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Regulatory T-cell therapy: is it ready for the clinic?

Nature Reviews Immunology volume 5, pages 343–349 (2005)Cite this article

Abstract

The identification of suppressor T cells as important regulators of basic processes that are designed to maintain tolerance has opened an important area of potential clinical investigation in autoimmunity, graft-versus-host disease and transplantation. However, the field has been limited by an inability to define the antigenic specificities of these cells and by the small numbers of circulating regulatory T cells. Recently, new methods for expanding polyclonal and antigen-specific regulatory T cells have emerged. This article summarizes efforts to exploit regulatory T-cell therapy for the treatment of immunological diseases and poses the question of when and where regulatory T cells will first impact on clinical diseases.

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Figure 1: Methods for expanding regulatory T cells in vitro.
Figure 2: Effect of CD4+CD25+ regulatory T cells on migration of antigen-specific effector T cells.

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References

  1. Awwad, M. & North, R. J. Immunologically mediated regression of a murine lymphoma after treatment with anti-L3T4 antibody. A consequence of removing L3T4+ suppressor T cells from a host generating predominantly Lyt-2+ T cell-mediated immunity. J. Exp. Med. 168, 2193–2206 (1988).

    Article  CAS  PubMed  Google Scholar 

  2. Sakaguchi, S., Takahashi, T. & Nishizuka, Y. 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 (1982).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Mason, D. & Powrie, F. Control of immune pathology by regulatory T cells. Curr. Opin. Immunol. 10, 649–655 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Cobbold, S. & Waldmann, H. Infectious tolerance. Curr. Opin. Immunol. 10, 518–524 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Gershon, R. K. & Kondo, K. Infectious immunological tolerance. Immunology 21, 903–914 (1971).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Salomon, B. et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12, 431–440 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Malek, T. R. & Bayer, A. L. Tolerance, not immunity, crucially depends on IL-2. Nature Rev. Immunol. 4, 665–674 (2004).

    Article  CAS  Google Scholar 

  9. 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 

  10. Ehrenstein, M. R. et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFα therapy. J. Exp. Med. 200, 277–285 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lindley, S. et al. Defective suppressor function in CD4+CD25+ T-cells from patients with type 1 diabetes. Diabetes 54, 92–99 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Viglietta, V., Baecher-Allan, C., Weiner, H. L. & Hafler, D. A. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J. Exp. Med. 199, 971–979 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sakaguchi, S. et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol. Rev. 182, 18–32 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Jordan, M. S. et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nature Immunol. 2, 301–306 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Horwitz, D. A. et al. Regulatory T cells generated ex vivo as an approach for the therapy of autoimmune disease. Semin. Immunol. 16, 135–143 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Roncarolo, M. G., Bacchetta, R., Bordignon, C., Narula, S. & Levings, M. K. Type 1 T regulatory cells. Immunol. Rev. 182, 68–79 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Belghith, M. et al. TGF-β-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nature Med. 9, 1202–1208 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Mahnke, K., Qian, Y., Knop, J. & Enk, A. H. Induction of CD4+/CD25+ regulatory T cells by targeting of antigens to immature dendritic cells. Blood 101, 4862–4869 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Bluestone, J. A. & Abbas, A. K. Natural versus adaptive regulatory T cells. Nature Rev. Immunol. 3, 253–257 (2003).

    Article  CAS  Google Scholar 

  21. Lerman, M. A., Larkin, J., Cozzo, C., Jordan, M. S. & Caton, A. J. CD4+CD25+ regulatory T cell repertoire formation in response to varying expression of a neo-self-antigen. J. Immunol. 173, 236–244 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Tang, Q. et al. CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. J. Immunol. 171, 3348–3352 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Hsieh, C. S. et al. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 21, 267–277 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. 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).

    Article  CAS  PubMed  Google Scholar 

  25. 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 

  26. Takahashi, T. et al. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 192, 303–310 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Read, S., Malmstrom, V. & Powrie, F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J. Exp. Med. 192, 295–302 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kingsley, C. I., Karim, M., Bushell, A. R. & Wood, K. J. CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. J. Immunol. 168, 1080–1086 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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 

  31. Hara, M. et al. IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. J. Immunol. 166, 3789–3796 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Tang, Q. et al. Distinct roles of CTLA-4 and TGF-β in CD4+CD25+ regulatory T cell function. Eur. J. Immunol. 34, 2996–3005 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Hanash, A. M. & Levy, R. B. Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC mismatched hematopoietic cell transplantation. Blood 105, 1828–1836 (2004).

    Article  PubMed  Google Scholar 

  34. Trenado, A. et al. Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia. J. Clin. Invest. 112, 1688–1696 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Edinger, M. et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nature Med. 9, 1144–1150 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Taylor, P. A., Lees, C. J. & Blazar, B. R. The infusion of ex vivo activated and expanded CD4+CD25+ immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99, 3493–3499 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Waldmann, H. et al. Regulatory T cells and organ transplantation. Semin. Immunol. 16, 119–126 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. 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 

  39. Annunziato, F. et al. Phenotype, localization, and mechanism of suppression of CD4+CD25+ human thymocytes. J. Exp. Med. 196, 379–387 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Baecher-Allan, C., Viglietta, V. & Hafler, D. A. Inhibition of human CD4+CD25high regulatory T cell function. J. Immunol. 169, 6210–6217 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Levings, M. K. et al. Human CD25+CD4+ T suppressor cell clones produce transforming growth factor β, but not interleukin 10, and are distinct from type 1 T regulatory cells. J. Exp. Med. 196, 1335–1346 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 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 

  43. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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 

  45. Godfrey, W. R. et al. In vitro-expanded human CD4+CD25+ T-regulatory cells can markedly inhibit allogeneic dendritic cell-stimulated MLR cultures. Blood 104, 453–461 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. 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 

  47. Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).

