelle P, Saoudi A, Berrih-Aknin S (2004) Functional defect of regulatory CD4+CD25+ T cells in the thymus of patients with autoimmune Myasthenia Gravis. Blood 105:735–741; e-pub Sept. 28 DOI 15454488

    PubMed  Google Scholar 

  12. Barrat FJ, Cua DJ, Boonstra A, Richards DF, Crain C, Savelkoul HF, de Waal-Malefyt R, Coffman RL, Hawrylowicz CM, O’Garra A (2002) In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)-and Th2-inducing cytokines. J Exp Med 195:603–616

    Article  PubMed  CAS  Google Scholar 

  13. Battaglia M, Stabilini A, Draghici E, Gregori S, Bonifacio E, Roncarolo MG (2004) Rapamycin and IL-10 treatment induces antigen specific T regulatory type 1 (Tr1) cells that mediate transplantation tolerance (submitted)

    Google Scholar 

  14. Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL (2002) CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420:502–507

    Article  PubMed  CAS  Google Scholar 

  15. Bellinghausen I, Klostermann B, Knop J, Saloga J (2003) Human CD4+CD25+ T cells derived from the majority of atopic donors are able to suppress TH1 and TH2 cytokine production. J Allergy Clin Immunol 111:862–868

    Article  PubMed  CAS  Google Scholar 

  16. Bensinger SJ, Walsh PT, Zhang J, Carroll M, Parsons R, Rathmell JC, Thompson CB, Burchill MA, Farrar MA, Turka LA (2004) Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J Immunol 172:5287–5296

    PubMed  CAS  Google Scholar 

  17. Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27:68–73

    Article  PubMed  CAS  Google Scholar 

  18. Buenafe AC, Tsaknaridis L, Spencer L, Hicks KS, McMahan RH, Watson L, Culbertson NE, Latocha D, Wegmann K, Finn T et al (2004) Specificity of regulatory CD4+CD25+ T cells for self-T cell receptor determinants. J Neurosci Res 76:129–140

    Article  PubMed  CAS  Google Scholar 

  19. Camara NO, Sebille F, Lechler RI (2003) Human CD4+CD25+ regulatory cells have marked and sustained effects on CD8+ T cell activation. Eur J Immunol 33:3473–3483

    PubMed  CAS  Google Scholar 

  20. Cao D, Malmstrom V, Baecher-Allan C, Hafler D, Klareskog L, Trollmo C (2003) Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur J Immunol 33:215–223

    Article  PubMed  CAS  Google Scholar 

  21. Cavani A, Nasorri F, Ottaviani C, Sebastiani S, De Pita O, Girolomoni G (2003) Human CD25+ regulatory T cells maintain immune tolerance to nickel in healthy, nonallergic individuals. J Immunol 171:5760–5768

    PubMed  CAS  Google Scholar 

  22. Cavani A, Nasorri F, Prezzi C, Sebastiani S, Albanesi C, Girolomoni G (2000) Human CD4+ T lymphocytes with remarkable regulatory functions on dendritic cells and nickel-specific Th1 immune responses. J Invest Dermatol 114:295–302

    Article  PubMed  CAS  Google Scholar 

  23. Chen Y, Kuchroo VK, Inobe J, Hafler DA, Weiner HL (1994) Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265:1237–1240

    PubMed  CAS  Google Scholar 

  24. Chen ZM, O’shaughnessy MJ, Gramaglia I, Panoskaltsis-Mortari A, Murphy WJ, Narula S, Roncarolo MG, Blazar BR (2003) IL-10 and TGF-beta induce alloreactive CD4+CD25− T cells to acquire regulatory cell function. Blood 101:5076–5083

    Article  PubMed  CAS  Google Scholar 

  25. Clark FJ, Gregg R, Piper K, Dunnion D, Freeman L, Griffiths M, Begum G, Mahendra P, Craddock C, Moss P, Chakraverty R (2004) Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4+CD25high regulatory T cells. Blood 103:2410–2416

