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The development and function of regulatory T cells

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Abstract

Regulatory T cells (Tregs) are a critical subset of T cells that mediate peripheral tolerance. There are two types of Tregs: natural Tregs, which develop in the thymus, and induced Tregs, which are derived from naive CD4+ T cells in the periphery. Tregs utilize a variety of mechanisms to suppress the immune response. While Tregs are critical for the peripheral maintenance of potential autoreactive T cells, they can also be detrimental by preventing effective anti-tumor responses and sterilizing immunity against pathogens. In this review, we will discuss the development of natural and induced Tregs as well as the role of Tregs in a variety of disease settings and the mechanisms they utilize for suppression.

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References

  1. Gershon RK (1975) A disquisition on suppressor T cells. Transplant Rev 26:170–185

    PubMed  CAS  Google Scholar 

  2. Gershon RK, Cohen P, Hencin R, Liebhaber SA (1972) Suppressor T cells. J Immunol 108:586–590

    PubMed  CAS  Google Scholar 

  3. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164

    PubMed  CAS  Google Scholar 

  4. 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 

  5. 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 

  6. 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 

  7. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27:20–21

    Article  PubMed  CAS  Google Scholar 

  8. Gambineri E, Torgerson TR, Ochs HD (2003) Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol 15:430–435

    Article  PubMed  CAS  Google Scholar 

  9. 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 

  10. Asano M, Toda M, Sakaguchi N, Sakaguchi S (1996) Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 184:387–396

    Article  PubMed  CAS  Google Scholar 

  11. Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, Fazekas de St Groth B, Clayberger C, Soper DM, Ziegler SF, Bluestone JA (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 203:1701–1711

    Article  PubMed  CAS  Google Scholar 

  12. Paust S, Lu L, McCarty N, Cantor H (2004) Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease. Proc Natl Acad Sci USA 101:10398–10403

    Article  PubMed  CAS  Google Scholar 

  13. Ndhlovu LC, Takeda I, Sugamura K, Ishii N (2004) Expanding role of T-cell costimulators in regulatory T-cell function: recent advances in accessory molecules expressed on both regulatory and nonregulatory T cells. Crit Rev Immunol 24:251–266

    Article  PubMed  CAS  Google Scholar 

  14. Vignali DA, Collison LW, Workman CJ (2008) How regulatory T cells work. Nat Rev Immunol 8:523–532

    Article  PubMed  CAS  Google Scholar 

  15. Ziegler SF (2006) FOXP3: of mice and men. Annu Rev Immunol 24:209–226

    Article  PubMed  CAS  Google Scholar 

  16. Keir ME, Sharpe AH (2005) The B7/CD28 costimulatory family in autoimmunity. Immunol Rev 204:128–143

    Article  PubMed  CAS  Google Scholar 

  17. Malek TR, Yu A, Vincek V, Scibelli P, Kong L (2002) CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17:167–178

    Article  PubMed  CAS  Google Scholar 

  18. Su L, Creusot RJ, Gallo EM, Chan SM, Utz PJ, Fathman CG, Ermann J (2004) Murine CD4+CD25+ regulatory T cells fail to undergo chromatin remodeling across the proximal promoter region of the IL-2 gene. J Immunol 173:4994–5001

    PubMed  CAS  Google Scholar 

  19. Gorelik L, Flavell RA (2000) Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12:171–181

    Article  PubMed  CAS  Google Scholar 

  20. Marie JC, Letterio JJ, Gavin M, Rudensky AY (2005) TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med 201:1061–1067

    Article  PubMed  CAS  Google Scholar 

  21. Hogquist KA, Baldwin TA, Jameson SC (2005) Central tolerance: learning self-control in the thymus. Nat Rev Immunol 5:772–782

    Article  PubMed  CAS  Google Scholar 

  22. Kronenberg M, Rudensky A (2005) Regulation of immunity by self-reactive T cells. Nature 435:598–604

    Article  PubMed  CAS  Google Scholar 

  23. Jordan MS, Boesteanu A, Reed AJ, Petrone AL, Holenbeck AE, Lerman MA, Naji A, Caton AJ (2001) Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat Immunol 2:301–306

    Article  PubMed  CAS  Google Scholar 

  24. Pacholczyk R, Ignatowicz H, Kraj P, Ignatowicz L (2006) Origin and T cell receptor diversity of Foxp3+CD4+CD25+ T cells. Immunity 25:249–259

    Article  PubMed  CAS  Google Scholar 

  25. Pacholczyk R, Kern J, Singh N, Iwashima M, Kraj P, Ignatowicz L (2007) Nonself-antigens are the cognate specificities of Foxp3+ regulatory T cells. Immunity 27:493–504

    Article  PubMed  CAS  Google Scholar 

  26. Takahashi M, Nakamura K, Honda K, Kitamura Y, Mizutani T, Araki Y, Kabemura T, Chijiiwa Y, Harada N, Nawata H (2006) An inverse correlation of human peripheral blood regulatory T cell frequency with the disease activity of ulcerative colitis. Dig Dis Sci 51:677–686

    Article  PubMed  Google Scholar 

  27. Thornton AM, Shevach EM (2000) Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol 164:183–190

    PubMed  CAS  Google Scholar 

  28. Takahashi T, Kuniyasu Y, Toda M, Sakaguchi N, Itoh M, Iwata M, Shimizu J, Sakaguchi S (1998) Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol 10:1969–1980

    Article  PubMed  CAS  Google Scholar 

  29. Szymczak-Workman AL, Workman CJ, Vignali DAA (2009) Cutting edge: regulatory T cells do not require stimulation through their T cell receptor to suppress. J Immunol (in press)

  30. Hsieh CS, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY (2004) Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 21:267–277

    Article  PubMed  CAS  Google Scholar 

  31. Picca CC, Caton AJ (2005) The role of self-peptides in the development of CD4+ CD25+ regulatory T cells. Curr Opin Immunol 17:131–136

