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.

  • Review Article
  • Published:

Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans

Nature Reviews Immunology volume 7, pages 585–598 (2007)Cite this article

Key Points

  • Regulatory T cells represent a distinct T-cell subset that has a key role in inducing and maintaining immunological tolerance. Several different regulatory T-cell subsets have been described. This Review focuses on forkhead box P3 (FOXP3)+CD4+CD25+ T cells, being the only natural occurring regulatory T-cell subset described so far, and on T regulatory type 1 cells, being the only inducible subset used in the clinic to date.

  • Compelling data generated in preclinical animal models indicate that regulatory T cells can be used as therapeutic agents for inducing tolerance to alloantigens after transplantation or for re-establishing self-tolerance in autoimmune diseases.

  • The possibility that human regulatory T cells might have an application for the treatment of T-cell-mediated diseases has recently gained increasing momentum. However, it is still unclear: which regulatory T-cell subset is most appropriate for adoptive transfer; which method should be used for their ex vivo expansion or differentiation; which human disease would benefit the most from regulatory T-cell transfer; and whether a combined therapy with other drugs will be needed.

  • At present, a few clinical trials of human regulatory T-cell-based immunotherapy are ongoing after bone-marrow transplantation. These trials will hopefully pave the way for the application of this therapy to other immune-mediated diseases.

  • The common future clinical application of regulatory T-cell-based immunotherapy strongly depends on safety, ethical and economical issues. This therapeutic approach must be safe and prove to be of superior efficacy over conventional therapy. Furthermore, in its initial experimental phase, regulatory T-cell-based immunotherapy is extremely expensive and requires good manufacturing practice certified facilities.

  • Should this immunotherapy meet its therapeutic target, one could envisage that not only academic institutions but also pharmaceutical companies will be interested in adopting this therapeutic approach.

Abstract

Substantial progress in understanding the biology of regulatory T cells and their roles in health and disease has been achieved in the past 10 years. This has led to an increasing interest in the possibility of using regulatory T cells as a biological therapy to preserve and restore tolerance to self antigens and alloantigens. Immunotherapy by the adoptive transfer of regulatory T cells may have several advantages over conventional treatments. However, several hurdles have to be overcome before such a therapy can enter clinical practice. This Review summarizes our current knowledge of regulatory T cells, illustrates the ongoing regulatory T-cell-based clinical trials, analyses the strengths and pitfalls of this new therapeutic approach, and highlights the future perspectives.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Pathogenesis of graft-versus-host disease and control by regulatory T cells.
Figure 2: Pathogenesis of type 1 diabetes and control by regulatory T cells.
Figure 3: Development and assessment of human cell therapy products.

Similar content being viewed by others

References

  1. Shevach, E. M. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 25, 195–201 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997). In this paper, both human and mouse IL-10-producing T R 1 cells were characterized for the first time.

    Article  CAS  PubMed  Google Scholar 

  3. 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 

  4. Sakaguchi, S., Setoguchi, R., Yagi, H. & Nomura, T. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in self-tolerance and autoimmune disease. Curr. Top. Microbiol. Immunol. 305, 51–66 (2006).

    CAS  PubMed  Google Scholar 

  5. 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 

  6. Wing, K. et al. CD4 T cell activation by myelin oligodendrocyte glycoprotein is suppressed by adult but not cord blood CD25+ T cells. Eur. J. Immunol. 33, 579–587 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. 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 

  8. Kitani, A., Chua, K., Nakamura, K. & Strober, W. Activated self-MHC-reactive T cells have the cytokine phenotype of Th3/T regulatory cell 1 T cells. J. Immunol. 165, 691–702 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Arif, S. et al. Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J. Clin. Invest. 113, 451–463 (2004). This is the first study providing evidence that patients with type 1 diabetes have reduced numbers of circulating islet-specific T R 1 cells compared with HLA-matched healthy controls.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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 

  11. Yudoh, K., Matsuno, H., Nakazawa, F., Yonezawa, T. & Kimura, T. Reduced expression of the regulatory CD4+ T cell subset is related to Th1/Th2 balance and disease severity in rheumatoid arthritis. Arthritis Rheum. 43, 617–627 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Miura, Y. et al. Association of Foxp3 regulatory gene expression with graft-versus-host disease. Blood 104, 2187–2193 (2004). This study shows for the first time a significant reduction of FOXP3 mRNA levels in PBMCs from patients with GVHD compared with those without GVHD.

