IMMUNE NETWORK

The Korean Association of Immunobiologists (대한면역학회)
권호 표지

Peripheral Generation of $CD4^+CD25^+Foxp3^+$ Regulatory T Cells

  • Kim, Byung-Seok (Laboratory of Immunology, Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University) ;
  • Park, Young-Jun (Laboratory of Immunology, Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University) ;
  • Kang, Chang-Yuil (Laboratory of Immunology, Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University)
  • Published : 2007.03.30
Download PDF
⟨ Previous Next ⟩

Abstract

[ $CD4^+CD25^+$ ] regulatory T cells (Tregs) expressing the lineage-specific marker Foxp3 represent an important regulatory T cell that is essential for maintaining peripheral tolerance. Although it was believed that Treg development is solely dependent on the thymus, accumulating evidence demonstrates that Tregs can also be induced in the periphery. Considering the various origins of peripherally developed $CD4^+CD25^+Foxp3^+$ regulatory T cells, it seems likely that multiple factors are involved in the peripheral generation of Tregs.

Keywords

References

  1. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M: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, 1995
  2. Sakaguchi S: Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22;531-562, 2004 https://doi.org/10.1146/annurev.immunol.21.120601.141122
  3. Kappler JW, Roehm N, Marrack P: T cell tolerance by clonal elimination in the thymus. Cell 49;273-280, 1987 https://doi.org/10.1016/0092-8674(87)90568-X
  4. Jones LA, Chin LT, Longo DL, Kruisbeek AM: Peripheral clonal elimination of functional T cells. Science 250;1726-1729, 1990 https://doi.org/10.1126/science.2125368
  5. Webb S, Morris C, Sprent J: Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity. Cell 63;1249-1256, 1990 https://doi.org/10.1016/0092-8674(90)90420-J
  6. van Parijs L, Perez VL, Abbas AK: Mechanisms of peripheral T cell tolerance. Novartis Found Symp 215;5-14, 1998
  7. Lechler R, Chai JG, Marelli-Berg F, Lombardi G: The contributions of T-cell anergy to peripheral T-cell tolerance. Immunology 103;262-269, 2001 https://doi.org/10.1046/j.1365-2567.2001.01250.x
  8. Miller JFAP, Heath WR: Self-ignorance in the peripheral T-cell pool. Immunol Rev 133;131-150, 1993 https://doi.org/10.1111/j.1600-065X.1993.tb01514.x
  9. Oliveira V, Agua-Doce A, Duarte J, Soares MP, Graca L: Regulatory T cell maintenance of dominant tolerance: induction of tissue self-defense? Transpl Immunol 17;7-10, 2006 https://doi.org/10.1016/j.trim.2006.09.028
  10. Coutinho A, Hori S, Carvalho T, Caramalho I, Demengeot J: Regulatory T cells: the physiology of autoreactivity in dominant tolerance and 'quality control' of immune responses. Immunol Rev 182;89-98, 2001 https://doi.org/10.1034/j.1600-065X.2001.1820107.x
  11. Groux H, O'Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG: A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389;737-742, 1997 https://doi.org/10.1038/39614
  12. Chen Y, Kuchroo VK, Inobe J, Hafler DA, Weiner HL: Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265; 1237-1240, 1994 https://doi.org/10.1126/science.7520605
  13. Zou W: Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6;295-307, 2006 https://doi.org/10.1038/nri1806
  14. Piccirillo CA, Thornton AM: Cornerstone of peripheral tolerance: naturally occurring CD4+ CD25+ regulatory T cells. Trends Immunol 25;374-380, 2004 https://doi.org/10.1016/j.it.2004.04.009
  15. Piccirillo CA, Shevach EM: Naturally-occurring CD4+ CD25+ immunoregulatory T cells: central players in the arena of peripheral tolerance. Semin Immunol 16;81-88, 2004 https://doi.org/10.1016/j.smim.2003.12.003
  16. Nishizuka Y, Sakakura T: Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 166;753-755, 1969 https://doi.org/10.1126/science.166.3906.753
  17. Wing K, Suri-Payer E, Rudin A: CD4+ CD25+-regulatory T cells from mouse to man. Scand J Immunol 62;1-15, 2005
  18. Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science 299;1057-1061, 2003 https://doi.org/10.1126/science.1079490