    Article  PubMed  CAS  Google Scholar 

  32. Pacholczyk R, Kraj P, Ignatowicz L (2002) Peptide specificity of thymic selection of CD4+CD25+ T cells. J Immunol 168:613–620

    PubMed  CAS  Google Scholar 

  33. Pennington DJ, Silva-Santos B, Silberzahn T, Escorcio-Correia M, Woodward MJ, Roberts SJ, Smith AL, Dyson PJ, Hayday AC (2006) Early events in the thymus affect the balance of effector and regulatory T cells. Nature 444:1073–1077

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  35. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D (2002) Projection of an immunological self shadow within the thymus by the aire protein. Science 298:1395–1401

    Article  PubMed  CAS  Google Scholar 

  36. Kyewski B, Klein L (2006) A central role for central tolerance. Annu Rev Immunol 24:571–606

    Article  PubMed  CAS  Google Scholar 

  37. Aschenbrenner K, D’Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, Swee LK, Rolink A, Klein L (2007) Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol 8:351–358

    Article  PubMed  CAS  Google Scholar 

  38. Gavin MA, Rasmussen JP, Fontenot JD, Vasta V, Manganiello VC, Beavo JA, Rudensky AY (2007) Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445:771–775

    Article  PubMed  CAS  Google Scholar 

  39. Lin W, Haribhai D, Relland LM, Truong N, Carlson MR, Williams CB, Chatila TA (2007) Regulatory T cell development in the absence of functional Foxp3. Nat Immunol 8:359–368

    Article  PubMed  CAS  Google Scholar 

  40. Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D (2005) The cellular mechanism of Aire control of T cell tolerance. Immunity 23:227–239

    Article  PubMed  CAS  Google Scholar 

  41. Kuroda N, Mitani T, Takeda N, Ishimaru N, Arakaki R, Hayashi Y, Bando Y, Izumi K, Takahashi T, Nomura T, Sakaguchi S, Ueno T, Takahama Y, Uchida D, Sun S, Kajiura F, Mouri Y, Han H, Matsushima A, Yamada G, Matsumoto M (2005) Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice. J Immunol 174:1862–1870

    PubMed  CAS  Google Scholar 

  42. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY (2005) A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6:1142–1151

    Article  PubMed  CAS  Google Scholar 

  43. Watanabe N, Wang YH, Lee HK, Ito T, Cao W, Liu YJ (2005) Hassall’s corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 436:1181–1185

    Article  PubMed  CAS  Google Scholar 

  44. Kurobe H, Liu C, Ueno T, Saito F, Ohigashi I, Seach N, Arakaki R, Hayashi Y, Kitagawa T, Lipp M, Boyd RL, Takahama Y (2006) CCR7-dependent cortex-to-medulla migration of positively selected thymocytes is essential for establishing central tolerance. Immunity 24:165–177

    Article  PubMed  CAS  Google Scholar 

  45. Liston A, Nutsch KM, Farr AG, Lund JM, Rasmussen JP, Koni PA, Rudensky AY (2008) Differentiation of regulatory Foxp3+ T cells in the thymic cortex. Proc Natl Acad Sci USA 105:11903–11908

    Article  PubMed  CAS  Google Scholar 

  46. Lio CW, Hsieh CS (2008) A two-step process for thymic regulatory T cell development. Immunity 28:100–111

    Article  PubMed  CAS  Google Scholar 

  47. Marie JC, Liggitt D, Rudensky AY (2006) Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity 25:441–454

    Article  PubMed  CAS  Google Scholar 

  48. Sempowski GD, Cross SJ, Heinly CS, Scearce RM, Haynes BF (2004) CD7 and CD28 are required for murine CD4+CD25+ regulatory T cell homeostasis and prevention of thyroiditis. J Immunol 172:787–794

    PubMed  CAS  Google Scholar 

  49. Tang Q, Henriksen KJ, Boden EK, Tooley AJ, Ye J, Subudhi SK, Zheng XX, Strom TB, Bluestone JA (2003) Cutting edge: CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. J Immunol 171:3348–3352

    PubMed  CAS  Google Scholar 

  50. Vella A, Cooper JD, Lowe CE, Walker N, Nutland S, Widmer B, Jones R, Ring SM, McArdle W, Pembrey ME, Strachan DP, Dunger DB, Twells RC, Clayton DG, Todd JA (2005) Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am J Hum Genet 76:773–779

    Article  PubMed  CAS  Google Scholar 

  51. Bayer AL, Yu A, Adeegbe D, Malek TR (2005) Essential role for interleukin-2 for CD4(+)CD25(+) T regulatory cell development during the neonatal period. J Exp Med 201:769–777

    Article  PubMed  CAS  Google Scholar 

  52. Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352

    Article  PubMed  CAS  Google Scholar 

  53. Bluestone JA, Abbas AK (2003) Natural versus adaptive regulatory T cells. Nat Rev Immunol 3:253–257

    Article  PubMed  CAS  Google Scholar 

  54. 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

    Article  PubMed  CAS  Google Scholar 

  55. 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 

  56. Weiner HL (2001) Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev 182:207–214

    Article  PubMed  CAS  Google Scholar 

  57. Skapenko A, Kalden JR, Lipsky PE, Schulze-Koops H (2005) The IL-4 receptor alpha-chain-binding cytokines, IL-4 and IL-13, induce forkhead box P3-expressing CD25+CD4+ regulatory T cells from CD25-CD4+ precursors. J Immunol 175:6107–6116

    PubMed  CAS  Google Scholar 

  58. Zheng SG (2008) The critical role of TGF-beta1 in the development of induced Foxp3+ regulatory T cells. Int J Clin Exp Med 1:192–202

    PubMed  CAS  Google Scholar 

  59. Chen W, Jin W, Hardegen N, Lei Kj, Li L, Marinos N, McGrady G, Wahl SM (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 198:1875–1886

    Article  PubMed  CAS  Google Scholar 

  60. Kohm AP, Carpentier PA, Anger HA, Miller SD (2002) Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol 169:4712–4716

