Regulatory T Cells: History and Perspective

  • Shimon Sakaguchi
Part of the Methods in Molecular Biology book series (MIMB, volume 707)


Despite the skepticism that once prevailed among immunologists, it is now widely accepted that the normal immune system harbors a T-cell population, called regulatory T cells (Treg cells), specialized for immune suppression. It was first shown that depletion of a T-cell subpopulation from normal rodents produced autoimmune disease. Search for a molecular marker specific for such autoimmune-preventive Treg cells has revealed that the majority, if not all, of them constitutively express the CD25 molecule as depletion of CD25+CD4+ T cells spontaneously evokes autoimmune disease in otherwise normal rodents. The expression of CD25 by Treg cells has made it possible to delineate their developmental pathways, in particular their thymic development, and establish simple in vitro assay for assessing their suppressive activity. The marker and the in vitro assay have helped to identify human Treg cells with similar functional and phenotypic characteristics. Recent efforts have shown that natural Treg cells specifically express the transcription factor Foxp3 and that mutations of the Foxp3 gene produce a variety of immunological diseases in humans and rodents. Specific expression of Foxp3 in natural Treg cells has enabled their functional and developmental characterization by genetic approach. These studies altogether have provided firm evidence for Foxp3+CD25+CD4+ Treg cells as an indispensable cellular constituent of the normal immune system for establishing and maintaining immunologic self-tolerance and immune homeostasis. Treg cells are now within the scope of clinical use to treat immunological diseases and control physiological and pathological immune responses.

Key words

Regulatory T cells Suppressor T cells Immunological self-tolerance CD25 Il-2 Foxp3 IPEX 