  19. Fontenot JD, Gavin MA, Rudensky AY: Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat Immunol 4;330-336, 2003 https://doi.org/10.1038/ni904
  20. Shevach EM: CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2;389-400, 2002 https://doi.org/10.1038/nrc801
  21. Mills KH: Regulatory T cells: friend or foe in immunity to infection? Nat Rev Immunol 4;841-855, 2004 https://doi.org/10.1038/nri1485
  22. Wood KJ, Sakaguchi S: Regulatory T cells in transplantation tolerance. Nature Reviews Immunology 3;199-210, 2003 https://doi.org/10.1038/nri1027
  23. Liston A, Rudensky AY: Thymic development and peripheral homeostasis of regulatory T cells. Curr Opin Immunol 19;176-185, 2007 https://doi.org/10.1016/j.coi.2007.02.005
  24. Pacholczyk R, Ignatowicz H, Kraj P, Ignatowicz L: Origin and T cell receptor diversity of Foxp3^+ CD4+ CD25+ T cells. Immunity 25;249-259, 2006 https://doi.org/10.1016/j.immuni.2006.05.016
  25. Asano M, Toda M, Sakaguchi N, Sakaguchi S: Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 184;387-396, 1996 https://doi.org/10.1084/jem.184.2.387
  26. Itoh M, Takahashi T, Sakaguchi N, Kuniyasu Y, Shimizu J, Otsuka F, Sakaguchi S: 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;5317-5326, 1999
  27. Cosmi L, Liotta F, Lazzeri E, Francalanci M, Angeli R, Mazzinghi B, Santarlasci V, Manetti R, Vanini V, Romagnani P, Maggi E, Romagnani S, Annunziato F: Human CD8+ CD25+ thymocytes share phenotypic and functional features with CD4+ CD25+ regulatory thymocytes. Blood 102; 4107-4114, 2003 https://doi.org/10.1182/blood-2003-04-1320
  28. Wing K, Ekmark A, Karlsson H, Rudin A, Suri-Payer E: Characterization of human CD25+ CD4+ T cells in thymus, cord and adult blood. Immunology 106;190-199, 2002 https://doi.org/10.1046/j.1365-2567.2002.01412.x
  29. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY: Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22;329- 341, 2005 https://doi.org/10.1016/j.immuni.2005.01.016
  30. Akbar AN, Taams LS, Salmon M, Vukmanovic-Stejic M: The peripheral generation of CD4+ CD25+ regulatory T cells. Immunology 109;319-325, 2003 https://doi.org/10.1046/j.1365-2567.2003.01678.x
  31. Bluestone JA, Abbas AK: Natural versus adaptive regulatory T cells. Nat Rev Immunol 3;253-257, 2003 https://doi.org/10.1038/nri1032
  32. Taams LS, Akbar AN: Peripheral generation and function of CD4+ CD25+ regulatory T cells. Curr Top Microbiol Immunol 293;115-131, 2005 https://doi.org/10.1007/3-540-27702-1_6
  33. Lohr J, Knoechel B, Abbas AK: Regulatory T cells in the periphery. Immunol Rev 212;149-162, 2006 https://doi.org/10.1111/j.0105-2896.2006.00414.x
  34. Akbar AN, Vukmanovic-Stejic M, Taams LS, Macallan DC: The dynamic co-evolution of memory and regulatory CD4+ T cells in the periphery. Nat Rev Immunol 7;231-237, 2007 https://doi.org/10.1038/nri2037
  35. Thorstenson KM, Khoruts A: Generation of anergic and potentially immunoregulatory CD25+ CD4 T cells in vivo after induction of peripheral tolerance with intravenous or oral antigen. J Immunol 167;188-195, 2001 https://doi.org/10.4049/jimmunol.167.1.188
  36. Apostolou I, von Boehmer H: In vivo instruction of suppressor commitment in naive T cells. J Exp Med 199;1401-1408, 2004 https://doi.org/10.1084/jem.20040249
  37. Curotto de Lafaille MA, Lino AC, Kutchukhidze N, Lafaille JJ: CD25- T cells generate CD25+ Foxp3+ regulatory T cells by peripheral expansion. J Immunol 173;7259-7268, 2004 https://doi.org/10.4049/jimmunol.173.12.7259
  38. Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H: Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 6;1219-1227, 2005 https://doi.org/10.1038/ni1265
  39. Laurie KL, Van Driel IR, Gleeson PA: The role of CD4+ CD25+ immunoregulatory T cells in the induction of autoimmune gastritis. Immunol Cell Biol 80;567-573, 2002 https://doi.org/10.1046/j.1440-1711.2002.01127.x
  40. Knoechel B, Lohr J, Kahn E, Bluestone JA, Abbas AK: Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen. J Exp Med 202;1375-1386, 2005 https://doi.org/10.1084/jem.20050855