    PubMed  CAS  Google Scholar 

  61. 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 

  62. Zheng SG, Wang JH, Koss MN, Quismorio F Jr, Gray JD, Horwitz DA (2004) CD4+ and CD8+ regulatory T cells generated ex vivo with IL-2 and TGF-{beta} suppress a stimulatory graft-versus-host disease with a lupus-like syndrome. J Immunol 172:1531–1539

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  64. Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H (2005) Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 6:1219–1227

    Article  PubMed  CAS  Google Scholar 

  65. Apostolou I, Sarukhan A, Klein L, von Boehmer H (2002) Origin of regulatory T cells with known specificity for antigen. Nat Immunol 3:756–763

    PubMed  CAS  Google Scholar 

  66. Taylor PA, 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

    Article  PubMed  CAS  Google Scholar 

  67. Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ (2007) All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med 204:1765–1774

    Article  PubMed  CAS  Google Scholar 

  68. Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, Schlawe K, Chang HD, Bopp T, Schmitt E, Klein-Hessling S, Serfling E, Hamann A, Huehn J (2007) Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 5:e38

    Article  PubMed  CAS  Google Scholar 

  69. Steinbrink K, Graulich E, Kubsch S, Knop J, Enk AH (2002) CD4(+) and CD8(+) anergic T cells induced by interleukin-10-treated human dendritic cells display antigen-specific suppressor activity. Blood 99:2468–2476

    Article  PubMed  CAS  Google Scholar 

  70. Verhasselt V, Vosters O, Beuneu C, Nicaise C, Stordeur P, Goldman M (2004) Induction of FOXP3-expressing regulatory CD4pos T cells by human mature autologous dendritic cells. Eur J Immunol 34:762–772

    Article  PubMed  CAS  Google Scholar 

  71. Masuyama J, Kaga S, Kano S, Minota S (2002) A novel costimulation pathway via the 4C8 antigen for the induction of CD4+ regulatory T cells. J Immunol 169:3710–3716

    PubMed  CAS  Google Scholar 

  72. Grundstrom S, Cederbom L, Sundstedt A, Scheipers P, Ivars F (2003) Superantigen-induced regulatory T cells display different suppressive functions in the presence or absence of natural CD4+CD25+ regulatory T cells in vivo. J Immunol 170:5008–5017

    PubMed  Google Scholar 

  73. 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

    PubMed  CAS  Google Scholar 

  74. 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 

  75. 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 

  76. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H (2007) Reciprocal TH17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid. Science 317:256–260

    Article  PubMed  CAS  Google Scholar 

  77. Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, Belkaid Y (2007) Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med 204:1775–1785

    Article  PubMed  CAS  Google Scholar 

  78. Moseman EA, Liang X, Dawson AJ, Panoskaltsis-Mortari A, Krieg AM, Liu YJ, Blazar BR, Chen W (2004) Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4+CD25+ regulatory T cells. J Immunol 173:4433–4442

    PubMed  CAS  Google Scholar 

  79. Verginis P, Li HS, Carayanniotis G (2005) Tolerogenic semimature dendritic cells suppress experimental autoimmune thyroiditis by activation of thyroglobulin-specific CD4+CD25+ T cells. J Immunol 174:7433–7439

    PubMed  CAS  Google Scholar 

  80. Coombes JL, Siddiqui KRR, Rancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F (2007) A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-{beta} and retinoic acid dependent mechanism. J Exp Med 204:1757–1764

    Article  PubMed  CAS  Google Scholar 

  81. Ghiringhelli F, Puig PE, Roux S, Parcellier A, Schmitt E, Solary E, Kroemer G, Martin F, Chauffert B, Zitvogel L (2005) Tumor cells convert immature myeloid dendritic cells into TGF-{beta}-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J Exp Med 202:919–929

    Article  PubMed  CAS  Google Scholar 

  82. Min WP, Zhou D, Ichim TE, Strejan GH, Xia X, Yang J, Huang X, Garcia B, White D, Dutartre P, Jevnikar AM, Zhong R (2003) Inhibitory feedback loop between tolerogenic dendritic cells and regulatory T cells in transplant tolerance. J Immunol 170:1304–1312

    PubMed  CAS  Google Scholar 

  83. Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B (2007) Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol 8:1086–1094

    Article  PubMed  CAS  Google Scholar 

  84. Roelofs-Haarhuis K, Wu X, Gleichmann E (2004) Oral tolerance to nickel requires CD4+ invariant NKT cells for the infectious spread of tolerance and the induction of specific regulatory T cells. J Immunol 173:1043–1050

    PubMed  CAS  Google Scholar 

  85. Liu R, La CA, Bai XF, Jee Y, Price M, Campagnolo DI, Christadoss P, Vollmer TL, Van KL, Shi FD (2005) Cooperation of invariant NKT cells and CD4+CD25+ T regulatory cells in the prevention of autoimmune myasthenia. J Immunol 175:7898–7904

    PubMed  CAS  Google Scholar 

  86. Qin S, Cobbold SP, Pope H, Elliott J, Kioussis D, Davies J, Waldmann H (1993) “Infectious” transplantation tolerance. Science 259:974–977

    Article  PubMed  CAS  Google Scholar 

  87. Cobbold SP, Castejon R, Adams E, Zelenika D, Graca L, Humm S, Waldmann H (2004) Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J Immunol 172:6003–6010

    PubMed  CAS  Google Scholar 

  88. 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 

  89. 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 

  90. Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 Cells. Annu Rev Immunol (in press)

  91. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238

    Article  PubMed  CAS  Google Scholar 

  92. Xu L, Kitani A, Fuss I, Strober W (2007) 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 178:6725–6729

    PubMed  CAS  Google Scholar 

  93. Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK (2006) Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 212:28–50

    Article  PubMed  CAS  Google Scholar 

  94. 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 

  95. 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 

  96. Burkhart C, Liu GY, Anderton SM, Metzler B, Wraith DC (1999) Peptide-induced T cell regulation of experimental autoimmune encephalomyelitis: a role for IL-10. Int Immunol 11:1625–1634