    Article  PubMed  CAS  Google Scholar 

  26. Cong Y, Weaver CT, Lazenby A, Elson CO (2002) Bacterial-reactive T regulatory cells inhibit pathogenic immune responses to the enteric flora. J Immunol 169:6112–6119

    Google Scholar 

  27. Cosmi L, Liotta F, Angeli R, Mazzinghi B, Santarlasci V, Manetti R, Lasagni L, Vanini V, Romagnani P, Maggi E et al (2004) Th2 cells are less susceptible than Th1 cells to the suppressive activity of CD25+ regulatory thymocytes because of their responsiveness to different cytokines. Blood 103:3117–3121

    Article  PubMed  CAS  Google Scholar 

  28. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949

    Article  PubMed  CAS  Google Scholar 

  29. De Kleer IM, Wedderburn LR, Taams LS, Patel A, Varsani H, Klein M, De Jager W, Pugayung G, Giannoni F, Rijkers G et al (2004) CD4(+)CD25(bright) regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J Immunol 172:6435–6443

    PubMed  Google Scholar 

  30. Dieckmann D, Bruett CH, Ploettner H, Lutz MB, Schuler G (2002) Human CD4(+)CD25(+) regulatory, contact-dependent T cells induce interleukin 10-producing, contact-independent type 1-like regulatory T cells. J Exp Med 196:247–253

    Article  PubMed  CAS  Google Scholar 

  31. Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler S (2001) Ex vivo isolation and characterization of CD4+CD25+ T cells with regulatory properties from human blood. J Exp Med 193:1303–1310

    Article  PubMed  CAS  Google Scholar 

  32. Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF (2004) Cutting edge: TGF-beta Induces a regulatory phenotype in CD4(+)CD25(−) T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 172:5149–5153

    PubMed  CAS  Google Scholar 

  33. Fisson S, Darrasse-Jeze G, Litvinova E, Septier F, Klatzmann D, Liblau R, Salomon BL (2003) Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J Exp Med 198:737–746

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  35. Foussat A, Cottrez F, Brun V, Fournier N, Breittmayer JP, Groux H (2003) A comparative study between T regulatory type 1 and CD4+CD25+ T cells in the control of inflammation. J Immunol 171:5018–5026

    PubMed  CAS  Google Scholar 

  36. Francis JN, Till SJ, Durham SR (2003) Induction of IL-10+CD4+CD25+ T cells by grass pollen immunotherapy. J Allergy Clin Immunol 111:1255–1261

    Article  PubMed  CAS  Google Scholar 

  37. Gianfrani C, Levings MK, Sartirana C, Mazzarella G, Zanzi D, Iaquinto G, Giardullo N, Auricchio S, Troncone R, Roncarolo MG (2004) Gliadin-specific type 1 T regulatory cells are present in the intestinal mucosa of treated coeliac disease patients. (submitted)

    Google Scholar 

  38. Godfrey WR, Ge YG, Spoden DJ, Levine BL, June CH, Blazar BR, Porter SB (2004) In vitro-expanded human CD4(+)CD25(+) T-regulatory cells can markedly inhibit allogeneic dendritic cell-stimulated MLR cultures. Blood 104:453–461

    Article  PubMed  CAS  Google Scholar 

  39. Groux H (2003) Type 1 T-regulatory cells: their role in the control of immune responses. Transplantation 75:8S–12S

    PubMed  CAS  Google Scholar 

  40. Groux H, Bigler M, de Vries JE, Roncarolo MG (1996) Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. J Exp Med 184:19–29