    Article  CAS  PubMed  Google Scholar 

  13. Rezvani, K. et al. High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT. Blood 108, 1291–1297 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zorn, E. et al. Reduced frequency of FOXP3+CD4+CD25+ regulatory T cells in patients with chronic graft-versus-host disease. Blood 106, 2903–2911 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Clark, F. J. et al. Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4+CD25high regulatory T cells. Blood 103, 2410–2416 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Meignin, V. et al. Numbers of Foxp3-expressing CD4+CD25high T cells do not correlate with the establishment of long-term tolerance after allogeneic stem cell transplantation. Exp. Hematol. 33, 894–900 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Rieger, K. et al. Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD. Blood 107, 1717–1723 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Meloni, F. et al. Monocyte chemoattractant protein-1 levels in bronchoalveolar lavage fluid of lung-transplanted patients treated with tacrolimus as rescue treatment for refractory acute rejection. Transplant Proc. 35, 1523–1526 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Demirkiran, A. et al. Low circulating regulatory T-cell levels after acute rejection in liver transplantation. Liver Transpl. 12, 277–284 (2006).

    Article  PubMed  Google Scholar 

  20. Salama, A. D., Najafian, N., Clarkson, M. R., Harmon, W. E. & Sayegh, M. H. Regulatory CD25+ T cells in human kidney transplant recipients. J. Am. Soc. Nephrol. 14, 1643–1651 (2003).

    Article  PubMed  Google Scholar 

  21. Bacchetta, R. et al. High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. J. Exp. Med. 179, 493–502 (1994). This study describes the successful isolation of CD4+ host-reactive T-cell clones from SCID patients transplanted with allogeneic HSCs, which produce high amounts of IL-10 in the absence of IL-4 after antigen-specific stimulation in vitro . The presence of these IL-10-producing CD4+ T cells correlated with the absence of GVHD and long-term tolerance.

    Article  CAS  PubMed  Google Scholar 

  22. Baker, K. et al. High spontaneous IL-10 production in unrelated bone marrow transplant recipients is associated with fewer transplant-related complications and early deaths. Bone Marrow Transplant. 23, 1123–1129 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Weston, L. E., Geczy, A. F. & Briscoe, H. Production of IL-10 by alloreactive sibling donor cells and its influence on the development of acute GVHD. Bone Marrow Transplant. 37, 207–212 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. VanBuskirk, A. M. et al. Human allograft acceptance is associated with immune regulation. J. Clin. Invest. 106, 145–155 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bacchetta, R. et al. Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J. Clin. Invest. 116, 1713–1722 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Marangoni, F. et al. WASP regulates suppressor activity of human and murine CD4+CD25+FOXP3+ natural regulatory T cells. J. Exp. Med. 204, 369–380 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kriegel, M. A. et al. Defective suppressor function of human CD4+ CD25+ regulatory T cells in autoimmune polyglandular syndrome type II. J. Exp. Med. 199, 1285–1291 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bleesing, J. J. et al. Immunophenotypic profiles in families with autoimmune lymphoproliferative syndrome. Blood 98, 2466–2473 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Mottet, C., Uhlig, H. H. & Powrie, F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J. Immunol. 170, 3939–3943 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. 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 