    Article  PubMed  CAS  Google Scholar 

  97. Curotto de Lafaille MA, Kutchukhidze N, Shen S, Ding Y, Yee H, Lafaille JJ (2008) Adaptive Foxp3+ regulatory T cell-dependent and -independent control of allergic inflammation. Immunity 29:114–126

    Article  PubMed  CAS  Google Scholar 

  98. Curotto de Lafaille MA, Lino AC, Kutchukhidze N, Lafaille JJ (2004) CD25- T cells generate CD25+Foxp3+ regulatory T cells by peripheral expansion. J Immunol 173:7259–7268

    PubMed  CAS  Google Scholar 

  99. Mucida D, Kutchukhidze N, Erazo A, Russo M, Lafaille JJ, Curotto de Lafaille MA (2005) Oral tolerance in the absence of naturally occurring Tregs. J Clin Invest 115:1923–1933

    Article  PubMed  CAS  Google Scholar 

  100. Fukaura H, Kent SC, Pietrusewicz MJ, Khoury SJ, Weiner HL, Hafler DA (1996) Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-beta1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients. J Clin Invest 98:70–77

    Article  PubMed  CAS  Google Scholar 

  101. Li MO, Wan YY, Flavell RA (2007) T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 26:579–591

    Article  PubMed  CAS  Google Scholar 

  102. Mamura M, Lee W, Sullivan TJ, Felici A, Sowers AL, Allison JP, Letterio JJ (2004) CD28 disruption exacerbates inflammation in Tgf-{beta}1-/- mice: in vivo suppression by CD4+CD25+ regulatory T cells independent of autocrine TGF-{beta}1. Blood 103:4594–4601

    Article  PubMed  CAS  Google Scholar 

  103. Fahlen L, Read S, Gorelik L, Hurst SD, Coffman RL, Flavell RA, Powrie F (2005) T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells. J Exp Med 201:737–746

    Article  PubMed  CAS  Google Scholar 

  104. Chen ML, Pittet MJ, Gorelik L, Flavell RA, Weissleder R, von BH, Khazaie K (2005) Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci USA 102:419–424

    Article  PubMed  CAS  Google Scholar 

  105. Hamann A, Andrew DP, Jablonski-Westrich D, Holzmann B, Butcher EC (1994) Role of alpha 4-integrins in lymphocyte homing to mucosal tissues in vivo. J Immunol 152:3282–3293

    PubMed  CAS  Google Scholar 

  106. Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY (2004) Retinoic acid imprints gut-homing specificity on T cells. Immunity 21:527–538

    Article  PubMed  CAS  Google Scholar 

  107. Carroll MW, Overwijk WW, Surman DR, Tsung K, Moss B, Restifo NP (1998) Construction and characterization of a triple-recombinant vaccinia virus encoding B7-1, interleukin 12, and a model tumor antigen. J Natl Cancer Inst 90:1881–1887

    Article  PubMed  CAS  Google Scholar 

  108. Vignali D (2008) How many mechanisms do regulatory T cells need? Eur J Immunol 38:908–911

    Article  PubMed  CAS  Google Scholar 

  109. Tang Q, Bluestone JA (2008) The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol 9:239–244

    Article  PubMed  CAS  Google Scholar 

  110. Sojka DK, Huang YH, Fowell DJ (2008) Mechanisms of regulatory T-cell suppression - a diverse arsenal for a moving target. Immunology 124:13–22

    Article  PubMed  CAS  Google Scholar 

  111. Gondek DC, Lu LF, Quezada SA, Sakaguchi S, Noelle RJ (2005) Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J Immunol 174:1783–1786

    PubMed  CAS  Google Scholar 

  112. Cao X, Cai SF, Fehniger TA, Song J, Collins LI, Piwnica-Worms DR, Ley TJ (2007) Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 27:635–646

    Article  PubMed  CAS  Google Scholar 

  113. Mellor AL, Munn DH (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4:762–774

    Article  PubMed  CAS  Google Scholar 

  114. Mottet C, Uhlig HH, Powrie F (2003) Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol 170:3939–3943

    PubMed  CAS  Google Scholar 

  115. Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, Cross R, Sehy D, Blumberg RS, Vignali DA (2007) The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450:566–569

    Article  PubMed  CAS  Google Scholar 

  116. Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W (1993) Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75:263–274

    Article  PubMed  CAS  Google Scholar 

  117. Powrie F, Correa-Oliveira R, Mauze S, Coffman RL (1994) Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity. J Exp Med 179:589–600

    Article  PubMed  CAS  Google Scholar 

  118. Asseman C, Mauze S, Leach MW, Coffman RL, Powrie F (1999) An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 190:995–1004

    Article  PubMed  CAS  Google Scholar 

  119. Asseman C, Read S, Powrie F (2003) Colitogenic Th1 cells are present in the antigen-experienced T cell pool in normal mice: control by CD4+ regulatory T cells and IL-10. J Immunol 171:971–978

    PubMed  CAS  Google Scholar 

  120. Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X, Treuting P, Siewe L, Roers A, Henderson WR Jr, Muller W, Rudensky AY (2008) Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28:546–558

    Article  PubMed  CAS  Google Scholar 

  121. Uhlig HH, Coombes J, Mottet C, Izcue A, Thompson C, Fanger A, Tannapfel A, Fontenot JD, Ramsdell F, Powrie F (2006) Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J Immunol 177:5852–5860

    PubMed  CAS  Google Scholar 

  122. Hvas CL, Kelsen J, Agnholt J, Hollsberg P, Tvede M, Moller JK, Dahlerup JF (2007) Crohn’s disease intestinal CD4+ T cells have impaired interleukin-10 production which is not restored by probiotic bacteria. Scand J Gastroenterol 42:592–601

    Article  PubMed  CAS  Google Scholar 

  123. Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlsson S (1993) Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA 90:770–774

    Article  PubMed  CAS  Google Scholar 

  124. Fahlen L, Read S, Gorelik L, Hurst SD, Coffman RL, Flavell RA, Powrie F (2005) T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells. J Exp Med 201:737–746

    Article  PubMed  CAS  Google Scholar 

  125. Powrie F, Carlino J, Leach MW, Mauze S, Coffman RL (1996) A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J Exp Med 183:2669–2674

    Article  PubMed  CAS  Google Scholar 

  126. Oida T, Zhang X, Goto M, Hachimura S, Totsuka M, Kaminogawa S, Weiner HL (2003) CD4+CD25- T cells that express latency-associated peptide on the surface suppress CD4+CD45RBhigh-induced colitis by a TGF-beta-dependent mechanism. J Immunol 170:2516–2522

    PubMed  CAS  Google Scholar 

  127. Kullberg MC, Hay V, Cheever AW, Mamura M, Sher A, Letterio JJ, Shevach EM, Piccirillo CA (2005) TGF-beta1 production by CD4+ CD25+ regulatory T cells is not essential for suppression of intestinal inflammation. Eur J Immunol 35:2886–2895

    Article  PubMed  CAS  Google Scholar 

  128. Kang SG, Lim HW, Andrisani OM, Broxmeyer HE, Kim CH (2007) Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells. J Immunol 179:3724–3733

    PubMed  CAS  Google Scholar 

  129. Collison LW, Pillai MR, Chaturvedi V, Vignali DAA (2009) Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner. J Immunol (in press)

  130. Bardel E, Larousserie F, Charlot-Rabiega P, Coulomb-L’Hermine A, Devergne O (2008) Human CD4+ CD25+ Foxp3+ regulatory T cells do not constitutively express IL-35. J Immunol 181:6898–6905

    PubMed  CAS  Google Scholar 

  131. Lewkowich IP, Herman NS, Schleifer KW, Dance MP, Chen BL, Dienger KM, Sproles AA, Shah JS, Kohl J, Belkaid Y, Wills-Karp M (2005) CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J Exp Med 202:1549–1561

    Article  PubMed  CAS  Google Scholar 

  132. Ling EM, Smith T, Nguyen XD, Pridgeon C, Dallman M, Arbery J, Carr VA, Robinson DS (2004) Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 363:608–615

    Article  PubMed  CAS  Google Scholar 

  133. Ou LS, Goleva E, Hall C, Leung DY (2004) T regulatory cells in atopic dermatitis and subversion of their activity by superantigens. J Allergy Clin Immunol 113:756–763

    Article  PubMed  CAS  Google Scholar 

  134. Hartl D, Koller B, Mehlhorn AT, Reinhardt D, Nicolai T, Schendel DJ, Griese M, Krauss-Etschmann S (2007) Quantitative and functional impairment of pulmonary CD4+CD25hi regulatory T cells in pediatric asthma. J Allergy Clin Immunol 119:1258–1266

    Article  PubMed  CAS  Google Scholar 

  135. Akdis CA, Blesken T, Akdis M, Wuthrich B, Blaser K (1998) Role of interleukin 10 in specific immunotherapy. J Clin Invest 102:98–106

    Article  PubMed  CAS  Google Scholar 

  136. Kearley J, Barker JE, Robinson DS, Lloyd CM (2005) Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent. J Exp Med 202:1539–1547

    Article  PubMed  CAS  Google Scholar 

  137. Ostroukhova M, Seguin-Devaux C, Oriss TB, Dixon-McCarthy B, Yang L, Ameredes BT, Corcoran TE, Ray A (2004) Tolerance induced by inhaled antigen involves CD4(+) T cells expressing membrane-bound TGF-beta and FOXP3. J Clin Invest 114:28–38

    PubMed  CAS  Google Scholar 

  138. 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 

  139. Oh JW, Seroogy CM, Meyer EH, Akbari O, Berry G, Fathman CG, Dekruyff RH, Umetsu DT (2002) CD4 T-helper cells engineered to produce IL-10 prevent allergen-induced airway hyperreactivity and inflammation. J Allergy Clin Immunol 110:460–468

    Article  PubMed  CAS  Google Scholar 

  140. Hansen G, McIntire JJ, Yeung VP, Berry G, Thorbecke GJ, Chen L, DeKruyff RH, Umetsu DT (2000) CD4(+) T helper cells engineered to produce latent TGF-beta1 reverse allergen-induced airway hyperreactivity and inflammation. J Clin Invest 105:61–70

    Article  PubMed  CAS  Google Scholar 

  141. Presser K, Schwinge D, Wegmann M, Huber S, Schmitt S, Quaas A, Maxeiner JH, Finotto S, Lohse AW, Blessing M, Schramm C (2008) Coexpression of TGF-beta1 and IL-10 enables regulatory T cells to completely suppress airway hyperreactivity. J Immunol 181:7751–7758

    PubMed  CAS  Google Scholar 

  142. Meiler F, Zumkehr J, Klunker S, Ruckert B, Akdis CA, Akdis M (2008) In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure. J Exp Med 205:2887–2898

    Article  PubMed  CAS  Google Scholar 

  143. Meiler F, Klunker S, Zimmermann M, Akdis CA, Akdis M (2008) Distinct regulation of IgE, IgG4 and IgA by T regulatory cells and toll-like receptors. Allergy 63:1455–1463

    Article  PubMed  CAS  Google Scholar 

  144. Wilson MS, Pesce JT, Ramalingam TR, Thompson RW, Cheever A, Wynn TA (2008) Suppression of murine allergic airway disease by IL-2:anti-IL-2 monoclonal antibody-induced regulatory T cells. J Immunol 181:6942–6954

    PubMed  CAS  Google Scholar 

  145. Boyman O, Surh CD, Sprent J (2006) Potential use of IL-2/anti-IL-2 antibody immune complexes for the treatment of cancer and autoimmune disease. Expert Opin Biol Ther 6:1323–1331