    CAS  PubMed  Google Scholar 

  48. Barrat, F. J. et al. 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 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Levings, M. K. et al. IFN-α and IL-10 induce the differentiation of human type 1 T regulatory cells. J. Immunol. 166, 5530–5539 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Weiner, H. L. Induction and mechanism of action of transforming growth factor-β-secreting TH3 regulatory cells. Immunol. Rev. 182, 207–214 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Chang, C. C. et al. Tolerization of dendritic cells by TS cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nature Immunol. 3, 237–243 (2002).

    Article  CAS  Google Scholar 

  52. Liu, J. et al. Rat CD8+FOXP3+ T suppressor cells mediate tolerance to allogeneic heart transplants, inducing PIR-B in APC and rendering the graft invulnerable to rejection. Transpl. Immunol. 13, 239–247 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Gregg, R. K. et al. A sudden decline in active membrane-bound TGF-β impairs both T regulatory cell function and protection against autoimmune diabetes. J. Immunol. 173, 7308–7316 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Tang, Q. et al. Distinct roles of CTLA-4 and TGF-β in CD4+CD25+ regulatory T cell function. Eur. J. Immunol. 34, 2996–3005 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Tang, Q. et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J. Exp. Med. 199, 1455–1465 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 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 

  57. Walker, L. S., Chodos, A., Eggena, M., Dooms, H. & Abbas, A. K. Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J. Exp. Med. 198, 249–258 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Stockinger, B., Barthlott, T. & Kassiotis, G. T cell regulation: a special job or everyone's responsibility? Nature Immunol. 2, 757–758 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  60. Crispin, J. C., Martinez, A. & Alcocer-Varela, J. Quantification of regulatory T cells in patients with systemic lupus erythematosus. J. Autoimmun. 21, 273–276 (2003).

    Article  PubMed  Google Scholar 

  61. Suvas, S., Azkur, A. K., Kim, B. S., Kumaraguru, U. & Rouse, B. T. CD4+CD25+ regulatory T cells control the severity of viral immunoinflammatory lesions. J. Immunol. 172, 4123–4132 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Kinter, A. L. et al. 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 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Oswald-Richter, K. et al. HIV infection of naturally occurring and genetically reprogrammed human regulatory T-cells. PLoS Biol. 2, e198 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yamazaki, S. et al. Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J. Exp. Med. 198, 235–247 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Maus, M. V. et al. Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4-1BB. Nature Biotechnol. 20, 143–148 (2002).

    Article  CAS  Google Scholar 

  67. Battaglia, M. & Roncarolo, M. G. The role of cytokines (and not only) in inducing and expanding T regulatory type 1 cells. Transplantation 77, S16–S18 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Bacchetta, R. et al. 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 (2002).

    CAS  PubMed  Google Scholar 

  69. Jaeckel, E., von Boehmer, H. & Manns, M. P. Antigen-specific FoxP3-transduced T-cells can control established type 1 diabetes. Diabetes 54, 306–310 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Mekala, D. J. & Geiger, T. L. Immunotherapy of autoimmune encephalomyelitis with re-directed CD4+CD25+ T-lymphocytes. Blood 105, 2090–2092 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Yamamoto, A. M. et al. The activity of immunoregulatory T cells mediating active tolerance is potentiated in nonobese diabetic mice by an IL-4-based retroviral gene therapy. J. Immunol. 166, 4973–4980 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Horwitz, M. S. et al. Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry. Nature Med. 4, 781–785 (1998).

    Article  CAS  PubMed  Google Scholar 

  73. Levine, B. L. et al. Adoptive transfer of costimulated CD4+ T cells induces expansion of peripheral T cells and decreased CCR5 expression in HIV infection. Nature Med. 8, 47–53 (2002).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The author would like to thank Q. Tang, K. Earle and D. Gross for helpful discussions and review of the manuscript. This manuscript was supported by grants from the National Institutes of Health (United States) and Juvenile Diabetes Research Foundation (United States).

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  1. the University of California at San Francisco Diabetes Center, University of California, San Francisco, Box 0540, 513 Parnassus Avenue, San Francisco, 94143-0540, California, USA

    Jeffrey A. Bluestone

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DATABASES

Entrez Gene

CD4

CD25

CD62L

CTLA4

FOXP3

GITR

IL-10

TGF-β

OMIM

IPEX

multiple sclerosis

rheumatoid arthritis

type 1 diabetes

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Bluestone, J. Regulatory T-cell therapy: is it ready for the clinic?. Nat Rev Immunol 5, 343–349 (2005). https://doi.org/10.1038/nri1574

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