  31. Tarbell, K. V. et al. Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J. Exp. Med. 204, 191–201 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Joffre, O., Gorsse, N., Romagnoli, P., Hudrisier, D. & van Meerwijk, J. P. Induction of antigen-specific tolerance to bone marrow allografts with CD4+CD25+ T lymphocytes. Blood 103, 4216–4221 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Taylor, P. A. et al. L-selectinhi but not the L-selectinlo CD4+25+ T-regulatory cells are potent inhibitors of GVHD and BM graft rejection. Blood 104, 3804–3812 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Cohen, J. L., Trenado, A., Vasey, D., Klatzmann, D. & Salomon, B. L. CD4+CD25+ immunoregulatory T cells: new therapeutics for graft-versus-host disease. J. Exp. Med. 196, 401–406 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hoffmann, P., Ermann, J., Edinger, M., Fathman, C. G. & Strober, S. Donor-type CD4+CD25+ regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J. Exp. Med. 196, 389–399 (2002). References 35, 36 and 96 are the first to show that the adoptive transfer of CD4+CD25+ regulatory T cells significantly delays or even prevents GVHD in preclinical mouse models of BMT.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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 

  38. Zeller, J. C. et al. Induction of CD4+ T cell alloantigen-specific hyporesponsiveness by IL-10 and TGF-β. J. Immunol. 163, 3684–3691 (1999).

    CAS  PubMed  Google Scholar 

  39. Gregori, S. et al. Regulatory T cells induced by 1α,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J. Immunol. 167, 1945–1953 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Lee, M. K. 4th. et al. Promotion of allograft survival by CD4+CD25+ regulatory T cells: evidence for in vivo inhibition of effector cell proliferation. J. Immunol. 172, 6539–6544 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Battaglia, M., Stabilini, A. & Roncarolo, M. G. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 105, 4743–4748 (2005). In this study, we showed, for the first time, that rapamycin has the ability to allow the selective proliferation of T Reg cells.

    Article  CAS  PubMed  Google Scholar 

  42. Battaglia, M. et al. Rapamycin and interleukin-10 treatment induces T regulatory type 1 cells that mediate antigen-specific transplantation tolerance. Diabetes 55, 40–49 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Waldmann, H., Adams, E., Fairchild, P. & Cobbold, S. Infectious tolerance and the long-term acceptance of transplanted tissue. Immunol. Rev. 212, 301–313 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. 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 

  45. Hoffmann, P. et al. Isolation of CD4+CD25+ regulatory T cells for clinical trials. Biol. Blood Marrow Transplant. 12, 267–274 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. 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 

  47. 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 

  48. 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 

  49. Liu, W. et al. 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 

  50. 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, 1693–1700 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jiang, S., Camara, N., Lombardi, G. & Lechler, R. I. Induction of allopeptide-specific human CD4+CD25+ regulatory T cells ex vivo. Blood 102, 2180–2186 (2003). References 50 and 51 show that CD4+CD25+ T Reg cells are CD127low/− and open new venues for a better isolation and purification of T Reg cells.

    Article  CAS  PubMed  Google Scholar 

  52. 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 

  53. Battaglia, M. & Roncarolo, M. G. Induction of transplantation tolerance via regulatory T cells. Inflamm. Allergy Drug Targets 5, 157–165 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Zeiser, R. et al. Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood 108, 390–399 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Achenbach, P., Bonifacio, E. & Ziegler, A. G. Predicting type 1 diabetes. Curr. Diab. Rep. 5, 98–103 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Ermann, J. et al. Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD. Blood 105, 2220–2226 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Nguyen, V. H. et al. In vivo dynamics of regulatory T cell trafficking and survival predict effective strategies to control graft-versus-host disease following allogeneic transplantation. Blood 109, 2649–2656 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Misra, N., Bayry, J., Lacroix-Desmazes, S., Kazatchkine, M. D. & Kaveri, S. V. Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells. J. Immunol. 172, 4676–4680 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Venet, F. et al. Human CD4+CD25+ regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism. J. Immunol. 177, 6540–6547 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Taams, L. S. et al. Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells. Hum. Immunol. 66, 222–230 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lewkowicz, P., Lewkowicz, N., Sasiak, A. & Tchorzewski, H. Lipopolysaccharide-activated CD4+CD25+ T regulatory cells inhibit neutrophil function and promote their apoptosis and death. J. Immunol. 177, 7155–7163 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Wood, K. J. & Sawitzki, B. Interferon γ: a crucial role in the function of induced regulatory T cells in vivo. Trends Immunol. 27, 183–187 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Farrar, M. A. & Schreiber, R. D. The molecular cell biology of interferon-γ and its receptor. Annu. Rev. Immunol. 11, 571–611 (1993).

