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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References
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).
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).
Sakaguchi, S. Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101, 455–458 (2000).
Mason, D. & Powrie, F. Control of immune pathology by regulatory T cells. Curr. Opin. Immunol. 10, 649–655 (1998).
Cobbold, S. & Waldmann, H. Infectious tolerance. Curr. Opin. Immunol. 10, 518–524 (1998).
Gershon, R. K. & Kondo, K. Infectious immunological tolerance. Immunology 21, 903–914 (1971).
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).
Malek, T. R. & Bayer, A. L. Tolerance, not immunity, crucially depends on IL-2. Nature Rev. Immunol. 4, 665–674 (2004).
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).
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).
Lindley, S. et al. Defective suppressor function in CD4+CD25+ T-cells from patients with type 1 diabetes. Diabetes 54, 92–99 (2005).
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).
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).
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).
Apostolou, I. & von Boehmer, H. In vivo instruction of suppressor commitment in naive T cells. J. Exp. Med. 199, 1401–1408 (2004).
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).
Roncarolo, M. G., Bacchetta, R., Bordignon, C., Narula, S. & Levings, M. K. Type 1 T regulatory cells. Immunol. Rev. 182, 68–79 (2001).
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).
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).
Bluestone, J. A. & Abbas, A. K. Natural versus adaptive regulatory T cells. Nature Rev. Immunol. 3, 253–257 (2003).
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).
Tang, Q. et al. CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. J. Immunol. 171, 3348–3352 (2003).
Hsieh, C. S. et al. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 21, 267–277 (2004).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Waldmann, H. et al. Regulatory T cells and organ transplantation. Semin. Immunol. 16, 119–126 (2004).
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).
Annunziato, F. et al. Phenotype, localization, and mechanism of suppression of CD4+CD25+ human thymocytes. J. Exp. Med. 196, 379–387 (2002).
Baecher-Allan, C., Viglietta, V. & Hafler, D. A. Inhibition of human CD4+CD25high regulatory T cell function. J. Immunol. 169, 6210–6217 (2002).
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).
Ng, W. F. et al. Human CD4+ CD25+ cells: a naturally occurring population of regulatory T cells. Blood 98, 2736–2744 (2001).
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).
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).
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).
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).
Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).
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).
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).
Weiner, H. L. Induction and mechanism of action of transforming growth factor-β-secreting TH3 regulatory cells. Immunol. Rev. 182, 207–214 (2001).
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).
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).
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).
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).
Tang, Q. et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J. Exp. Med. 199, 1455–1465 (2004).
Fisson, S. et al. Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J. Exp. Med. 198, 737–746 (2003).
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).
Stockinger, B., Barthlott, T. & Kassiotis, G. T cell regulation: a special job or everyone's responsibility? Nature Immunol. 2, 757–758 (2001).
Pasare, C. & Medzhitov, R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299, 1033–1036 (2003).
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).
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).
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).
Oswald-Richter, K. et al. HIV infection of naturally occurring and genetically reprogrammed human regulatory T-cells. PLoS Biol. 2, e198 (2004).
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).
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).
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).
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).
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).
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).
Mekala, D. J. & Geiger, T. L. Immunotherapy of autoimmune encephalomyelitis with re-directed CD4+CD25+ T-lymphocytes. Blood 105, 2090–2092 (2005).
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).
Horwitz, M. S. et al. Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry. Nature Med. 4, 781–785 (1998).
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).
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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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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DOI: https://doi.org/10.1038/nri1574
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