Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

FOXP3+ regulatory T cells in the human immune system

Key Points

  • Regulatory T (TReg) cells are potent mediators of dominant tolerance in the periphery. The study of TReg cells in many models of animal disease has revealed their ability to prevent autoimmune pathogenesis and to restore immune homeostasis but also to promote cancer growth by repressing antitumour immune responses. Such findings have made TReg cells a promising target for clinical application.

  • Confusion as to the mechanism of the identity, function and stability of human TReg cells has, to date, impeded the general therapeutic use of these cells.

  • Several recent studies have suggested that human TReg cells possess functional and phenotypic diversity that has not been previously apparent. Indeed, based on recent findings, forkhead box P3 (FOXP3)+CD4+ T cells can be divided into several functionally unique populations based on their expression of CD45RA, CD45RO, HLA-DR and FOXP3.

  • A more detailed characterization of the ontogeny, phenotype and suppressive function of human TReg cells is needed for the study of TReg cells in the pathophysiology of autoimmune diseases, allergy, transplantation, pregnancy, infection and cancer.

  • Although several issues regarding long term reliability and safety still need to be addressed, TReg cell-based therapy is a promising therapeutic perspective that should be applicable in a wide range of immune diseases.

Abstract

Forkhead box P3 (FOXP3)+ regulatory T (TReg) cells are potent mediators of dominant self tolerance in the periphery. But confusion as to the identity, stability and suppressive function of human TReg cells has, to date, impeded the general therapeutic use of these cells. Recent studies have suggested that human TReg cells are functionally and phenotypically diverse. Here we discuss recent findings regarding human TReg cells, including the ontogeny and development of TReg cell subsets that have naive or memory phenotypes, the unique mechanisms of suppression mediated by TReg cell subsets and factors that regulate TReg cell lineage commitment. We discuss future studies that are needed for the successful therapeutic use of human TReg cells.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: FOXP3 expression in human TReg cells.
Figure 2: TReg cell differentiation.

Similar content being viewed by others

References

  1. Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Baecher-Allan, C. & Hafler, D. A. Human regulatory T cells and their role in autoimmune disease. Immunol. Rev. 212, 203–216 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Sakaguchi, S., Wing, K. & Miyara, M. Regulatory T cells — a brief history and perspective. Eur. J. Immunol. 37, S116–S123 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Costantino, C., Baecher-Allan, C. & Hafler, D. Human regulatory T cells and autoimmunity. Eur. J. Immunol. 38, 921–924 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Miyara, M. et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30, 899–911 (2009). This paper provides a phenotypic and functional characterization of human FOXP3+ T Reg cell subsets and shows that naive T Reg cells differentiate into effector T Reg cells.

    Article  CAS  PubMed  Google Scholar 

  6. Jiang, H. & Chess, L. Regulation of immune responses by T cells. N. Engl. J. Med. 354, 1166–1176 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Baecher-Allan, C., Brown, J. A., Freeman, G. J. & Hafler, D. A. CD4+CD25high regulatory cells in human peripheral blood. J. Immunol. 167, 1245–1253 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Taams, L. S. et al. Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells. Eur. J. Immunol. 32, 1621–1630 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Levings, M. K., Sangregorio, R. & Roncarolo, M. G. Human CD25+CD4+ T regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J. Exp. Med. 193, 1295–1302 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ng, W. F. et al. Human CD4+CD25+ cells: a naturally occurring population of regulatory T cells. Blood 98, 2736–2744 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Jonuleit, H. et al. Identification and functional characterization of human CD4+CD25+ T cells with regulatory properties isolated from peripheral blood. J. Exp. Med. 193, 1285–1294 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dieckmann, D., Plottner, H., Berchtold, S., Berger, T. & Schuler, G. Ex vivo isolation and characterization of CD4+CD25+ T cells with regulatory properties from human blood. J. Exp. Med. 193, 1303–1310 (2001). References 7–12 show that, similar to mouse CD25+CD4+ T cells, human CD25+CD4+ T cells have suppressive properties in vitro . Of note, reference 7 shows that CD4+ T cells with the highest expression of CD25 have the strongest suppressive activity, that is, contain pure T Reg cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-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 (1995).

    CAS  PubMed  Google Scholar 

  14. Khattri, R., Cox, T., Yasayko, S. A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nature Immunol. 4, 337–342 (2003).