    Article  CAS  PubMed  Google Scholar 

  64. Tang, Q. et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nature Immunol. 7, 83–92 (2006).

    Article  CAS  Google Scholar 

  65. Sarween, N. et al. CD4+CD25+ cells controlling a pathogenic CD4 response inhibit cytokine differentiation, CXCR-3 expression, and tissue invasion. J. Immunol. 173, 2942–2951 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Chen, Z., Herman, A. E., Matos, M., Mathis, D. & Benoist, C. Where CD4+CD25+ T reg cells impinge on autoimmune diabetes. J. Exp. Med. 202, 1387–1397 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Roncarolo, M. G., Battaglia, M. & Gregori, S. The role of interleukin 10 in the control of autoimmunity. J. Autoimmun. 20, 269–272 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Peng, Y., Laouar, Y., Li, M. O., Green, E. A. & Flavell, R. A. TGF-β regulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes. Proc. Natl Acad. Sci. USA 101, 4572–4577 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Battaglia, M. et al. Induction of tolerance in type 1 diabetes via both CD4+CD25+ T regulatory cells and T regulatory type 1 cells. Diabetes 55, 1571–1580 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Chen, C., Lee, W. H., Zhong, L. & Liu, C. P. Regulatory T cells can mediate their function through the stimulation of APCs to produce immunosuppressive nitric oxide. J. Immunol. 176, 3449–3460 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Battaglia, M., Gregori, S., Bacchetta, R. & Roncarolo, M. G. Tr1 cells: from discovery to their clinical application. Semin. Immunol. 18, 120–127 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Sakaguchi, S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nature Immunol. 6, 345–352 (2005).

    Article  CAS  Google Scholar 

  73. 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 

  74. Singh, B. et al. Control of intestinal inflammation by regulatory T cells. Immunol. Rev. 182, 190–200 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Shevach, E. M. et al. The lifestyle of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells. Immunol. Rev. 212, 60–73 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Scheffold, A., Hühn, J. & Höfer, T. Regulation of CD4+CD25+ regulatory T cell activity: it takes (IL-) two to tango. Eur. J. Immunol. 35, 1336–1341 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Levings, M. K. et al. Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. Blood 105, 1162–1169 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. 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 

  79. Ziegler, S. F. FOXP3: of mice and men. Annu. Rev. Immunol. 24, 209–226 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. 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 

  81. 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 

  82. Zhao, D. M., Thornton, A. M., DiPaolo, R. J. & Shevach, E. M. Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood 107, 3925–3932 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Grossman, W. J. et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21, 589–601 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Chen, D. et al. CD4+CD25+ regulatory T-cells inhibit the islet innate immune response and promote islet engraftment. Diabetes 55, 1011–1021 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Ding, Q. et al. B7H1-Ig fusion protein activates the CD4+ IFN-γ receptor+ type 1 T regulatory subset through IFN-γ-secreting Th1 cells. J. Immunol. 177, 3606–3614 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. 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 