  41. Liang S, Alard P, Zhao Y, Parnell S, Clark SL, Kosiewicz MM: Conversion of CD4+ CD25- cells into CD4+ CD25+ regulatory T cells in vivo requires B7 costimulation, but not the thymus. J Exp Med 201;127-137, 2005 https://doi.org/10.1084/jem.20041201
  42. Zelenay S, Lopes-Carvalho T, Caramalho I, Moraes-Fontes MF, Rebelo M, Demengeot J: Foxp3+ CD25- CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion. Proc Natl Acad Sci USA 102;4091-4096, 2005
  43. Almeida ARM, Zaragoza B, Freitas AA: Competition controls the rate of transition between the peripheral pools of CD4+CD25- and CD4+CD25+ T cells. Int Immunol 18;1607-1613, 2006 https://doi.org/10.1093/intimm/dxl093
  44. Zhou G, Levitsky HI: Natural regulatory T cells and de novo-induced regulatory T cells contribute independently to tumor-specific tolerance. J Immunol 178;2155-2162, 2007 https://doi.org/10.4049/jimmunol.178.4.2155
  45. Karim M, Kingsley CI, Bushell AR, Sawitzki BS, Wood KJ: Alloantigen-induced CD25+ CD4+ regulatory T cells can develop in vivo from CD25- CD4+ precursors in a thymus-independent process. J Immunol 172;923-928, 2004 https://doi.org/10.4049/jimmunol.172.2.923
  46. Valzasina B, Piconese S, Guiducci C, Colombo MP: Tumorinduced expansion of regulatory T cells by conversion of CD4+ CD25- lymphocytes is thymus and proliferation independent. Cancer Res 66;4488-4495, 2006 https://doi.org/10.1158/0008-5472.CAN-05-4217
  47. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM: 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, 2003 https://doi.org/10.1084/jem.20030152
  48. Walker MR, Kasprowicz DJ, Gersuk VH, Benard A, Van Landeghen M, Buckner JH, Ziegler SF: Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25- T cells. J Clin Invest 112;1437-1443, 2003 https://doi.org/10.1172/JCI19441
  49. Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF: 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, 2004 https://doi.org/10.4049/jimmunol.172.9.5149
  50. Park HB, Paik DJ, Jang E, Hong S, Youn J: Acquisition of anergic and suppressive activities in transforming growth factor-beta-costimulated CD4+CD25- T cells. Int Immunol 16;1203-1213, 2004 https://doi.org/10.1093/intimm/dxh123
  51. Zheng SG, Wang JH, Gray JD, Soucier H, Horwitz DA: Natural and induced CD4+CD25+ cells educate CD4+CD25- cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10. J Immunol 172;5213-5221, 2004 https://doi.org/10.4049/jimmunol.172.9.5213
  52. Skapenko A, Kalden JR, Lipsky PE, Schulze-Koops H: 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, 2005 https://doi.org/10.4049/jimmunol.175.9.6107
  53. Walker MR, Carson BD, Nepom GT, Ziegler SF, Buckner JH: De novo generation of antigen-specific CD4+CD25+ regulatory T cells from human CD4+CD25- cells. Proc Natl Acad Sci USA 102;4103-4108, 2005
  54. Wang Z, Hong J, Sun W, Xu G, Li N, Chen X, Liu A, Xu L, Sun B, Zhang JZ: Role of IFN-{gamma} in induction of Foxp3 and conversion of CD4+ CD25- T cells to CD4+ Tregs. J Clin Invest 116;2434-2441, 2006
  55. Zheng SG, Wang JH, Stohl W, Kim KS, Gray JD, Horwitz DA: TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J Immunol 176;3321-3329, 2006 https://doi.org/10.4049/jimmunol.176.6.3321
  56. Davidson TS, Dipaolo RJ, Andersson J, Shevach EM: Cutting edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells. J Immunol 178;4022-4026, 2007 https://doi.org/10.4049/jimmunol.178.7.4022
  57. Liu VC, Wong LY, Jang T, Shah AH, Park I, Yang X, Zhang Q, Lonning S, Teicher BA, Lee C: 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;2883-2892, 2007 https://doi.org/10.4049/jimmunol.178.5.2883
  58. Zheng SG, Wang J, Wang P, Gray JD, Horwitz DA: IL-2 is essential for TGF-beta to convert naive CD4+Cd25- Cells to CD25+Foxp3+ Regulatory T Cells and for Expansion of These Cells. J Immunol 178;2018-2027, 2007 https://doi.org/10.4049/jimmunol.178.4.2018
  59. Mucida D, Kutchukhidze N, Erazo A, Russo M, Lafaille JJ, Curotto de Lafaille MA: Oral tolerance in the absence of naturally occurring Tregs. J Clin Invest 115;1923-1933, 2005 https://doi.org/10.1172/JCI24487