Antigen-presenting cell


Adult thymectomy


Inflammatory bowel disease


Immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome


Neonatal thymectomy


Type 1 diabetes mellitus


T-cell receptor

Treg cells

Regulatory T cells


  1. 1.
    Sakaguchi, S. (2000) Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101, 455–458.PubMedCrossRefGoogle Scholar
  2. 2.
    Gershon, R. K. and Kondo, K. (1970) Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology 18, 723–737.PubMedGoogle Scholar
  3. 3.
    Green, D. R., Flood, P. M. and Gershon, R. K. (1983) Immunoregulatory T-cell pathways. Annu. Rev. Immunol. 1,439–463.PubMedCrossRefGoogle Scholar
  4. 4.
    Kronenberg, M., Steinmetz, M., Kobori, J., Kraig, E., Kapp, J. A., Pierce, C. W., et al. (1983) RNA transcripts for I-J polypeptides are apparently not encoded between the I-A and I-E subregions of the murine major histocompatibility complex. Proc. Natl. Acad. Sci. U.S.A. 80, 5704–5708.PubMedCrossRefGoogle Scholar
  5. 5.
    Bloom B. R., Salgame, P. and Diamond, B. (1992) Revisiting and revising suppressor T cells. Immunol. Today 13, 131–136.PubMedCrossRefGoogle Scholar
  6. 6.
    O’Garra, A. and Murphy, K. (1994) Role of cytokines in determining T-lymphocyte function. Curr. Opin. Immunol. 6, 458–466.PubMedCrossRefGoogle Scholar
  7. 7.
    Chen, Y., Kuchroo, V. K., Inobe, J., Hafler, D. A. and Weiner, H. L. (1994) Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalitis. Science 265, 1237–1240.PubMedCrossRefGoogle Scholar
  8. 8.
    Groux, H., O’Garra, A., Bigler, M., Rouleau, M., Antonenko, S., de Vries, J. E. and Roncarolo, M. G. (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742.PubMedCrossRefGoogle Scholar
  9. 9.
    Nishizuka, Y. and Sakakura, T. (1969) Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 166, 753–755.PubMedCrossRefGoogle Scholar
  10. 10.
    Kojima, A. and Prehn, R. T. (1981) Genetic susceptibility to post-thymectomy autoimmune diseases in mice. Immunogenetics 14, 15–27.PubMedCrossRefGoogle Scholar
  11. 11.
    Penhale, W. J., Farmer, A., McKenna, R. P. and Irvine, W. J. (1973) Spontaneous thyroiditis in thymectomized and irradiated Wistar rats. Clin. Exp. Immunol. 15, 225–236.PubMedGoogle Scholar
  12. 12.
    Penhale, W. J., Stumbles, P. A., Huxtable, C. R., Sutherland, R. J. and Pethick, D. W. (1990) Induction of diabetes in PVG/c strain rats by manipulation of the immune system. Autoimmunity 7, 169–179.PubMedCrossRefGoogle Scholar
  13. 13.
    Fowell, D. and Mason, D. (1993) Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential. J. Exp. Med. 177, 627–636.PubMedCrossRefGoogle Scholar
  14. 14.
    Sakaguchi, S., Takahashi, T. and Nishizuka, Y. (1982) Study on cellular events in post-thymectomy autoimmune oophoritis in mice. II. Requirement of Lyt-1 cells in normal female mice for the prevention of oophoritis. J. Exp. Med. 156, 1577–1586.PubMedCrossRefGoogle Scholar
  15. 15.
    Penhale, W. J., Irvine, W. J., Inglis, J. R. and Farmer, A. (1976) Thyroiditis in T cell-depleted rats: suppression of the autoallergic response by reconstitution with normal lymphoid cells. Clin. Exp. Immunol. 25, 6–16.PubMedGoogle Scholar
  16. 16.
    Sakaguchi, S., Takahashi, T. and Nishizuka, Y. (1982) Study on cellular events in postthymectomy autoimmune oophoritis in mice. I. Requirement of Lyt-1 effector cells for oocytes damage after adoptive transfer. J. Exp. Med. 156, 1565–1576.PubMedCrossRefGoogle Scholar
  17. 17.
    Sakaguchi, S., Fukuma, K., Kuribayashi, K. and Masuda, T. (1985) Organ-specific autoimmune diseases induced in mice by elimination of T-cell subset. I. Evidence for the active participation of T cells in natural self-tolerance: deficit of a T-cell subset as a possible cause of autoimmune disease. J. Exp. Med. 161, 72–87.PubMedCrossRefGoogle Scholar
  18. 18.
    Sugihara, S., Izumi, Y., Yoshioka, T., Yagi, H., Tsujimura, T., Tarutani, O., et al. (1988) Autoimmune thyroiditis induced in mice depleted of particular T-cell subset. I. Requirement of Lyt-1dull L3T4bright normal T cells for the induction of thyroiditis. J. Immunol. 141, 105–113.PubMedGoogle Scholar
  19. 19.
    Smith, H., Lou, Y. H., lacy, P. and Tung, K. S. K. (1992) Tolerance mechanism in experimental ovarian and gastric autoimmune disease. J. Immunol. 149, 2212–2218.PubMedGoogle Scholar
  20. 20.
    Powrie, F. and Mason, D. (1990) OX-22high CD4+ T cells induce wasting disease with multiple organ pathology: prevention by OX-22low subset. J. Exp. Med. 172, 1701–1708.PubMedCrossRefGoogle Scholar
  21. 21.
    McKeever, U., Mordes, J. P., Greiner, D. L., Appel, M. C., Rozing, J., Handler, E. S. and Rossini, A. A. (1990) Adoptive transfer of autoimmune diabetes and thyroiditis to athymic rats. Proc. Natl. Acad. Sci. U.S.A. 87, 7618–7622.PubMedCrossRefGoogle Scholar
  22. 22.
    Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. and Toda, M. (1995) Immunologic tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164.PubMedGoogle Scholar
  23. 23.
    Asano, M., Toda, M., Sakaguchi, N. and Sakaguchi, S. (1996) Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J. Exp. Med. 184, 387–396.PubMedCrossRefGoogle Scholar
  24. 24.
    Powrie, F., Leach, M. W., Mauze, S., Caddle, L. B. and Coffman, R. L. (1993) Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int. Immunol. 5, 1461–1471.PubMedCrossRefGoogle Scholar
  25. 25.
    Morrissey, P. J., Charrier, K., Braddy, S., Liggitt, D. and Watson, J. D. (1993) CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells. J. Exp. Med. 178, 237–244.PubMedCrossRefGoogle Scholar
  26. 26.
    Itoh, M., Takahashi, T., Sakaguchi, N., Kuniyasu, Y., Shimizu, J., Otsuka, F. and Sakaguchi, S. (1999) Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J. Immunol. 162, 5317–5326.PubMedGoogle Scholar
  27. 27.
    Suri-Payer, E., Amar, A. Z., Thornton, A. M. and Shevach, E. M. (1998) CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells. J. Immunol. 160, 1212–1218.PubMedGoogle Scholar
  28. 28.
    Qin, S., Cobbold, S. P., Pope, H., Elliott, J., Kioussis, D., Davies, J. and Waldmann, H. (1993) “Infectious” transplantation tolerance. Science 259, 974–977.PubMedCrossRefGoogle Scholar
  29. 29.
    Hall, B. M., Pearce, N. W., Gurley, K. E. and Dorsch, S. E. (1990) Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. III. Further characterization of the CD4+ suppressor cell and its mechanisms of action. J. Exp. Med. 171, 141–157.PubMedCrossRefGoogle Scholar
  30. 30.
    Le Douarin, N., Corbel, C., Bandeira, A., Thomas-Vaslin, V., Modigliani, Y., Coutinho, A. and Salaun, J. (1996) Evidence for a thymus-dependent form of tolerance that is not based on elimination or anergy of reactive T cells. Immunol. Rev. 149, 35–53.PubMedCrossRefGoogle Scholar
  31. 31.
    Waldmann, H., Adams, E., Fairchild, P. and Cobbold, S. (2006) Infectious tolerance and the long-term acceptance of transplanted tissue. Immunol. Rev. 212, 301–313.PubMedCrossRefGoogle Scholar
  32. 32.
    Schorle, H., Holtschke, T., Hunig, T., Schimpl, A. and Horak, I. (1991) Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 352, 621–624.PubMedCrossRefGoogle Scholar
  33. 33.
    Almeida, A. R., Legrand, N., Papiernik, M. and Freitas, A. A. (2002) Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. J. Immunol. 169, 4850–4860.PubMedGoogle Scholar
  34. 34.
    Willerford, D. M., Chen, J., Ferry, J. A., Davidson, L., Ma, A. and Alt, F. W. (1995) Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521–530.PubMedCrossRefGoogle Scholar
  35. 35.
    Suzuki, H., Zhou, Y. W., Kato, M., Mak, T. W. and Nakashima, I. (1999) Normal regulatory alpha/beta T cells effectively eliminate abnormally activated T cells lacking the interleukin 2 receptor beta in vivo. J. Exp. Med. 190, 1561–1572.PubMedCrossRefGoogle Scholar
  36. 36.
    Malek. T. R., Yu, A., Vincek, V., Scibelli, P. and 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.PubMedCrossRefGoogle Scholar
  37. 37.
    Setoguchi, R., Hori, S., Takahashi, T. and Sakaguchi, S. (2005) 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.PubMedCrossRefGoogle Scholar
  38. 38.
    Takahashi, T., Kuniyasu, Y., Toda, M., Sakaguchi, N., Itoh, M., Iwata, M., Shimizu, J. and 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.PubMedCrossRefGoogle Scholar
  39. 39.
    Thornton, A. M. and Shevach, E. M. (1998) CD4+ CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188, 287–296.PubMedCrossRefGoogle Scholar
  40. 40.
    Shevach, E. M. (2001) Certified professionals: CD4+CD25+ suppressor T cells. J. Exp. Med. 193, F41–F46.PubMedCrossRefGoogle Scholar
  41. 41.
    Brunkow, M. E., Jeffery, E. W., Hjerrild, K. A., Paeper, B., Clark, L. B., Yasayko, S. A., et al. (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.PubMedCrossRefGoogle Scholar
  42. 42.
    Chatila, T. A., Blaeser, F., Ho, N., Lederman, H. M., Voulgaropoulos, C., Helms, C. and Bowcock, A. M. (2000) JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J. Clin. Invest. 106, R75–R81.PubMedCrossRefGoogle Scholar
  43. 43.
    Wildin, R. S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J. L., Buist, N., et al. (2001) X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27, 18–20.PubMedCrossRefGoogle Scholar
  44. 44.
    Bennett, C. L., Christie, J., Ramsdell, F., Brunkow, M. E., Ferguson, P. J., Whitesell, L., et al. (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20–21.PubMedCrossRefGoogle Scholar
  45. 45.
    Hori, S., Nomura, T. and Sakaguchi, S. (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061.PubMedCrossRefGoogle Scholar
  46. 46.
    Fontenot, J. D., Gavin, M. A. and Rudensky, A. Y. (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336.PubMedCrossRefGoogle Scholar
  47. 47.
    Khattri, R., Cox, T., Yasayko, S. A. and Ramsdell, F. (2003) An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4, 337–342.PubMedCrossRefGoogle Scholar
  48. 48.
    Fontenot, J. D., Rasmussen, J. P., Williams, L. M., Dooley, J. L., Farr, A. G. and Rudensky, A. Y. (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22, 329–341.PubMedCrossRefGoogle Scholar
  49. 49.
    Kim, J. M., Rasmussen, J. P. and Rudensky, A. Y. (2007) Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8, 191–197.PubMedCrossRefGoogle Scholar
  50. 50.
    Lahl, K., Loddenkemper, C., Drouin, C., Freyer, J., Arnason, J., Eberl, G., et al. (2007) Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J. Exp. Med. 204, 57–63.PubMedCrossRefGoogle Scholar
  51. 51.
    Roncador, G., Brown, P. J., Maestre, L., Hue, S., Martinez-Torrecuadrada, J. L., Ling, et al. (2005) Analysis of FOXP3 protein expression in human CD4+CD25+ regulatory T cells at the single-cell level. Eur. J. Immunol. 35, 1681–1691.PubMedCrossRefGoogle Scholar
  52. 52.
    Zheng, Y., Josefowicz, S. Z., Kas, A., Chu, T. T., Gavin, M. A. and Rudensky, A. Y. (2007) Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445, 936–940.PubMedCrossRefGoogle Scholar
  53. 53.
    Marson, A., Kretschmer, K., Frampton, G. M., Jacobsen, E. S., Polansky, J. K., MacIsaac, K. D., et al. (2007) Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445, 931–935.PubMedCrossRefGoogle Scholar
  54. 54.
    Wu, Y., Borde, M., Heissmeyer, V., Feuerer, M., Lapan, A. D., Stroud, J. C. et al. (2006) FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375–387.PubMedCrossRefGoogle Scholar
  55. 55.
    Ono, M., Yaguchi, H., Ohkura, N., Kitabayashi, I., Nagamura, Y., Nomura, T., et al. (2007) Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 446, 685–689.PubMedCrossRefGoogle Scholar
  56. 56.
    von Boehmer H. (2005) Mechanisms of suppression by suppressor T cells. Nat. Immunol. 6, 338–344.CrossRefGoogle Scholar
  57. 57.
    Tang, Q. and Bluestone, J. A. (2008) The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat. Immunol. 9, 239–244.PubMedCrossRefGoogle Scholar
  58. 58.
    Vignali, D. A., Collison, L. W. and Workman, C. J. (2008) How regulatory T cells work. Nat. Rev. Immunol. 8, 523–532.PubMedCrossRefGoogle Scholar
  59. 59.
    Shevach, E. M. (2009) Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 30, 636–645.PubMedCrossRefGoogle Scholar
  60. 60.
    Sakaguchi, S., Yamaguchi, T., Nomura, T. and Ono, M. (2008) Regulatory T cells and immune tolerance. Cell 133, 775–787.PubMedCrossRefGoogle Scholar
  61. 61.
    Gavin, M. A., Rasmussen, J. P., Fontenot, J. D., Vasta, V., Manganiello, V.C., Beavo, J. A. and Rudensky, A. Y. (2007) Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771–775.PubMedCrossRefGoogle Scholar
  62. 62.
    Lin, W., Haribhai, D., Relland, L. M., Truong, N., Carlson, M. R., Williams, C. B., and Chatila, T. A. (2007) Regulatory T cell development in the absence of functional Foxp3. Nat. Immunol. 8, 359–368.PubMedCrossRefGoogle Scholar
  63. 63.
    Hill, J. A., Feuerer, M., Tash, K., Haxhinasto, S., Perez, J., Melamed, R., et al. (2007) Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity 27, 786–800.PubMedCrossRefGoogle Scholar
  64. 64.
    Chen, W., Jin, W., Hardegen, N., Lei, K. J., Li, L., Marinos, N., et al. (2003) Conversion of peripheral CD4+CD25 naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886.PubMedCrossRefGoogle Scholar
  65. 65.
    Apostolou, I. and von Boehmer, H. (2004) In vivo instruction of suppressor commitment in naive T cells. J. Exp. Med. 199, 1401–1408.PubMedCrossRefGoogle Scholar
  66. 66.
    Yamazaki, S., Iyoda, T., Tarbell, K., Olson, K., Velinzon, K., Inaba, K. and Steinman, R. M. (2003) Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J. Exp. Med. 198, 235–247.PubMedCrossRefGoogle Scholar
  67. 67.
    Fehervari, Z. and Sakaguchi, S. (2004) Control of Foxp3+ CD25+CD4+ regulatory cell activation and function by dendritic cells. Int. Immunol. 16, 1769–1780.PubMedCrossRefGoogle Scholar
  68. 68.
    Pasare, C. and Medzhitov, R. (2003) Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299, 1033–1036.PubMedCrossRefGoogle Scholar
  69. 69.
    Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. and Stockinger, B. (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189.PubMedCrossRefGoogle Scholar
  70. 70.
    Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T. B., Oukka, M., et al. (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238.PubMedCrossRefGoogle Scholar
  71. 71.
    Laurence, A., Tato, C. M., Davidson, T. S., Kanno, Y., Chen, Z., Yao, Z., et al. (2007) Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381.PubMedCrossRefGoogle Scholar
  72. 72.
    Wellcome Trust Case Control Consortium. (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678.CrossRefGoogle Scholar
  73. 73.
    Encinas, J. A., Wicker, L. S., Peterson, L. B., Mukasa, A., Teuscher, C., Sobel, R., et al. (1999) QTL influencing autoimmune diabetes and encephalomyelitis map to a 0.15-cM region containing Il2. Nat. Genet. 21, 158–160.PubMedCrossRefGoogle Scholar
  74. 74.
    Sakaguchi, S., Ono, M., Setoguchi, R., Yagi, H., Hori, S., Fehervari, Z., et al. (2006) Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol. Rev. 212, 8–27.PubMedCrossRefGoogle Scholar
  75. 75.
    Nishikawa, H. and Sakaguchi, S. (2010) Regulatory T cells in tumor immunity. Int. J. Cancer 127, 759–777.PubMedGoogle Scholar
  76. 76.
    Li, Y., Zhao, X., Cheng, D., Haga, H., Tsuruyama, T., Wood, K., et al. (2008) The presence of FOXP3 expressing T cells within grafts of tolerance human liver transplant recipients. Transplantation 86, 1837–1843.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Shimon Sakaguchi
    • 1
    • 2
  1. 1.Department of Experimental Pathology, Institute for Frontier Medical SciencesKyoto UniversityKyotoJapan
  2. 2.WPI Immunology Frontier Research CenterOsaka UniversitySuitaJapan

Personalised recommendations