    Article  PubMed  CAS  Google Scholar 

  41. Groux H, Cottrez F (2003) The complex role of interleukin-10 in autoimmunity. J Autoimmun 20:281–285

    Article  PubMed  CAS  Google Scholar 

  42. Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389:737–742

    PubMed  CAS  Google Scholar 

  43. Hall AM, Ward FJ, Vickers MA, Stott LM, Urbaniak SJ, Barker RN (2002) Interleukin-10-mediated regulatory T-cell responses to epitopes on a human red blood cell autoantigen. Blood 100:4529–4536

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  45. Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, Fujii H (2003) Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clin Cancer Res 9:4404–4408

    PubMed  Google Scholar 

  46. Iellem A, Mariani M, Lang R, Recalde H, Panina-Bordignon P, Sinigaglia F, D’Ambrosio D (2001) Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J Exp Med 194:847–853

    Article  PubMed  CAS  Google Scholar 

  47. Jonuleit H, Schmitt E, Kakirman H, Stassen M, Knop J, Enk AH (2002) Infectious tolerance: human CD25(+) regulatory T cells convey suppressor activity to conventional CD4(+) T helper cells. J Exp Med 196:255–260

    Article  PubMed  CAS  Google Scholar 

  48. Jonuleit H, Schmitt E, Schuler G, Knop J, Enk AH (2000) Induction of interleukin-10-producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogenic immature human dendritic cells. J Exp Med 192:1213–1222

    Article  PubMed  CAS  Google Scholar 

  49. Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH (2001) Identification and functional characterization of human CD4+CD25+ T cells with regulatory properties isolated from peripheral blood. J Exp Med 193:1285–1294

    Article  PubMed  CAS  Google Scholar 

  50. Jutel M, Akdis M, Budak F, Aebischer-Casaulta C, Wrzyszcz M, Blaser K, Akdis CA (2003) IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol 33:1205–1214

    Article  PubMed  CAS  Google Scholar 

  51. Kasow KA, Chen X, Knowles J, Wichlan D, Handgretinger R, Riberdy JM (2004) Human CD4(+)CD25(+) regulatory T cells share equally complex and comparable repertoires with CD4(+)CD25(−) counterparts. J Immunol 172:6123–6128

    PubMed  CAS  Google Scholar 

  52. Kemper C, Chan AC, Green JM, Brett KA, Murphy KM, Atkinson JP (2003) Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature 421:388–392

    Article  PubMed  CAS  Google Scholar 

  53. Khattri R, Cox T, Yasayko SA, Ramsdell F (2003) An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4:337–342

    Article  PubMed  CAS  Google Scholar 

  54. Kitani A, Chua K, Nakamura K, Strober W (2000) Activated self-MHC-reactive T cells have the cytokine phenotype of Th3/T regulatory cell 1 T cells. J Immunol 165:691–702

    PubMed  CAS  Google Scholar 

  55. Koenen HJ, Fasse E, Joosten I (2003) IL-15 and cognate antigen successfully expand de novo-induced human antigen-specific regulatory CD4+ T cells that require antigen-specific activation for suppression. J Immunol 171:6431–6441

    PubMed  CAS  Google Scholar 

  56. Kriegel MA, Lohmann T, Gabler C, Blank N, Kalden JR, Lorenz HM (2004) Defective Suppressor Function of Human CD4+ CD25+ Regulatory T Cells in Autoimmune Polyglandular Syndrome Type II. J Exp Med 199:1285–1291

    Article  PubMed  CAS  Google Scholar 

  57. Kullberg MC, Jankovic D, Gorelick PL, Caspar P, Letterio JJ, Cheever AW, Sher A (2002) Bacteria-triggered CD4(+) T regulatory cells suppress Helicobacter hepaticus-induced colitis. J Exp Med 196:505–515

    Article  PubMed  CAS  Google Scholar 

  58. Lavelle EC, Jarnicki A, McNeela E, Armstrong ME, Higgins SC, Leavy O, Mills KH (2004) Effects of cholera toxin on innate and adaptive immunity and its application as an immunomodulatory agent. J Leukoc Biol 75:756–763

    PubMed  CAS  Google Scholar 

  59. Lecart S, Boulay V, Raison-Peyron N, Bousquet J, Meunier L, Yssel H, Pene J (2001) Phenotypic characterization of human CD4+ regulatory T cells obtained from cutaneous dinitrochlorobenzene-induced delayed type hypersensitivity reactions. J Invest Dermatol 117:318–325

    Article  PubMed  CAS  Google Scholar 

  60. Levings MK, Bacchetta R, Schulz U, Roncarolo MG (2002) The role of IL-10 and TGF-beta in the differentiation and effector function of T regulatory cells. Int Arch Allergy Immunol 129:263–276

    Article  PubMed  CAS  Google Scholar 

  61. Levings MK, Gregori S, Tresoldi E, Cazzaniga S, Bonini C, Roncarolo MG (2004) Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Treg cells. Blood 105:1162–1169; e-pub Oct12 DOI 15479730

    Article  PubMed  Google Scholar 

  62. Levings MK, Sangregorio R, Galbiati F, Squadrone S, de Waal Malefyt R, Roncarolo MG (2001) IFN-alpha and IL-10 Induce the differentiation of human type 1 T regulatory cells. J Immunol 166:5530–5539

    PubMed  CAS  Google Scholar 

  63. Levings MK, Sangregorio R, Roncarolo MG (2001) Human CD25+CD4+ T regulatory cells suppress naive and memory T-cell proliferation and can be expanded in vitro without loss of function. J Exp Med 193:1295–1302

    Article  PubMed  CAS  Google Scholar 

  64. Levings MK, Sangregorio R, Sartirana C, Moschin AL, Battaglia M, Orban PC, Roncarolo MG (2002) Human CD25+CD4+ T suppressor cell clones produce TGF-ß, but not IL-10 and are distinct from type 1 T regulatory cells. J Exp Med 196:1335–1346

    Article  PubMed  CAS  Google Scholar 

  65. Liu MF, Wang CR, Fung LL, Wu CR (2004) Decreased CD4+CD25+ T cells in peripheral blood of patients with systemic lupus erythematosus. Scand J Immunol 59:198–202

    Article  PubMed  Google Scholar 

  66. MacDonald AJ, Duffy M, Brady MT, McKiernan S, Hall W, Hegarty J, Curry M, Mills KH (2002) CD4 T helper type 1 and regulatory T cells induced against the same epitopes on the core protein in hepatitis C virus-infected persons. J Infect Dis 185:720–727

    Article  PubMed  CAS  Google Scholar 

  67. Maloy KJ, Salaun L, Cahill R, Dougan G, Saunders NJ, Powrie F (2003) CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J Exp Med 197:111–119

    Article  PubMed  CAS  Google Scholar 

  68. Marshall NA, Christie LE, Munro LR, Culligan DJ, Johnston PW, Barker RN, Vickers MA (2004) Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 103:1755–1762

    PubMed  CAS  Google Scholar 

  69. Marshall NA, Vickers MA, Barker RN (2003) Regulatory T cells secreting IL-10 dominate the immune response to EBV latent membrane protein 1. J Immunol 170:6183–6189

    PubMed  CAS  Google Scholar 

  70. Martin E, O’sullivan B, Low P, Thomas R (2003) Antigen-specific suppression of a primed immune response by dendritic cells mediated by regulatory T cells secreting interleukin-10. Immunity 18:155–167

    Article  PubMed  CAS  Google Scholar 

  71. McGuirk P, McCann C, Mills KH (2002) Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis. J Exp Med 195:221–231

    Article  PubMed  CAS  Google Scholar 

  72. Misra N, Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Kaveri SV (2004) Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells. J Immunol 172:4676–4680

    PubMed  CAS  Google Scholar 

  73. Nakamura K, Kitani A, Fuss I, Pedersen A, Harada N, Nawata H, Strober W (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 172:834–842