    Article  PubMed  CAS  Google Scholar 

  146. Bach JF, Chatenoud L (2001) Tolerance to islet autoantigens in type 1 diabetes. Annu Rev Immunol 19:131–161

    Article  PubMed  CAS  Google Scholar 

  147. You S, Alyanakian MA, Segovia B, Damotte D, Bluestone J, Bach JF, Chatenoud L (2008) Immunoregulatory pathways controlling progression of autoimmunity in NOD mice. Ann NY Acad Sci 1150:300–310

    Article  PubMed  CAS  Google Scholar 

  148. Wu AJ, Hua H, Munson SH, McDevitt HO (2002) Tumor necrosis factor-alpha regulation of CD4+CD25+ T cell levels in NOD mice. Proc Natl Acad Sci USA 99:12287–12292

    Article  PubMed  CAS  Google Scholar 

  149. Szanya V, Ermann J, Taylor C, Holness C, Fathman CG (2002) The subpopulation of CD4+CD25+ splenocytes that delays adoptive transfer of diabetes expresses L-selectin and high levels of CCR7. J Immunol 169:2461–2465

    PubMed  CAS  Google Scholar 

  150. You S, Belghith M, Cobbold S, Alyanakian MA, Gouarin C, Barriot S, Garcia C, Waldmann H, Bach JF, Chatenoud L (2005) Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T-cells. Diabetes 54:1415–1422

    Article  PubMed  CAS  Google Scholar 

  151. Lawson JM, Tremble J, Dayan C, Beyan H, Leslie RD, Peakman M, Tree TI (2008) Increased resistance to CD4+CD25hi regulatory T cell-mediated suppression in patients with type 1 diabetes. Clin Exp Immunol 154:353–359

    Article  PubMed  CAS  Google Scholar 

  152. You S, Leforban B, Garcia C, Bach JF, Bluestone JA, Chatenoud L (2007) Adaptive TGF-beta-dependent regulatory T cells control autoimmune diabetes and are a privileged target of anti-CD3 antibody treatment. Proc Natl Acad Sci USA 104:6335–6340

    Article  PubMed  CAS  Google Scholar 

  153. Billiard F, Litvinova E, Saadoun D, Djelti F, Klatzmann D, Cohen JL, Marodon G, Salomon BL (2006) Regulatory and effector T cell activation levels are prime determinants of in vivo immune regulation. J Immunol 177:2167–2174

    PubMed  CAS  Google Scholar 

  154. Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM (2004) CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 199:1467–1477

    Article  PubMed  CAS  Google Scholar 

  155. Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12:431–440

    Article  PubMed  CAS  Google Scholar 

  156. Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA, Bluestone JA (2002) Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 346:1692–1698

    Article  PubMed  CAS  Google Scholar 

  157. Herold KC, Gitelman SE, Masharani U, Hagopian W, Bisikirska B, Donaldson D, Rother K, Diamond B, Harlan DM, Bluestone JA (2005) A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 54:1763–1769

    Article  PubMed  CAS  Google Scholar 

  158. Battaglia M, Stabilini A, Draghici E, Migliavacca B, Gregori S, Bonifacio E, Roncarolo MG (2006) Induction of tolerance in type 1 diabetes via both CD4+CD25+ T regulatory cells and T regulatory type 1 cells. Diabetes 55:1571–1580

    Article  PubMed  CAS  Google Scholar 

  159. Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, Masteller EL, McDevitt H, Bonyhadi M, Bluestone JA (2004) In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 199:1455–1465

    Article  PubMed  CAS  Google Scholar 

  160. McFarland HF, Martin R (2007) Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 8:913–919

    Article  PubMed  CAS  Google Scholar 

  161. 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 

  162. Haas J, Hug A, Viehover A, Fritzsching B, Falk CS, Filser A, Vetter T, Milkova L, Korporal M, Fritz B, Storch-Hagenlocher B, Krammer PH, Suri-Payer E, Wildemann B (2005) Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. Eur J Immunol 35:3343–3352

    Article  PubMed  CAS  Google Scholar 

  163. Venken K, Hellings N, Hensen K, Rummens JL, Medaer R, D’Hooghe M, Dubois B, Raus J, Stinissen P (2006) Secondary progressive in contrast to relapsing-remitting multiple sclerosis patients show a normal CD4+CD25+ regulatory T-cell function and FOXP3 expression. J Neurosci Res 83:1432–1446

    Article  PubMed  CAS  Google Scholar 

  164. Huan J, Culbertson N, Spencer L, Bartholomew R, Burrows GG, Chou YK, Bourdette D, Ziegler SF, Offner H, Vandenbark AA (2005) Decreased FOXP3 levels in multiple sclerosis patients. J Neurosci Res 81:45–52

    Article  PubMed  CAS  Google Scholar 

  165. McGeachy MJ, Stephens LA, Anderton SM (2005) Natural recovery and protection from autoimmune encephalomyelitis: contribution of CD4+CD25+ regulatory cells within the central nervous system. J Immunol 175:3025–3032

    PubMed  CAS  Google Scholar 

  166. Zhang X, Koldzic DN, Izikson L, Reddy J, Nazareno RF, Sakaguchi S, Kuchroo VK, Weiner HL (2004) IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells. Int Immunol 16:249–256

    Article  PubMed  CAS  Google Scholar 

  167. Spach KM, Nashold FE, Dittel BN, Hayes CE (2006) IL-10 signaling is essential for 1,25-dihydroxyvitamin D3-mediated inhibition of experimental autoimmune encephalomyelitis. J Immunol 177:6030–6037

    PubMed  CAS  Google Scholar 

  168. Korn T, Reddy J, Gao W, Bettelli E, Awasthi A, Petersen TR, Backstrom BT, Sobel RA, Wucherpfennig KW, Strom TB, Oukka M, Kuchroo VK (2007) Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat Med 13:423–431