  87. Masteller, E. L. et al. Expansion of functional endogenous antigen-specific CD4+CD25+ regulatory T cells from nonobese diabetic mice. J. Immunol. 175, 3053–3059 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Chen, C., Lee, W. H., Yun, P., Snow, P. & Liu, C. P. Induction of autoantigen-specific Th2 and Tr1 regulatory T cells and modulation of autoimmune diabetes. J. Immunol. 171, 733–744 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. You, S. et al. Presence of diabetes-inhibiting, glutamic acid decarboxylase-specific, IL-10-dependent, regulatory T cells in naive nonobese diabetic mice. J. Immunol. 173, 6777–6785 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Hori, S., Haury, M., Coutinho, A. & Demengeot, J. Specificity requirements for selection and effector functions of CD25+4+ regulatory T cells in anti-myelin basic protein T cell receptor transgenic mice. Proc. Natl Acad. Sci. USA 99, 8213–8218 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kohm, A. P., Carpentier, P. A., Anger, H. A. & Miller, S. D. Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J. Immunol. 169, 4712–4716 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Morgan, M. E. et al. Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis Rheum. 52, 2212–2221 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Cong, Y., Weaver, C. T., Lazenby, A. & Elson, C. O. Bacterial-reactive T regulatory cells inhibit pathogenic immune responses to the enteric flora. J. Immunol. 169, 6112–6119 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Scalapino, K. J., Tang, Q., Bluestone, J. A., Bonyhadi, M. L. & Daikh, D. I. Suppression of disease in New Zealand Black/New Zealand White lupus-prone mice by adoptive transfer of ex vivo expanded regulatory T cells. J. Immunol. 177, 1451–1459 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. 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 

  96. 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 

Download references

Acknowledgements

The authors thank R. Bacchetta and S. Gregori (HSR-TIGET) for scientific discussions. M.-G.R. is supported by grants from the Telethon Foundation, RISET and the Juvenile Diabetes Research Foundation (JDRF). M.B. is supported by grants from Telethon and the JDRF.

Author information

Authors and Affiliations

  1. San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Via Olgettina-58, Milan, 20132, Italy

    Maria-Grazia Roncarolo & Manuela Battaglia

  2. Vita-Salute San Raffaele University, Milan, 20132, Italy

    Maria-Grazia Roncarolo

  3. San Raffaele Scientific Institute, Immunology of Diabetes Unit, Milan, 20132, Italy

    Manuela Battaglia

Authors
  1. Maria-Grazia Roncarolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manuela Battaglia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria-Grazia Roncarolo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Maria-Grazia Roncarolo's homepage

RISET transplantation tolerance

The European Agency for the Evaluation of Medicinal Products

U.S. Food and Drug Administration

Glossary

Negative selection

The deletion of self-reactive thymocytes in the thymus. Thymocytes expressing T-cell receptors that strongly recognize self peptide bound to self MHC molecules undergo apoptosis in response to the signalling generated by high-affinity binding.

Graft-versus-host disease

(GVHD). A frequent complication after allogeneic stem-cell transplantation caused by the expansion of donor lymphocytes with helper and cytotoxic reactivity against host histocompatibility antigens. It can occur as two distinct syndromes: acute GVHD (occurring within 100 days) and chronic GVHD (occurring after 100 days). Complete depletion of T cells from the transplant largely eliminates GVHD but significantly increases the risk of graft failure and infections.

Mixed chimerism

A state of coexistence of the host and allogeneic donor haematopoietic cells.

IPEX

(Immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome). A disease caused by mutations in FOXP3 (forkhead box P3) and characterized by refractory enteritis and, in some patients, autoimmune endocrinopathies, autoimmune diabetes and thyroiditis. Unlike scurfy mice, peripheral-blood mononuclear cells from IPEX patients fail to produce cytokines after in vitro stimulation.

WAS

(Wiskott–Aldrich syndrome). A life-threatening X-linked immunodeficiency caused by mutation in the WAS protein. It is characterized by thrombocytopaenia with small platelets, eczema, recurrent infections caused by immunodeficiency, and an increased incidence of autoimmune manifestations and malignancies.