    Article  CAS  Google Scholar 

  15. Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol. 4, 330–336 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Roncador, G. et al. Analysis of FOXP3 protein expression in human CD4+CD25+ regulatory T cells at the single-cell level. Eur. J. Immunol. 35, 1681–1691 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Gavin, M. A. et al. Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc. Natl Acad. Sci. USA 103, 6659–6664 (2006). This manuscript first reported that naive CD4+ T cells can upregulate FOXP3 expression at the protein level following in vitro activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Baecher-Allan, C., Wolf, E. & Hafler, D. MHC class II expression identifies functionally distinct human regulatory T cells. J. Immunol. 176, 4622–4631 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Ito, T. et al. Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity 28, 870–880 (2008). References 19 and 20 provide further information on the phenotype of effector T Reg cells, that is, the expression of HLA-DR and ICOS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Itoh, M. et al. 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).

    CAS  PubMed  Google Scholar 

  22. Fontenot, J. D., Dooley, J. L., Farr, A. G. & Rudensky, A. Y. Developmental regulation of Foxp3 expression during ontogeny. J. Exp. Med. 202, 901–906 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol. 4, 330–336 (2003).

    Article  CAS  Google Scholar 

  25. Fattorossi, A. et al. Thymopoiesis, regulatory T cells, and TCRVβ expression in thymoma with and without myasthenia gravis, and modulatory effects of steroid therapy. J. Clin. Immunol. 28, 194–206 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Tuovinen, H., Kekalainen, E., Rossi, L. H., Puntila, J. & Arstila, T. P. Cutting edge: human CD4CD8 thymocytes express FOXP3 in the absence of a TCR. J. Immunol. 180, 3651–3654 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Tuovinen, H., Pekkarinen, P. T., Rossi, L. H., Mattila, I. & Arstila, T. P. The FOXP3+ subset of human CD4+CD8+ thymocytes is immature and subject to intrathymic selection. Immunol. Cell Biol. 86, 523–529 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Lee, H. M. & Hsieh, C. S. Rare development of Foxp3+ thymocytes in the CD4+CD8+ subset. J. Immunol. 183, 2261–2266 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Liston, A. et al. Differentiation of regulatory Foxp3+ T cells in the thymic cortex. Proc. Natl Acad. Sci. USA 105, 11903–11908 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Picca, C. C. et al. Role of TCR specificity in CD4+ CD25+ regulatory T-cell selection. Immunol. Rev. 212, 74–85 (2006).

    Article  PubMed  Google Scholar 

  31. Malek, T. R. et al. IL-2 family of cytokines in T regulatory cell development and homeostasis. J. Clin. Immunol. 28, 635–639 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Spits, H. Development of αβ T cells in the human thymus. Nature Rev. Immunol. 2, 760–772 (2002).

    Article  CAS  Google Scholar 

  33. Watanabe, N. et al. Human thymic stromal lymphopoietin promotes dendritic cell-mediated CD4+ T cell homeostatic expansion. Nature Immunol. 5, 426–434 (2004).

    Article  CAS  Google Scholar 

  34. Hanabuchi, S. et al. Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus. J. Immunol. 184, 2999–3007 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Watanabe, N. et al. Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 436, 1181–1185 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Liu, Y. J. et al. TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Annu. Rev. Immunol. 25, 193–219 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Stites, D. P. & Pavia, C. S. Ontogeny of human T cells. Pediatrics 64, 795–802 (1979).

    Article  CAS  PubMed  Google Scholar 

  38. Darrasse-Jeze, G., Marodon, G., Salomon, B. L., Catala, M. & Klatzmann, D. Ontogeny of CD4+CD25+ regulatory/suppressor T cells in human fetuses. Blood 105, 4715–4721 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Brunkow, M. E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nature Genet. 27, 68–73 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Wildin, R. S. et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nature Genet. 27, 18–20 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nature Genet. 27, 20–21 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Yagi, H. et al. Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. Int. Immunol. 16, 1643–1656 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Buckner, J. H. & Ziegler, S. F. Functional analysis of FOXP3. Ann. N. Y Acad. Sci. 1143, 151–169 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Allan, S. E. et al. The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J. Clin. Invest. 115, 3276–3284 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Aarts-Riemens, T., Emmelot, M. E., Verdonck, L. F. & Mutis, T. Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4+CD25 cells. Eur. J. Immunol. 38, 1381–1390 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Du, J., Huang, C., Zhou, B. & Ziegler, S. F. Isoform-specific inhibition of RORα-mediated transcriptional activation by human FOXP3. J. Immunol. 180, 4785–4792 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Bettelli, E., Dastrange, M. & Oukka, M. Foxp3 interacts with nuclear factor of activated T cells and NF-κB to repress cytokine gene expression and effector functions of T helper cells. Proc. Natl Acad. Sci. USA 102, 5138–5143 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lopes, J. E. et al. Analysis of FOXP3 reveals multiple domains required for its function as a transcriptional repressor. J. Immunol. 177, 3133–3142 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Walker, M. R. et al. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25 T cells. J. Clin. Invest. 112, 1437–1443 (2003). This paper reports that naive CD4+ T cells can upregulate FOXP3 expression at the mRNA level in vitro following activation.

