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Regulatory T cells as therapeutic targets in rheumatoid arthritis

Nature Reviews Rheumatology volume 5, pages 560–565 (2009)Cite this article

Abstract

Regulatory T cells (TREG) are a subset of CD4+ T cells with a critical role in the prevention of autoimmunity. Whether defects in TREG contribute to the pathogenesis of rheumatoid arthritis (RA) is unclear. However, a variety of approved and experimental drugs for RA may work, in part, by promoting the function or increasing numbers of TREG. Furthermore, animal studies demonstrate that direct injection of TREG ameliorates a wide range of experimental models of inflammatory and autoimmune diseases. Thus, cell-based therapy with TREG has the potential to produce durable disease remission in patients with RA.

Key Points

  • FOXP3+ regulatory T cells (TREG) control autoimmunity in humans

  • Some evidence suggests that patients with rheumatoid arthritis have defects in TREG, but whether these defects are the cause or result of chronic inflammation is not clear

  • Several approved and experimental drugs promote function or increase numbers of TREG, and these effects may be responsible for these drugs' efficacy in treating RA

  • Cellular therapy with autologous ex vivo expanded TREG may prove effective as a treatment for patients with RA

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Figure 1: Effects on TREG of various therapies for RA.

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References

  1. Tang, Q. & Bluestone, J. A. Regulatory T-cell physiology and application to treat autoimmunity. Immunol. Rev. 212, 217–237 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Liu, W. et al. CD127 expression inversely correlates with FOXP3 and suppressive function of human CD4+ TREG cells. J. Exp. Med. 203, 1701–1711 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Putnam, A. L. et al. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes 58, 652–662 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Shevach, E. M. Mechanisms of Foxp3+ T regulatory cell-mediated suppression. Immunity 30, 636–645 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Andre, S., Tough, D. F., Lacroix-Desmazes, S., Kaveri, S. V. & Bayry, J. Surveillance of antigen-presenting cells by CD4+ CD25+ regulatory T cells in autoimmunity: immunopathogenesis and therapeutic implications. Am. J. Pathol. 174, 1575–1587 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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 

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

    Article  CAS  PubMed  Google Scholar 

  8. 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 

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

    Article  CAS  PubMed  Google Scholar 

  10. Mazzolari, E. et al. A new case of IPEX receiving bone marrow transplantation. Bone Marrow Transplant. 35, 1033–1034 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Dorsey, M. J., Petrovic, A., Morrow, M. R., Dishaw, L. J. & Sleasman, J. W. FOXP3 expression following bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Immunol. Res. 44, 179–184 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Baud, O. et al. Treatment of the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) by allogeneic bone marrow transplantation. N. Engl. J. Med. 344, 1758–1762 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Rao, A. et al. Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Blood 109, 383–385 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Seidel, M. G. et al. Selective engraftment of donor CD4+25high FOXP3-positive T cells in IPEX syndrome after nonmyeloablative hematopoietic stem cell transplantation. Blood 113, 5689–5691 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Wang, J., Wicker, L. S. & Santamaria, P. IL-2 and its high-affinity receptor: genetic control of immunoregulation and autoimmunity. Semin. Immunol. doi:10.1016/j.smim.2009.04.004.

    Article  CAS  PubMed  Google Scholar 

  16. 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 

  17. Miyara, M. et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FOXP3 transcription factor. Immunity 30, 899–911 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Floess, S. et al. Epigenetic control of the FOXP3 locus in regulatory T cells. PLoS Biol. 5, e38 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhou, L., Chong, M. M. & Littman, D. R. Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646–655 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Wieczorek, G. et al. Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue. Cancer Res. 69, 599–608 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Brusko, T. M., Putnam, A. L. & Bluestone, J. A. Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. Immunol. Rev. 223, 371–390 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. 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 

  23. Michel, L. et al. Patients with relapsing–remitting multiple sclerosis have normal TREG function when cells expressing IL-7 receptor α-chain are excluded from the analysis. J. Clin. Invest. 118, 3411–3419 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. van Amelsfort, J. M., Jacobs, K. M., Bijlsma, J. W., Lafeber, F. P. & Taams, L. S. CD4+CD25+ regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum. 50, 2775–2785 (2004).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mottonen, M. et al. CD4+ CD25+ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis. Clin. Exp. Immunol. 140, 360–367 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Flores-Borja, F., Jury, E. C., Mauri, C. & Ehrenstein, M. R. Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 105, 19396–19401 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cao, D. et al. Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur. J. Immunol. 33, 215–223 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Lawson, C. A. et al. Early rheumatoid arthritis is associated with a deficit in the CD4+CD25high regulatory T cell population in peripheral blood. Rheumatology (Oxford) 45, 1210–1217 (2006).