    Article  PubMed  CAS  Google Scholar 

  169. Liu GZ, Gomes AC, Putheti P, Karrenbauer V, Kostulas K, Press R, Hillert J, Hjelmstrom P, Gao XG (2006) Increased soluble 4-1BB ligand (4-1BBL) levels in peripheral blood of patients with multiple sclerosis. Scand J Immunol 64:412–419

    Article  PubMed  CAS  Google Scholar 

  170. Zhang X, Reddy J, Ochi H, Frenkel D, Kuchroo VK, Weiner HL (2006) Recovery from experimental allergic encephalomyelitis is TGF-beta dependent and associated with increases in CD4+LAP+ and CD4+CD25+ T cells. Int Immunol 18:495–503

    Article  PubMed  CAS  Google Scholar 

  171. Chen ML, Yan BS, Bando Y, Kuchroo VK, Weiner HL (2008) Latency-associated peptide identifies a novel CD4+CD25+ regulatory T cell subset with TGFbeta-mediated function and enhanced suppression of experimental autoimmune encephalomyelitis. J Immunol 180:7327–7337

    PubMed  CAS  Google Scholar 

  172. Mekala DJ, Alli RS, Geiger TL (2005) IL-10-dependent suppression of experimental allergic encephalomyelitis by Th2-differentiated, anti-TCR redirected T lymphocytes. J Immunol 174:3789–3797

    PubMed  CAS  Google Scholar 

  173. 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 

  174. Yang ZZ, Novak AJ, Stenson MJ, Witzig TE, Ansell SM (2006) Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. Blood 107:3639–3646

    Article  PubMed  CAS  Google Scholar 

  175. Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, Rubin SC, Kaiser LR, June CH (2001) Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 61:4766–4772

    PubMed  CAS  Google Scholar 

  176. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (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 

  177. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen YT, Ohtani H, Old LJ, Odunsi K (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102:18538–18543

    Article  PubMed  CAS  Google Scholar 

  178. Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, Linehan DC (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169:2756–2761

    PubMed  CAS  Google Scholar 

  179. Kawaida H, Kono K, Takahashi A, Sugai H, Mimura K, Miyagawa N, Omata H, Ooi A, Fujii H (2005) Distribution of CD4+CD25high regulatory T-cells in tumor-draining lymph nodes in patients with gastric cancer. J Surg Res 124:151–157

    Article  PubMed  CAS  Google Scholar 

  180. 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 

  181. Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F (2005) Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res 65:2457–2464

    Article  PubMed  CAS  Google Scholar 

  182. Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B (2008) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 14:8228–8235

    Google Scholar 

  183. Carreras J, Lopez-Guillermo A, Fox BC, Colomo L, Martinez A, Roncador G, Montserrat E, Campo E, Banham AH (2006) High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood 108:2957–2964

    Article  PubMed  CAS  Google Scholar 

  184. Alvaro T, Lejeune M, Salvado MT, Bosch R, Garcia JF, Jaen J, Banham AH, Roncador G, Montalban C, Piris MA (2005) Outcome in Hodgkin’s lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res 11:1467–1473

    Article  PubMed  Google Scholar 

  185. Morgan ME, van Bilsen JH, Bakker AM, Heemskerk B, Schilham MW, Hartgers FC, Elferink BG, van der ZL, de Vries RR, Huizinga TW, Ottenhoff TH, Toes RE (2005) Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans. Hum Immunol 66:13–20

    Article  PubMed  CAS  Google Scholar 

  186. Allan SE, Crome SQ, Crellin NK, Passerini L, Steiner TS, Bacchetta R, Roncarolo MG, Levings MK (2007) Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol 19:345–354

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  188. Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E (1999) Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 59:3128–3133

    PubMed  CAS  Google Scholar 

  189. Shimizu J, Yamazaki S, Sakaguchi S (1999) Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163:5211–5218

    PubMed  CAS  Google Scholar 

  190. Ghiringhelli F, Menard C, Terme M, Flament C, Taieb J, Chaput N, Puig PE, Novault S, Escudier B, Vivier E, Lecesne A, Robert C, Blay JY, Bernard J, Caillat-Zucman S, Freitas A, Tursz T, Wagner-Ballon O, Capron C, Vainchencker W, Martin F, Zitvogel L (2005) CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J Exp Med 202:1075–1085

    Article  PubMed  CAS  Google Scholar 

  191. Gil-Guerrero L, Dotor J, Huibregtse IL, Casares N, Lopez-Vazquez AB, Rudilla F, Riezu-Boj JI, Lopez-Sagaseta J, Hermida J, Van DS, Bezunartea J, Llopiz D, Sarobe P, Prieto J, Borras-Cuesta F, Lasarte JJ (2008) In vitro and in vivo down-regulation of regulatory T cell activity with a peptide inhibitor of TGF-beta1. J Immunol 181:126–135

    PubMed  CAS  Google Scholar 

  192. Loser K, Apelt J, Voskort M, Mohaupt M, Balkow S, Schwarz T, Grabbe S, Beissert S (2007) IL-10 controls ultraviolet-induced carcinogenesis in mice. J Immunol 179:365–371

    PubMed  CAS  Google Scholar 

  193. Strauss L, Bergmann C, Szczepanski M, Gooding W, Johnson JT, Whiteside TL (2007) A unique subset of CD4+CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth factor-beta1 mediates suppression in the tumor microenvironment. Clin Cancer Res 13:4345–4354

    Article  PubMed  CAS  Google Scholar 

  194. Kryczek I, Wei S, Zou L, Zhu G, Mottram P, Xu H, Chen L, Zou W (2006) Cutting edge: induction of B7-H4 on APCs through IL-10: novel suppressive mode for regulatory T cells. J Immunol 177:40–44

    PubMed  CAS  Google Scholar 

  195. Kryczek I, Zou L, Rodriguez P, Zhu G, Wei S, Mottram P, Brumlik M, Cheng P, Curiel T, Myers L, Lackner A, Alvarez X, Ochoa A, Chen L, Zou W (2006) B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med 203:871–881