APS

(Autoimmune polyglandular syndrome; also known as APECED). APS type 1 is caused by the loss of central tolerance due to mutations in autoimmune regulator (AIRE), where as APS type 2 is of unknown pathogenesis besides an association with polymorphisms in CTLA4 and an HLA-extended haplotype. It is characterized by multiple endocrine diseases initiated by an autoimmune process.

ALPS

(Autoimmune lymphoproliferative syndrome). A syndrome associated with diffuse autoimmune manifestations. ALPS type Ia patients have mutations in TNFRSF6, which encodes CD95; ALPS type Ib patients have mutations in TNFSF6, which encodes CD95 ligand; ALPS type II patients have mutations in CASP10, which encodes caspase-10.

Homeostatic proliferation

Spontaneous proliferation of T cells in lymphopenic conditions, caused by chronic diseases or treatments such as thymectomy or irradiation. Factors that support T-cell homeostatic proliferation include peptide–MHC–TCR interactions and cytokines such as interleukin-7 and interleukin-15.

Rapamycin

An immunosuppressive drug that, in contrast to calcineurin inhibitors (such as cyclosporin A and FK506), does not prevent T-cell activation but blocks interleukin-2-mediated clonal expansion by blocking mTOR (mammalian target of rapamycin). It does not interfere with the function and expansion of naturally occurring regulatory T cells.

Bystander suppression

Suppression in which responses to a second, unrelated antigen can be inhibited when it is presented together with the antigen towards which tolerance has been already established.

Leukapheresis

A laboratory procedure for separating high numbers of leukocytes from peripheral blood.

Cytokine storm

A strong systemic immune response that results in the release of more than 150 inflammatory mediators (cytokines, oxygen free radicals and coagulation factors). Both pro-inflammatory cytokines (such as tumour-necrosis factor, interleukin-1 (IL-1) and IL-6) and anti-inflammatory cytokines (such as IL-10 and IL-1 receptor antagonist) are elevated in the serum of patients experiencing a cytokine storm.

Scurfy mice

Loss-of-function mutations of Foxp3 in scurfy mice inhibit the development of naturally occurring regulatory T cells, resulting in a highly dysregulated immune system and consequent aggressive autoimmunity. These mice show hyperproduction of cytokines and increased numbers of memory T cells.

CD95–CD95 ligand apoptotic pathway

CD95 ligand (also known as FAS ligand) binds to CD95 (FAS), which results in the formation of the death-inducing signalling complex and subsequent activation of caspases. Donor CD4+ T cells with killing capability preferentially use this pathway during acute graft-versus-host disease.

Interleukin-1 receptor antagonist

(IL-1RA). A secreted protein that binds to IL-1R, thereby blocking IL-1R downstream signalling. IL-1RA inhibits the pro-inflammatory properties of IL-1α and IL-1β.

Nitric oxide

(NO). A small molecule synthesized, mainly in macrophages, from arginine by nitric oxide synthase (NOS) enzymes. Increased levels of NO are found in inflammatory and autoimmune diseases, and during allograft rejection. It is the effector cytotoxic molecule responsible for macrophage-mediated cytotoxicity but can also suppress T-cell proliferation.

Graft-versus-leukaemia

(GVL). An immune response mounted by the transplanted cells against the tumour cells of the host and it is one of the reasons that allogeneic transplants can be curative for cancer.

Donor lymphocyte infusion

(DLI). Delayed administration of peripheral donor lymphocytes after T-cell-depleted bone-marrow transplantation in cancer patients. DLI plays a central role in both attacking the tumour cells and providing immune reconstitution. However, its use is limited by the risk of severe acute and chronic graft-versus-host disease.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roncarolo, MG., Battaglia, M. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat Rev Immunol 7, 585–598 (2007). https://doi.org/10.1038/nri2138

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2138

This article is cited by

Search

Advanced 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