    Article  CAS  PubMed  Google Scholar 

  50. Walker, M. R., Carson, B. D., Nepom, G. T., Ziegler, S. F. & Buckner, J. H. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Allan, S. E. et al. Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FOXP3. Mol. Ther. 16, 194–202 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Hoffmann, P. et al. Loss of FOXP3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation. Eur. J. Immunol. 39, 1088–1097 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Allan, S. E., Song-Zhao, G. X., Abraham, T., McMurchy, A. N. & Levings, M. K. Inducible reprogramming of human T cells into Treg cells by a conditionally active form of FOXP3. Eur. J. Immunol. 38, 3282–3289 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Coombes, J. L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hill, J. A. et al. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity 27, 786–800 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Feuerer, M., Hill, J. A., Mathis, D. & Benoist, C. Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nature Immunol. 10, 689–695 (2009).

    Article  CAS  Google Scholar 

  57. Tran, D. Q., Ramsey, H. & Shevach, E. M. Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-β dependent but does not confer a regulatory phenotype. Blood 110, 2983–2990 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Allan, S. E. et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int. Immunol. 19, 345–354 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Liu, W. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med. 203, 1701–1711 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Seddiki, N. et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J. Exp. Med. 203, 1693 (2006). References 59 and 60 show that separation of CD4+ T cells based on expression of low levels of CD127 combined with high levels of CD25 enables the isolation of FOXP3-expressing CD4+ T cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Mazzucchelli, R. & Durum, S. K. Interleukin-7 receptor expression: intelligent design. Nature Rev. Immunol. 7, 144–154 (2007).

    Article  CAS  Google Scholar 

  62. Aerts, N. E. et al. Activated T cells complicate the identification of regulatory T cells in rheumatoid arthritis. Cell. Immunol. 251, 109–115 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Hamann, A., Klugewitz, K., Austrup, F. & Jablonski-Westrich, D. Activation induces rapid and profound alterations in the trafficking of T cells. Eur. J. Immunol. 30, 3207–3218 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Seddiki, N. et al. Persistence of naive CD45RA+ regulatory T cells in adult life. Blood 107, 2830–2838 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Valmori, D., Merlo, A., Souleimanian, N. E., Hesdorffer, C. S. & Ayyoub, M. A peripheral circulating compartment of natural naive CD4 Tregs. J. Clin. Invest. 115, 1953–1962 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Fritzsching, B. et al. Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death. Blood 108, 3371–3378 (2006). References 64, 65 and 66 describe the phenotype and the function of naive T Reg cells.

    Article  CAS  PubMed  Google Scholar 

  67. Fisson, S. et al. Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J. Exp. Med. 198, 737–746 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Brod, S. A., Rudd, C. E., Purvee, M. & Hafler, D. A. Lymphokine regulation of CD45R expression on human T cell clones. J. Exp. Med. 170, 2147–2152 (1989).

    Article  CAS  PubMed  Google Scholar 

  69. Fritzsching, B. et al. In contrast to effector T cells, CD4+CD25+FoxP3+ regulatory T cells are highly susceptible to CD95 ligand- but not to TCR-mediated cell death. J. Immunol. 175, 32–36 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Ashley, C. W. & Baecher-Allan, C. Cutting Edge: Responder T cells regulate human DR+ effector regulatory T cell activity via granzyme B. J. Immunol. 183, 4843–4847 (2009).

    Article  CAS  PubMed  Google Scholar 

  71. Vukmanovic-Stejic, M. et al. Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo. J. Clin. Invest. 116, 2423–2433 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Putnam, A. et al. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes 58, 652–662 (2008).

    Article  PubMed  CAS  Google Scholar 

  73. Thornton, A. M. & Shevach, E. M. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188, 287–296 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Vignali, D. A., Collison, L. W. & Workman, C. J. How regulatory T cells work. Nature Rev. Immunol. 8, 523–532 (2008).

    Article  CAS  Google Scholar 

  75. Shevach, E. M. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 30, 636–645 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  77. Baecher-Allan, C., Viglietta, V. & Hafler, D. A. Inhibition of human CD4+CD25+high regulatory T cell function. J. Immunol. 169, 6210–6217 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. Beriou, G. et al. IL-17 producing human peripheral regulatory T cells retain suppressive function. Blood 30, 4240–4249 (2009).