    Article  CAS  Google Scholar 

  30. Lazarski, C. A., Hughson, A., Sojka, D. K. & Fowell, D. J. Regulating TREG cells at sites of inflammation. Immunity 29, 511–512 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Tang, Q. et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28, 687–697 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Valencia, X. et al. TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood 108, 253–261 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schneider, A. et al. The effector T cells of diabetic subjects are resistant to regulation via CD4+ FOXP3+ regulatory T cells. J. Immunol. 181, 7350–7355 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Nadkarni, S., Mauri, C. & Ehrenstein, M. R. Anti-TNF-α therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-β. J. Exp. Med. 204, 33–39 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Emery, P. et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann. Rheum. Dis. 67, 1516–1523 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Maini, R. N. et al. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum. 54, 2817–2829 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Jones, G. et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann. Rheum. Dis. doi:ard.2008.105197v1.

  38. Genovese, M. C. et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 58, 2968–2980 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. 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 

  40. Chen, X. et al. Blockade of interleukin-6 signaling augments regulatory T cell reconstitution and attenuates the severity of graft versus host disease. Blood 114, 891–900 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yang, L. et al. IL-21 and TGF-β are required for differentiation of human TH17 cells. Nature 454, 350–352 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dominitzki, S. et al. Cutting edge: trans-signaling via the soluble IL-6R abrogates the induction of FoxP3 in naive CD4+CD25 T cells. J. Immunol. 179, 2041–2045 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Acosta-Rodriguez, E. V., Napolitani, G., Lanzavecchia, A. & Sallusto, F. Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17-producing human T helper cells. Nat. Immunol. 8, 942–949 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. van Amelsfort, J. M. et al. Proinflammatory mediator-induced reversal of CD4+, CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis. Arthritis Rheum. 56, 732–742 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Linsley, P. S. & Nadler, S. G. The clinical utility of inhibiting CD28-mediated costimulation. Immunol. Rev. 229, 307–321 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Bluestone, J. A. et al. The effect of costimulatory and interleukin 2 receptor blockade on regulatory T cells in renal transplantation. Am. J. Transplant. 8, 2086–2096 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  48. Genovese, M. C. et al. Efficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy. Ann. Rheum. Dis. 67, 547–554 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Genovese, M. C. et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor α inhibition. N. Engl. J. Med. 353, 1114–1123 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Thomson, A. W., Turnquist, H. R. & Raimondi, G. Immunoregulatory functions of mTOR inhibition. Nat. Rev. Immunol. 9, 324–337 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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 

  52. Strauss, L., Czystowska, M., Szajnik, M., Mandapathil, M. & Whiteside, T. L. Differential responses of human regulatory T cells (TREG) and effector T cells to rapamycin. PLoS One 4, e5994 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nat. Immunol. 5, 987–995 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Conroy, H., Marshall, N. A. & Mills, K. H. TLR ligand suppression or enhancement of TREG cells? A double-edged sword in immunity to tumours. Oncogene 27, 168–180 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. van Maren, W. W., Jacobs, J. F., de Vries, I. J., Nierkens, S. & Adema, G. J. Toll-like receptor signalling on TREGs: to suppress or not to suppress? Immunology 124, 445–452 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hall, J. A. et al. Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. Immunity 29, 637–649 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Brentano, F., Schorr, O., Gay, R. E., Gay, S. & Kyburz, D. RNA released from necrotic synovial fluid cells activates rheumatoid arthritis synovial fibroblasts via Toll-like receptor 3. Arthritis Rheum. 52, 2656–2665 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Kyburz, D., Brentano, F. & Gay, S. Mode of action of hydroxychloroquine in RA—evidence of an inhibitory effect on Toll-like receptor signaling. Nat. Clin. Pract. Rheumatol. 2, 458–459 (2006).

    Article  PubMed  Google Scholar 

  59. Barrat, F. J., Meeker, T., Chan, J. H., Guiducci, C. & Coffman, R. L. Treatment of lupus-prone mice with a dual inhibitor of TLR7 and TLR9 leads to reduction of autoantibody production and amelioration of disease symptoms. Eur. J. Immunol. 37, 3582–3586 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  61. Lucas, J. L. et al. Induction of Foxp3+ regulatory T cells with histone deacetylase inhibitors. Cell. Immunol. 257, 97–104 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Koenen, H. J. et al. Human CD25highFOXP3+ regulatory T cells differentiate into IL-17-producing cells. Blood 112, 2340–2352 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. 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 