  60. Ziegler SF: FOXP3: not just for regulatory T cells anymore. Eur J Immunol 37;21-23, 2007 https://doi.org/10.1002/eji.200636929
  61. Wang J, Ioan-Facsinay A, van der Voort EI, Huizinga TW, Toes RE: Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol 37; 129-138, 2007 https://doi.org/10.1002/eji.200636435
  62. Youssef AR, Shen CR, Lin CL, Barker RN, Elson CJ: IL-4 and IL-10 modulate autoimmune haemolytic anaemia in NZB mice. Clin Exp Immunol 139;84-89, 2005 https://doi.org/10.1111/j.1365-2249.2005.02663.x
  63. Ostlie N, Milani M, Wang W, Okita D, Conti-Fine BM: Absence of IL-4 facilitates the development of chronic autoimmune myasthenia gravis in C57BL/6 mice. J Immunol 170;604-612, 2003 https://doi.org/10.4049/jimmunol.170.1.604
  64. Young DA, Lowe LD, Booth SS, Whitters MJ, Nicholson L, Kuchroo VK, Collins M: IL-4, IL-10, IL-13, and TGF-beta from an altered peptide ligand-specific Th2 cell clone down-regulate adoptive transfer of experimental autoimmune encephalomyelitis. J Immunol 164;3563-3572, 2000 https://doi.org/10.4049/jimmunol.164.7.3563
  65. Willenborg DO, Fordham S, Bernard CC, Cowden WB, Ramshaw IA: IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J Immunol 157;3223-3227, 1996
  66. Krakowski M, Owens T: Interferon-gamma confers resistance to experimental allergic encephalomyelitis. Eur J Immunol 26;1641-1646, 1996 https://doi.org/10.1002/eji.1830260735
  67. Ferber IA, Brocke S, Taylor-Edwards C, Ridgway W, Dinisco C, Steinman L, Dalton D, Fathman CG: Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol 156;5-7, 1996
  68. Setoguchi R, Hori S, Takahashi T, Sakaguchi S: Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 201; 723-735, 2005 https://doi.org/10.1084/jem.20041982
  69. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY: A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6;1142-1151, 2005 https://doi.org/10.1038/ni1263
  70. Zorn E, Nelson EA, Mohseni M, Porcheray F, Kim H, Litsa D, Bellucci R, Raderschall E, Canning C, Soiffer RJ, Frank DA, Ritz J: IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 108;1571-1579, 2006 https://doi.org/10.1182/blood-2006-02-004747
  71. Fehervari Z, Yamaguchi T, Sakaguchi S: The dichotomous role of IL-2: tolerance versus immunity. Trends Immunol 27;109-111, 2006 https://doi.org/10.1016/j.it.2006.01.005
  72. Surh CD, Sprent J, Webb SR: Exclusion of circulating T cells from the thymus does not apply in the neonatal period. J Exp Med 177;379-385, 1993 https://doi.org/10.1084/jem.177.2.379
  73. Jonuleit H, Schmitt E, Kakirman H, Stassen M, Knop J, Enk AH: Infectious tolerance: human CD25+ regulatory T cells convey suppressor activity to conventional CD4+ T helper cells. J Exp Med 196;255-260, 2002 https://doi.org/10.1084/jem.20020394
  74. Wan YY, Flavell RA: Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc Natl Acad Sci USA 102;5126-5131, 2005
  75. Vukmanovic-Stejic M, Zhang Y, Cook JE, Fletcher JM, McQuaid A, Masters JE, Rustin MH, Taams LS, Beverley PC, Macallan DC, Akbar AN: Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo. J Clin Invest 116;2423-2433, 2006 https://doi.org/10.1172/JCI28941
  76. Baecher-Allan C, Hafler DA: Human regulatory T cells and their role in autoimmune disease. Immunol Rev 212;203-216, 2006 https://doi.org/10.1111/j.0105-2896.2006.00417.x
  77. Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, Shimizu J, Takahashi T, Nomura T: Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 212;8-27, 2006 https://doi.org/10.1111/j.0105-2896.2006.00427.x
  78. Wing K, Sakaguchi S: Regulatory T cells as potential immunotherapy in allergy. Curr Opin Allergy Clin Immunol 6; 482-488, 2006 https://doi.org/10.1097/01.all.0000246625.79988.12
  79. Ahern DJ, Robinson DS: Regulatory T cells as a target for induction of immune tolerance in allergy. Curr Opin Allergy Clin Immunol 5;531-536, 2005 https://doi.org/10.1097/01.all.0000191239.20632.ab
  80. Akbari O, Stock P, DeKruyff RH, Umetsu DT: Role of regulatory T cells in allergy and asthma. Curr Opin Immunol 15;627-633, 2003 https://doi.org/10.1016/j.coi.2003.09.012