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  75. Ng WF, Duggan PJ, Ponchel F, Matarese G, Lombardi G, Edwards AD, Isaacs JD, Lechler RI (2001) Human CD4(+)CD25(+) cells: a naturally occurring population of regulatory T cells. Blood 98:2736–2744

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  77. Penna G, Adorini L (2000) 1Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol 164:2405–2411

    PubMed  CAS  Google Scholar 

  78. Piccirillo CA, Letterio JJ, Thornton AM, McHugh RS, Mamura M, Mizuhara H, Shevach EM (2002) CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness. J Exp Med 196:237–246

    Article  PubMed  CAS  Google Scholar 

  79. Piccirillo CA, Shevach EM (2004) Naturally-occurring CD4+CD25+ immunoregulatory T cells: central players in the arena of peripheral tolerance. Semin Immunol 16:81–88

    Article  PubMed  CAS  Google Scholar 

  80. Putheti P, Pettersson A, Soderstrom M, Link H, Huang YM (2004) Circulating CD4(+)CD25(+) T regulatory cells are not altered in multiple sclerosis and unaffected by disease-modulating drugs. J Clin Immunol 24:155–161

    Article  PubMed  CAS  Google Scholar 

  81. Reefer AJ, Carneiro RM, Custis NJ, Platts-Mills TA, Sung SS, Hammer J, Woodfolk JA (2004) A role for IL-10-mediated HLA-DR7-restricted T cell-dependent events in development of the modified Th2 response to cat allergen. J Immunol 172:2763–2772

    PubMed  CAS  Google Scholar 

  82. Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK (2001) Type 1 T regulatory cells. Immunol Rev 182:68–79

    Article  PubMed  CAS  Google Scholar 

  83. Roncarolo MG, Levings MK (2000) The role of different subsets of T regulatory cells in controlling autoimmunity. Curr Opin Immunol 12:676–683

    Article  PubMed  CAS  Google Scholar 

  84. Rutella S, Bonanno G, Pierelli L, Mariotti A, Capoluongo E, Contemi AM, Ameglio F, Curti A, de Ritis DG, Voso MT et al (2004) Granulocyte colony-stimulating factor promotes the generation of regulatory DC through induction of IL-10 and IFN-alpha. Eur J Immunol 34:1291–1302

    Article  PubMed  CAS  Google Scholar 

  85. Sakaguchi S (2000) Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101:455–458

    Article  PubMed  CAS  Google Scholar 

  86. Sakaguchi S (2004) Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531–562

    Article  PubMed  CAS  Google Scholar 

  87. Sasada T, Kimura M, Yoshida Y, Kanai M, Takabayashi A (2003) CD4+CD25+ regulatory T cells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression. Cancer 98:1089–1099

    Article  PubMed  Google Scholar 

  88. Satoguina J, Mempel M, Larbi J, Badusche M, Loliger C, Adjei O, Gachelin G, Fleischer B, Hoerauf A (2002) Antigen-specific T regulatory-1 cells are associated with immunosuppression in a chronic helminth infection (onchocerciasis). Microbes Infect 4:1291–1300

    Article  PubMed  CAS  Google Scholar 

  89. Sebastiani S, Allavena P, Albanesi C, Nasorri F, Bianchi G, Traidl C, Sozzani S, Girolomoni G, Cavani A (2001) Chemokine receptor expression and function in CD4+ T lymphocytes with regulatory activity. J Immunol 166:996–1002

    PubMed  CAS  Google Scholar 

  90. Shevach EM (2000) Regulatory T cells in autoimmmunity. Annu Rev Immunol 18:423–449

    Article  PubMed  CAS  Google Scholar 

  91. Stanzani M, Martins SL, Saliba RM, St John LS, Bryan S, Couriel D, McMannis J, Champlin RE, Molldrem JJ, Komanduri KV (2004) CD25 expression on donor CD4+ or CD8+ T cells is associated with an increased risk for graft-versus-host disease after HLA-identical stem cell transplantation in humans. Blood 103:1140–1146

    PubMed  CAS  Google Scholar 

  92. Stassen M, Fondel S, Bopp T, Richter C, Müller C, Kubach J, Becker C, Knop J, Enk AH, Schmitt S et al (2004) Human CD25+ regulatory T cells: two subsets defined by the integrins alpha4beta7 or alpha4beta1 confer distinct suppressive properties upon CD4+ T helper cells. Eur J Immunol 34:1303–1311

    Article  PubMed  CAS  Google Scholar 

  93. Stassen M, Schmitt E, Jonuleit H (2004) Human CD(4+)CD(25+) regulatory T cells and infectious tolerance. Transplantation 77:S23–S25

    PubMed  Google Scholar 

  94. Sullivan KE, McDonald-McGinn D, Zackai EH (2002) CD4(+) CD25(+) T-cell production in healthy humans and in patients with thymic hypoplasia. Clin Diagn Lab Immunol 9:1129–1131

    Article  PubMed  Google Scholar 

  95. Taams LS, Smith J, Rustin MH, Salmon M, Poulter LW, Akbar AN (2001) Human anergic/suppressive CD4(+)CD25(+) T cells: a highly differentiated and a poptosisprone population. Eur J Immunol 31:1122–1131

    Article  PubMed  CAS  Google Scholar 

  96. Taams LS, Vukmanovic-Stejic M, Smith J, Dunne PJ, Fletcher JM, Plunkett FJ, Ebeling SB, Lombardi G, Rustin MH, Bijlsma JW et al (2002) Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells. Eur J Immunol 32:1621–1630

    Article  PubMed  CAS  Google Scholar 

  97. Taylor P, Lees CJ, Blazar BR (2002) The infusion of ex vivo activated and expanded CD4+CD25+ immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99:3493–3499

    PubMed  CAS  Google Scholar 

  98. Thornton AM, Piccirillo CA, Shevach EM (2004) Activation requirements for the induction of CD4+CD25+ T cell suppressor function. Eur J Immunol 34:366–376

    Article  PubMed  CAS  Google Scholar 

  99. Tsaknaridis L, Spencer L, Culbertson N, Hicks K, LaTocha D, Chou YK, Whitham RH, Bakke A, Jones RE, Offner H et al (2003) Functional assay for human CD4+CD25+ Treg cells reveals an age-dependent loss of suppressive activity. J Neurosci Res 74:296–308

    Article  PubMed  CAS  Google Scholar 

  100. Veldman C, Hohne A, Dieckmann D, Schuler G, Hertl M (2004) Type I regulatory T cells specific fordesmoglein 3 are more frequently detected in healthy individuals than in patients with pemphigus vulgaris. J Immunol 172:6468–6475

    PubMed  CAS  Google Scholar 

  101. Vermeiren J, Ceuppens JL, Van Ghelue M, Witters P, Bullens D, Mages HW, Kroczek RA, Van Gool SW (2004) Human T cell activation by costimulatory signal-deficient allogeneic cells induces inducible costimulator-expressing anergic T cells with regulatory cell activity. J Immunol 172:5371–5378

    PubMed  CAS  Google Scholar 

  102. Vieira PL, Christensen JR, Minaee S, O’Neill EJ, Barrat FJ, Boonstra A, Barthlott T, Stockinger B, Wraith DC, O’Garra A (2004) IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4(+)CD25(+) regulatory T cells. J Immunol 172:5986–5993

    PubMed  CAS  Google Scholar 

  103. Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA (2004) Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 199:971–979

    Article  PubMed  CAS  Google Scholar 

  104. Viguier M, Lemaitre F, Verola O, Cho MS, Gorochov G, Dubertret L, Bachelez H, Kourilsky P, Ferradini L (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 173:1444–1453

    PubMed  CAS  Google Scholar 

  105. Wakkach A, Cottrez F, Groux H (2001) Differentiation of regulatory T cells 1 is induced by CD2 costimulation. J Immunol 167:3107–3113

    PubMed  CAS  Google Scholar 

  106. Wakkach A, Fournier N, Brun V, Breittmayer JP, Cottrez F, Groux H (2003) Characterization of dendritic cells that induce tolerance and T regulatory 1 cell differentiation in vivo. Immunity 18:605–617

    Article  PubMed  CAS  Google Scholar 

  107. Waldmann H, Graca L, Cobbold S, Adams E, Tone M, Tone Y (2004) Regulatory T cells and organ transplantation. Semin Immunol 16:119–126

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  109. Wang HY, Lee DA, Peng G, Guo Z, Li Y, Kiniwa Y, Shevach EM, Wang RF (2004) Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Immunity 20:107–118

    PubMed  CAS  Google Scholar 

  110. Wildin RS, Smyk-Pearson S, Filipovich AH (2002) Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet 39:537–545

    Article  PubMed  CAS  Google Scholar 

  111. Wing K, Ekmark A, Karlsson H, Rudin A, Suri-Payer E (2002) Characterization of human CD25+ CD4+ T cells in thymus, cord and adult blood. Immunology 106:190–199

    Article  PubMed  CAS  Google Scholar 

  112. Yamagiwa S, Gray JD, Hashimoto S, Horwitz DA (2001) A role for TGF-beta in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood. J Immunol 166:7282–7289

    PubMed  CAS  Google Scholar 

  113. Yoshimura S, Bondeson J, Brennan FM, Foxwell BM, Feldmann M (2001) Role of NFkappaB in antigen presentation and development of regulatory T cells elucidated by treatment of dendritic cells with the proteasome inhibitor PSI. Eur J Immunol 31:1883–1893

    Article  PubMed  CAS  Google Scholar 

  114. Zelenika D, Adams E, Humm S, Graca L, Thompson S, Cobbold SP, Waldmann H (2002) Regulatory T cells overexpress a subset of Th2 gene transcripts. J Immunol 168:1069–1079

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  116. Zuany-Amorim C, Sawicka E, Manlius C, Le Moine A, Brunet LR, Kemeny DM, Bowen G, Rook G, Walker C (2002) Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med 8:625–629

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, University of British Columbia and Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, 2660 Oak St., Vancouver B.C., V6H 3Z6, Canada

    M. K. Levings

  2. San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132, Milan, Italy

    M. G. Roncarolo

  3. Università Vita-Salute San Raffaele, 20132, Milan, Italy

    M. G. Roncarolo

Authors
  1. M. K. Levings
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Editor information

Editors and Affiliations

  1. Atlanta, Georgia

    R.W. Compans

  2. Birmingham, Alabama

    M.D. Cooper

  3. Kyoto

    T. Honjo

  4. Philadelphia, Pennsylvania

    H. Koprowski

  5. Basel

    F. Melchers

  6. La Jolla, California

    M.B.A. Oldstone  & P.K. Vogt  & 

  7. Oslo

    S. Olsnes

  8. Bethesda, Maryland

    M. Potter

  9. Munich

    H. Wagner

  10. Abteilung Entwicklungsimmunologie, Deutsches Krebsforschungszentrum Forschungsschwerpunkt Tumorimmunologie, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Bruno Kyewski

  11. Abteilung Immungenetik, Deutsches Krebsforschungszentrum Forschungsschwerpunkt Tumorimmunologie, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Elisabeth Suri-Payer

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Levings, M.K., Roncarolo, M.G. (2005). Phenotypic and Functional Differences Between Human CD4+CD25+ and Type 1 Regulatory T Cells. In: Compans, R., et al. CD4+CD25+ Regulatory T Cells: Origin, Function and Therapeutic Potential. Current Topics in Microbiology and Immunology, vol 293. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-27702-1_14

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