    Article  CAS  Google Scholar 

  79. Ayyoub, M. et al. Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the TH17 lineage-specific transcription factor RORγt. Proc. Natl Acad. Sci. USA 106, 8635–8640 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Bacchetta, R., Gambineri, E. & Roncarolo, M. G. Role of regulatory T cells and FOXP3 in human diseases. J. Allergy Clin. Immunol. 120, 227–235 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Miyara, M., Wing, K. & Sakaguchi, S. Therapeutic approaches to allergy and autoimmunity based on FoxP3+ regulatory T-cell activation and expansion. J. Allergy Clin. Immunol. 123, 749–755 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  83. Hoffmann, P., Eder, R., Kunz-Schughart, L. A., Andreesen, R. & Edinger, M. Large-scale in vitro expansion of polyclonal human CD4+CD25high regulatory T cells. Blood 104, 895–903 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Hoffmann, P. et al. Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. Blood 108, 4260–4267 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  86. Wan, Y. Y. & Flavell, R. A. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 445, 766–770 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Zhou, X. et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nature Immunol. 10, 1000–1007 (2009).

    Article  CAS  Google Scholar 

  88. Tao, R. et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nature Med. 13, 1299–1307 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Mann, B. S., Johnson, J. R., Cohen, M. H., Justice, R. & Pazdur, R. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 12, 1247–1252 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Med. 10, 942–949 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Colombo, M. P. & Piconese, S. Regulatory-T-cell inhibition versus depletion: the right choice in cancer immunotherapy. Nature Rev. Cancer 7, 880–887 (2007).

    Article  CAS  Google Scholar 

  92. Hodi, F. S. et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc. Natl Acad. Sci. USA 105, 3005–3010 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Belkaid, Y., Piccirillo, C. A., Mendez, S., Shevach, E. M. & Sacks, D. L. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420, 502–507 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Lund, J. M., Hsing, L., Pham, T. T. & Rudensky, A. Y. Coordination of early protective immunity to viral infection by regulatory T cells. Science 320, 1220–1224 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Boettler, T. et al. T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus-specific CD8+ T cells during chronic hepatitis C virus infection. J. Virol. 79, 7860–7867 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Weiss, L. et al. 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 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Venet, F. et al. Increased percentage of CD4+CD25+ regulatory T cells during septic shock is due to the decrease of CD4+CD25 lymphocytes. Crit. Care Med. 32, 2329–2331 (2004).

    Article  PubMed  Google Scholar 

  98. Sakaguchi, S., Wing, K., Onishi, Y., Prieto-Martin, P. & Yamaguchi, T. Regulatory T cells: how do they suppress immune responses? Int. Immunol. 21, 1105–1111 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Mold, J. E. et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science 322, 1562–1565 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Takahata, Y. et al. CD25+CD4+ T cells in human cord blood: an immunoregulatory subset with naive phenotype and specific expression of forkhead box p3 (Foxp3) gene. Exp. Hematol. 32, 622–629 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Huang, C. T. et al. Role of LAG-3 in regulatory T cells. Immunity 21, 503–513 (2004).

    Article  CAS  PubMed  Google Scholar 

  104. Gondek, D. C., Lu, L. F., Quezada, S. A., Sakaguchi, S. & Noelle, R. J. Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J. Immunol. 174, 1783–1786 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Cao, X. et al. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 27, 635–646 (2007).

    Article  CAS  PubMed  Google Scholar 

  106. Grossman, W. J. et al. Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells. Blood 104, 2840–2848 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Strauss, L., Bergmann, C. & Whiteside, T. L. Human circulating CD4+CD25highFoxp3+ regulatory T cells kill autologous CD8+ but not CD4+ responder cells by Fas-mediated apoptosis. J. Immunol. 182, 1469–1480 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Chen, W. et al. Conversion of peripheral CD4+CD25 naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Andersson, J. et al. CD4+ FoxP3+ regulatory T cells confer infectious tolerance in a TGF-β-dependent manner. J. Exp. Med. 205, 1975–1981 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Belkaid, Y. Regulatory T cells and infection: a dangerous necessity. Nature Rev. Immunol. 7, 875–888 (2007).

    Article  CAS  Google Scholar 

  111. Roncarolo, M. G. et al. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol. Rev. 212, 28–50 (2006).

    Article  CAS  PubMed  Google Scholar 

  112. Garin, M. I. et al. Galectin-1: a key effector of regulation mediated by CD4+CD25+ T cells. Blood 109, 2058–2065 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Pandiyan, P., Zheng, L., Ishihara, S., Reed, J. & Lenardo, M. J. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nature Immunol. 8, 1353–1362 (2007).