    Article  PubMed  CAS  Google Scholar 

  196. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322:271–275

    Article  PubMed  CAS  Google Scholar 

  197. Fallarino F, sselin-Paturel C, Vacca C, Bianchi R, Gizzi S, Fioretti MC, Trinchieri G, Grohmann U, Puccetti P (2004) Murine plasmacytoid dendritic cells initiate the immunosuppressive pathway of tryptophan catabolism in response to CD200 receptor engagement. J Immunol 173:3748–3754

    PubMed  CAS  Google Scholar 

  198. Sharma MD, Baban B, Chandler P, Hou DY, Singh N, Yagita H, Azuma M, Blazar BR, Mellor AL, Munn DH (2007) Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest 117:2570–2582

    Article  PubMed  CAS  Google Scholar 

  199. Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, Belladonna ML, Fioretti MC, Alegre ML, Puccetti P (2003) Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 4:1206–1212

    Article  PubMed  CAS  Google Scholar 

  200. Belkaid Y, Rouse BT (2005) Natural regulatory T cells in infectious disease. Nat Immunol 6:353–360

    Article  PubMed  CAS  Google Scholar 

  201. 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 

  202. Hisaeda H, Maekawa Y, Iwakawa D, Okada H, Himeno K, Kishihara K, Tsukumo S, Yasutomo K (2004) Escape of malaria parasites from host immunity requires CD4+ CD25+ regulatory T cells. Nat Med 10:29–30

    Article  PubMed  CAS  Google Scholar 

  203. Netea MG, Sutmuller R, Hermann C, Van der Graaf CA, Van der Meer JW, van Krieken JH, Hartung T, Adema G, Kullberg BJ (2004) Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells. J Immunol 172:3712–3718

    PubMed  CAS  Google Scholar 

  204. Kursar M, Bonhagen K, Fensterle J, Kohler A, Hurwitz R, Kamradt T, Kaufmann SH, Mittrucker HW (2002) Regulatory CD4+CD25+ T cells restrict memory CD8+ T cell responses. J Exp Med 196:1585–1592

    Article  PubMed  CAS  Google Scholar 

  205. Kursar M, Koch M, Mittrucker HW, Nouailles G, Bonhagen K, Kamradt T, Kaufmann SH (2007) Cutting edge: regulatory T cells prevent efficient clearance of Mycobacterium tuberculosis. J Immunol 178:2661–2665

    PubMed  CAS  Google Scholar 

  206. Guyot-Revol V, Innes JA, Hackforth S, Hinks T, Lalvani A (2006) Regulatory T cells are expanded in blood and disease sites in patients with tuberculosis. Am J Respir Crit Care Med 173:803–810

    Article  PubMed  CAS  Google Scholar 

  207. Suvas S, Kumaraguru U, Pack CD, Lee S, Rouse BT (2003) CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses. J Exp Med 198:889–901

    Article  PubMed  CAS  Google Scholar 

  208. Suvas S, Azkur AK, Kim BS, Kumaraguru U, Rouse BT (2004) CD4+CD25+ regulatory T cells control the severity of viral immunoinflammatory lesions. J Immunol 172:4123–4132

    PubMed  CAS  Google Scholar 

  209. Cabrera R, Tu Z, Xu Y, Firpi RJ, Rosen HR, Liu C, Nelson DR (2004) An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection. Hepatology 40:1062–1071

    Article  PubMed  CAS  Google Scholar 

  210. Stoop JN, van der Molen RG, Baan CC, van der Laan LJ, Kuipers EJ, Kusters JG, Janssen HL (2005) Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology 41:771–778

    Article  PubMed  CAS  Google Scholar 

  211. 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 

  212. Kinter AL, Hennessey M, Bell A, Kern S, Lin Y, Daucher M, Planta M, McGlaughlin M, Jackson R, Ziegler SF, Fauci AS (2004) CD25(+)CD4(+) regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals regulate CD4(+) and CD8(+) HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status. J Exp Med 200:331–343

    Article  PubMed  CAS  Google Scholar 

  213. Weiss L, Donkova-Petrini V, Caccavelli L, Balbo M, Carbonneil C, Levy Y (2004) Human immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients. Blood 104:3249–3256

    Article  PubMed  CAS  Google Scholar 

  214. Scott-Browne JP, Shafiani S, Tucker-Heard G, Ishida-Tsubota K, Fontenot JD, Rudensky AY, Bevan MJ, Urdahl KB (2007) Expansion and function of Foxp3-expressing T regulatory cells during tuberculosis. J Exp Med 204:2159–2169

    Article  PubMed  CAS  Google Scholar 

  215. Lund JM, Hsing L, Pham TT, Rudensky AY (2008) Coordination of early protective immunity to viral infection by regulatory T cells. Science 320:1220–1224

    Article  PubMed  CAS  Google Scholar 

  216. Belkaid Y (2008) Role of Foxp3-positive regulatory T cells during infection. Eur J Immunol 38:918–921

    Article  PubMed  CAS  Google Scholar 

  217. Anderson CF, Oukka M, Kuchroo VJ, Sacks D (2007) CD4(+)CD25(−)Foxp3(−) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J Exp Med 204:285–297

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-3678, USA

    Creg J. Workman, Andrea L. Szymczak-Workman, Lauren W. Collison, Meenu R. Pillai & Dario A. A. Vignali

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  1. Creg J. Workman
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  2. Andrea L. Szymczak-Workman
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  3. Lauren W. Collison
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  4. Meenu R. Pillai
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  5. Dario A. A. Vignali
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Correspondence to Dario A. A. Vignali.

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C. J. Workman, A. L. Szymczak-Workman, L. W. Collison, and M. R. Pillai contributed equally.

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Workman, C.J., Szymczak-Workman, A.L., Collison, L.W. et al. The development and function of regulatory T cells. Cell. Mol. Life Sci. 66, 2603–2622 (2009). https://doi.org/10.1007/s00018-009-0026-2

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  • DOI: https://doi.org/10.1007/s00018-009-0026-2

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