  64. Setoguchi, R., Hori, S., Takahashi, T. & Sakaguchi, S. Homeostatic maintenance of natural Foxp3+ CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J. Exp. Med. 201, 723–735 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Webster, K. E. et al. In vivo expansion of TREG cells with IL-2-mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J. Exp. Med. 206, 751–760 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wei, S. et al. Interleukin-2 administration alters the CD4+FOXP3+ T-cell pool and tumor trafficking in patients with ovarian carcinoma. Cancer Res. 67, 7487–7494 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Verburg, R. J. et al. High-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with rheumatoid arthritis: results of an open study to assess feasibility, safety, and efficacy. Arthritis Rheum. 44, 754–760 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Teng, Y. K. et al. Long-term followup of health status in patients with severe rheumatoid arthritis after high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation. Arthritis Rheum. 52, 2272–2276 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Snowden, J. A. et al. Autologous hemopoietic stem cell transplantation in severe rheumatoid arthritis: a report from the EBMT and ABMTR. J. Rheumatol. 31, 482–488 (2004).

    PubMed  Google Scholar 

  70. De Kleer, I. M. et al. Autologous stem cell transplantation for refractory juvenile idiopathic arthritis: analysis of clinical effects, mortality, and transplant related morbidity. Ann. Rheum. Dis. 63, 1318–1326 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Brinkman, D. M. et al. Autologous stem cell transplantation in children with severe progressive systemic or polyarticular juvenile idiopathic arthritis: long-term follow-up of a prospective clinical trial. Arthritis Rheum. 56, 2410–2421 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Snowden, J. A., Kapoor, S. & Wilson, A. G. Stem cell transplantation in rheumatoid arthritis. Autoimmunity 1, doi:10.1080/08916930802198550.

    Article  CAS  PubMed  Google Scholar 

  73. Komatsu, N. & Hori, S. Full restoration of peripheral Foxp3+ regulatory T cell pool by radioresistant host cells in scurfy bone marrow chimeras. Proc. Natl Acad. Sci. USA 104, 8959–8964 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Brusko, T. & Bluestone, J. Clinical application of regulatory T cells for treatment of type 1 diabetes and transplantation. Eur. J. Immunol. 38, 931–934 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Peters, J. H. et al. Clinical grade TREG: GMP isolation, improvement of purity by CD127 depletion, TREG expansion, and TREG cryopreservation. PLoS ONE 3, e3161 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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 

  77. 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 

  78. 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 

  79. 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 

  80. 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 

  81. Morgan, R. A. et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Arbour, N. et al. A new clinically relevant approach to expand myelin specific T cells. J. Immunol. Meth. 310, 53–61 (2006).

    Article  CAS  Google Scholar 

  83. Beriou, G. et al. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood 113, 4240–4249 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Voo, K. S. et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc. Natl Acad. Sci. USA 106, 4793–4798 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhou, X. et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. doi: 10.1038/ni.1774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Annunziato, F. et al. Phenotypic and functional features of human TH17 cells. J. Exp. Med. 204, 1849–1861 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Evans, H. G., Suddason, T., Jackson, I., Taams, L. S. & Lord, G. M. Optimal induction of T helper 17 cells in humans requires T cell receptor ligation in the context of Toll-like receptor-activated monocytes. Proc. Natl Acad. Sci. USA 104, 17034–17039 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Riley, J. L., June, C. H. & Blazar, B. R. Human T regulatory cell therapy: take a billion or so and call me in the morning. Immunity 30, 656–665 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Umbilical cord blood T-regulatory cell infusion followed by donor umbilical cord blood transplant in treating patients with high-risk leukemia or other hematologic diseases. ClinicalTrials.gov [online] (2009).

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Acknowledgements

The authors thank Todd Brusko and Amy Putnam for helpful discussions and for assistance with figure design.

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Authors and Affiliations

  1. Diabetes Center, University of California, San Francisco, CA, USA

    Jonathan H. Esensten & Jeffrey A. Bluestone

  2. Division of Rheumatology, University of California, San Francisco, CA, USA

    David Wofsy

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Correspondence to Jeffrey A. Bluestone.

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J. H. Esensten and D. Wofsy declare no competing interests. J. A. Bluestone has applied for a U.S. patent (“CD127 Expression Inversely Correlates with FoxP3 and Suppressive Function of CD4+ Tregs”, application number 20080131445) for a method of identifying of Tregs using CD127.

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Esensten, J., Wofsy, D. & Bluestone, J. Regulatory T cells as therapeutic targets in rheumatoid arthritis. Nat Rev Rheumatol 5, 560–565 (2009). https://doi.org/10.1038/nrrheum.2009.183

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