    Article  CAS  Google Scholar 

  114. Collison, L. W. et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566–569 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  116. Gershon, R. K. & Kondo, K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology 18, 723–737 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Sakaguchi, S., Fukuma, K., Kuribayashi, K. & Masuda, T. 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 (1985).

    Article  CAS  PubMed  Google Scholar 

  118. Powrie, F. & Mason, D. OX-22high CD4+ T cells induce wasting disease with multiple organ pathology: prevention by the OX-22low subset. J. Exp. Med. 172, 1701–1708 (1990).

    Article  CAS  PubMed  Google Scholar 

  119. Takahashi, T. et al. 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 (1998).

    Article  CAS  PubMed  Google Scholar 

  120. Nishizuka, Y. & Sakakura, T. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 166, 753–755 (1969).

    Article  CAS  PubMed  Google Scholar 

  121. Danke, N. A., Koelle, D. M., Yee, C., Beheray, S. & Kwok, W. W. Autoreactive T cells in healthy individuals. J. Immunol. 172, 5967–5972 (2004).

    Article  CAS  PubMed  Google Scholar 

  122. Ghiringhelli, F., Larmonier, N., Schmitt, E. et al. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur. J. Immunol. 34, 336–344 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

M.M. is currently supported by Fondation pour la Recherche Medicale and by the Japan Society for the Promotion of Science. This work was supported by grants-in-aid from the Ministry of Education, Sports and Culture of Japan, by US NIH grants: UO1DK6192601, RO1NS2424710, PO1AI39671 and PO1NS38037 and grants from the National Multiple Sclerosis Society: RG2172C9 and RG3308A10. M.M.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Shimon Sakaguchi or David A. Hafler.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Glossary

Dominant self tolerance

Refers to the active suppression of an autoimmune response in vitro or in vivo by suppressor cells, including regulatory T cells. By contrast, deletional tolerance and anergy are referred to as recessive or passive self tolerance mechanisms. Dominant self tolerance is transferable to naive recipients, whereas recessive self tolerance is not.

Central tolerance

Self tolerance that is created at the level of the central lymphoid organs. Developing T cells in the thymus, and B cells in the bone marrow, that strongly recognize self antigen face deletion or anergy induction.

Self tolerance

Tolerance to an individual's own tissue antigens that is achieved through both central and peripheral tolerance mechanisms, including T cell deletion, anergy and immune regulation. Without both central and peripheral tolerance mechanisms the immune system would be unable to distinguish self from foreign antigen, resulting in autoimmunity.

Hassall's corpuscles

Small clusters or concentric whorls of stratified keratinizing epithelium in the thymic medulla. They are probably end-stage differentiated epithelial cells that participate in negative selection of thymocytes and/or that undergo apoptosis themselves.

Scurfy mice

Mice with a spontaneous mutation in Foxp3, which leads to a rapidly fatal lymphoproliferative disease, causing death by 4 weeks of age.

Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome

A disease caused by mutations in FOXP3 and characterized by refractory enteritis, autoimmune endocrinopathies, including type 1 diabetes, thyroiditis and allergy.

Anergy

A state of non-responsiveness to antigen. Anergic B or T cells cannot respond to their cognate antigens under optimal conditions of stimulation.

Apoptosis

A common form of cell death, which is also known as intrinsic or programmed cell death. Many physiological and developmental stimuli cause apoptosis, and this mechanism is frequently used to delete unwanted, superfluous or potentially harmful cells, such as those undergoing transformation.

NOD/Shi-scid Il2rg/−/− (NOG) mice

Immunodeficient mice that can be adoptively transferred with human cells. When reconstituted with human cord blood stem cells, these mice allow the analysis of the behaviour of human cells in vivo.

Thymic involution

The age-dependent decrease of thymic epithelial volume, which results in decreased production of T cells.

Rapamycin

An immunosuppressive drug that does not prevent T cell activation but blocks IL-2-mediated clonal expansion by blocking mTOR (mammalian target of rapamycin).

Deacetylation

A post-translational modification of chromatin components, particularly histones. It correlates with actively transcribed chromatin. Histone deacetylases have been identified as components of nuclear co-repressor complexes, which reverse the actions of histone acetyltransferases, thereby inhibiting gene transcription.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sakaguchi, S., Miyara, M., Costantino, C. et al. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 10, 490–500 (2010). https://doi.org/10.1038/nri2785

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2785

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing