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  • Review Article
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TREG-cell therapies for autoimmune rheumatic diseases

Nature Reviews Rheumatology volume 10, pages 543–551 (2014)Cite this article

Subjects

Key Points

  • Regulatory T (TREG) cells maintain immunological tolerance and prevent autoimmunity by inhibiting the activation and proliferation of immune effector cells

  • Constitutive expression and induced expression of forkhead box protein 3 (FOXP3) are hallmarks of natural TREG cells and peripheral TREG cells, respectively

  • Human FOXP3-expressing cells are heterogeneous and some FOXP3+CD4+ T cells are not immunosuppresive

  • Defective TREG-cell function in mice can cause multisystemic diseases, including rheumatic diseases

  • Abnormal TREG-cell number and function are common in patients with rheumatic diseases, including systemic lupus erythematosus and rheumatoid arthritis

  • Based on the current knowledge of TREG-cell biology, several therapeutic strategies could be used to treat rheumatic diseases: in vitro expansion, in vivo expansion or in vitro induction of antigen-specific TREG cells

Abstract

Naturally occurring Foxp3+CD25+CD4+ regulatory T (TREG) cells maintain immunological self-tolerance and prevent a variety of autoimmune diseases, including rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus. In animal models of rheumatic disease, autoimmune responses can be controlled by re-establishing the T-cell balance in favour of TREG cells. Here we discuss three potential strategies for the clinical use of TREG cells to treat autoimmune rheumatic disease: expansion of self-antigen-specific natural TREG cells in vivo; propagation of antigen-specific natural TREG cells ex vivo, by in vitro antigenic stimulation, and subsequent transfer back into the host; or conversion of antigen-specific conventional T cells into TREG cells in vivo or ex vivo. These strategies require depletion of the effector T cells that mediate autoimmunity before initiating TREG-cell-based therapies. Immunotherapies that target TREG cells, and the balance of TREG cells and autoreactive T cells, are therefore an important modality for the treatment of autoimmune rheumatic disease.

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Figure 1: Ontogeny of human FOXP3-expressing CD4+ T cells.
Figure 2: Possible TREG-cell therapeutic strategies.

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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. 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 

  3. Kim, J. M., Rasmussen, J. P. & Rudensky, A. Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8, 191–197 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. 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 

  5. 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 

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

    Article  CAS  PubMed  Google Scholar 

  7. Wildin, R. S. & Freitas, A. IPEX and FOXP3: clinical and research perspectives. J. Autoimmun. 25 (Suppl.), 56–62 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930–939 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tse, K., Tse, H., Sidney, J., Sette, A. & Ley, K. T cells in atherosclerosis. Int. Immunol. 25, 615–622 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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 

  11. Miyara, M. et al. Human Foxp3+ regulatory T cells in systemic autoimmune diseases. Autoimmun. Rev. 10, 744–755 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. de Lafaille, M. A. C., Lino, A. C., Kutchukhidze, N. & Lafaille, J. J. CD25− T cells generate CD25+Foxp3+ regulatory T cells by peripheral expansion. J. Immunol. 173, 7259–7268 (2004).

    Article  Google Scholar 

  13. Fantini, M. C. et al. Cutting edge: TGF-β induces a regulatory phenotype in CD4+CD25− T cells through Foxp3 induction and down-regulation of Smad7. J. Immunol. 172, 5149–5153 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Fu, S. et al. TGF-β induces Foxp3+T-regulatory cells from CD4+CD25-precursors. Am. J. Transplant. 4, 1614–1627 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Zheng, S. G., Wang, J. H., Gray, J. D., Soucier, H. & Horwitz, D. A. Natural and induced CD4+CD25+ cells educate CD4+CD25− cells to develop suppressive activity: The role of IL-2, TGF-β, and IL-10. J. Immunol. 172, 5213–5221 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Liang, S. et al. Conversion of CD4+ CD25− cells into CD4+ CD25+ regulatory T cells in vivo requires B7 costimulation, but not the thymus. J. Exp. Med. 201, 127–137 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Thornton, A. M. et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J. Immunol. 184, 3433–3441 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Yadav, M. et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J. Exp. Med. 209, 1713–1722, S1–S19 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Weiss, J. M. et al. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J. Exp. Med. 209, 1723–1742, S1 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Benson, M. J., Pino-Lagos, K., Rosemblatt, M. & Noelle, R. J. All-trans retinoic acid mediates enhanced TREG cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J. Exp. Med. 204, 1765–1774 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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 

  22. Denning, T. L., Wang, Y. C., Patel, S. R., Williams, I. R. & Pulendran, B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat. Immunol. 8, 1086–1094 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Sun, C. M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 TREG cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Atarashi, K. et al. TREG induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic TREG cell homeostasis. Science 341, 569–573 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tanaka, S. et al. Graded attenuation of TCR signaling elicits distinct autoimmune diseases by altering thymic T cell selection and regulatory T cell function. J. Immunol. 185, 2295–2305 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Liu, W. H. 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 

  31. 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 

  32. Ukena, S. N. et al. Isolation strategies of regulatory T cells for clinical trials: phenotype, function, stability, and expansion capacity. Exp. Hematol. 39, 1152–1160 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. 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 

  34. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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-beta-dependent but does not confer a regulatory phenotype. Blood 110, 2983–2990 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang, J., Ioan-Facsinay, A., Van der Voort, E. I. H., Huizinga, T. W. J. & Toes, R. E. M. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur. J. Immunol. 37, 129–138 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. 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 

  38. Milpied, P. et al. Neuropilin-1 is not a marker of human Foxp3+ TREG . Eur. J. Immunol. 39, 1466–1471 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Akimova, T., Beier, U. H., Wang, L., Levine, M. H. & Hancock, W. W. Helios expression is a marker of T cell activation and proliferation. PLoS ONE 6, e24226 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Himmel, M. E., MacDonald, K. G., Garcia, R. V., Steiner, T. S. & Levings, M. K. Helios+ and Helios− cells coexist within the natural FOXP3+ T regulatory cell subset in humans. J. Immunol. 190, 2001–2008 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Miyara, M. & Sakaguchi, S. Human Foxp3+CD4+ regulatory T cells: their knowns and unknowns. Immunol. Cell Biol. 89, 346–351 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. 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 

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

    Article  CAS  PubMed  Google Scholar 

  44. 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 

  45. Rubtsov, Y. P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546–558 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. 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 

  47. Li, M. O., Wan, Y. Y. & Flavell, R. A. T cell-produced transforming growth factor-β1 controls T cell tolerance and regulates TH1- and TH17-cell differentiation. Immunity 26, 579–591 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. 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 

  49. Onishi, Y., Fehervari, Z., Yamaguchi, T. & Sakaguchi, S. Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc. Natl Acad. Sci. USA 105, 10113–10118 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  51. Puccetti, P. & Grohmann, U. IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-κB activation. Nat. Rev. Immunol. 7, 817–823 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Cobbold, S. P. et al. Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc. Natl Acad. Sci. USA 106, 12055–12060 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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 

  54. Thornton, A. M. & Shevach, E. M. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J. Immunol. 164, 183–190 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Sakaguchi, S., Vignali, D. A., Rudensky, A. Y., Niec, R. E. & Waldmann, H. The plasticity and stability of regulatory T cells. Nat. Rev. Immunol. 13, 461–467 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Zheng, Y. et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458, 351–356 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chaudhry, A. et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326, 986–991 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Bailey-Bucktrout, S. L. et al. Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity 39, 949–962 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Esposito, M. et al. IL-17- and IFN-γ-secreting Foxp3+ T cells infiltrate the target tissue in experimental autoimmunity. J. Immunol. 185, 7467–7473 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Marson, A. et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445, 931–935 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zheng, Y. et al. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445, 936–940 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Wu, Y. et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375–387 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Ono, M. et al. Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 446, 685–689 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Willerford, D. M. et al. Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521–530 (1995).

    Article  CAS  PubMed  Google Scholar 

  66. Suzuki, H. et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor β. Science 268, 1472–1476 (1995).

    Article  CAS  PubMed  Google Scholar 

  67. Fontenot, J. D., Rasmussen, J. P., Gavin, M. A. & Rudensky, A. Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6, 1142–1151 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Burchill, M. A., Yang, J., Vogtenhuber, C., Blazar, B. R. & Farrar, M. A. IL-2 receptor β-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J. Immunol. 178, 280–290 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Caudy, A. A., Reddy, S. T., Chatila, T., Atkinson, J. P. & Verbsky, J. W. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J. Allergy Clin. Immunol. 119, 482–487 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. 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 

  71. 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 

  72. Kawahata, K. et al. Generation of CD4+CD25+ regulatory T cells from autoreactive T cells simultaneously with their negative selection in the thymus and from nonautoreactive T cells by endogenous TCR expression. J. Immunol. 168, 4399–4405 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  74. Sakaguchi, S., Takahashi, T. & Nishizuka, Y. Study on cellular events in postthymectomy autoimmune oophoritis in mice. I. Requirement of Lyt-1 effector cells for oocytes damage after adoptive transfer. J. Exp. Med. 156, 1565–1576 (1982).

    Article  CAS  PubMed  Google Scholar 

  75. 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 

  76. 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 

  77. 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 

  78. Waterhouse, P. et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270, 985–988 (1995).

    Article  CAS  PubMed  Google Scholar 

  79. Tivol, E. A. et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3, 541–547 (1995).

    Article  CAS  PubMed  Google Scholar 

  80. Cao, D. J., van Vollenhoven, R., Klareskog, L., Trollmo, C. & Malmström, V. CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease. Arthritis Res. Ther. 6, R335–R346 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Liu, M. F., Wang, C. R., Fung, L. L., Lin, L. H. & Tsai, C. N. The presence of cytokine-suppressive CD4+CD25+ T cells in the peripheral blood and synovial fluid of patients with rheumatoid arthritis. Scand. J. Immunol. 62, 312–317 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Jiao, Z. et al. Accumulation of Foxp3-expressing CD4+CD25+ T cells with distinct chemokine receptors in synovial fluid of patients with active rheumatoid arthritis. Scand. J. Rheumatol. 36, 428–433 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. van Amelsfort, J. M. R., Jacobs, K. M. G., Bijlsma, J. W. J., Lafeber, F. & 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 

  84. Afzali, B. et al. CD161 expression characterizes a subpopulation of human regulatory T cells that produces IL-17 in a STAT3-dependent manner. Eur. J. Immunol. 43, 2043–2054 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Walter, G. J. et al. Interaction with activated monocytes enhances cytokine expression and suppressive activity of human CD4+CD45RO+CD25+CD127low regulatory T cells. Arthritis Rheum. 65, 627–638 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Herrath, J. et al. The inflammatory milieu in the rheumatic joint reduces regulatory T-cell function. Eur. J. Immunol. 41, 2279–2290 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. 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 

  88. Grinberg-Bleyer, Y. et al. Pathogenic T cells have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs. J. Clin. Invest. 120, 4558–4568 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ali, Y. & Shah, S. Infliximab-induced systemic lupus erythematosus. Ann. Intern. Med. 137, 625–626 (2002).

    Article  PubMed  Google Scholar 

  90. Favalli, E. G., Sinigaglia, L., Varenna, M. & Arnoldi, C. Drug-induced lupus following treatment with infliximab in rheumatoid arthritis. Lupus 11, 753–755 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. de Kleer, I. M. et al. CD4+CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J. Immunol. 172, 6435–6443 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Ruprecht, C. R. et al. Coexpression of CD25 and CD27 identifies Foxp3+ regulatory T cells in inflamed synovia. J. Exp. Med. 201, 1793–1803 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Haufe, S. et al. Impaired suppression of synovial fluid CD4+CD25− T cells from patients with juvenile idiopathic arthritis by CD4+CD25+ TREG cells. Arthritis Rheum. 63, 3153–3162 (2011).

    Article  CAS  PubMed  Google Scholar 

  94. Wehrens, E. J. et al. Functional human regulatory T cells fail to control autoimmune inflammation due to PKB/c-Akt hyperactivation in effector cells. Blood 118, 3538–3548 (2011).

    Article  CAS  PubMed  Google Scholar 

  95. de Kleer, I. et al. Autologous stem cell transplantation for autoimmunity induces immunologic self-tolerance by reprogramming autoreactive T cells and restoring the CD4+CD25+ immune regulatory network. Blood 107, 1696–1702 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Kishimoto, T. Interleukin-6: from basic science to medicine—40 years in immunology. Annu. Rev. Immunol. 23, 1–21 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Feldmann, M. & Maini, S. R. Role of cytokines in rheumatoid arthritis: an education in pathophysiology and therapeutics. Immunol. Rev. 223, 7–19 (2008).

    Article  CAS  PubMed  Google Scholar 

  98. Pieper, J. et al. CTLA4-Ig (abatacept) therapy modulates T cell effector functions in autoantibody-positive rheumatoid arthritis patients. BMC Immunol. 14, 34 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. 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 

  100. Miyara, M. et al. Global natural regulatory T cell depletion in active systemic lupus erythematosus. J. Immunol. 175, 8392–8400 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Venigalla, R. K. et al. Reduced CD4+, CD25− T cell sensitivity to the suppressive function of CD4+, CD25high, CD127−/low regulatory T cells in patients with active systemic lupus erythematosus. Arthritis Rheum. 58, 2120–2130 (2008).

    Article  PubMed  Google Scholar 

  102. Solomou, E. E., Juang, Y. T., Gourley, M. F., Kammer, G. M. & Tsokos, G. C. Molecular basis of deficient IL-2 production in T cells from patients with systemic lupus erythematosus. J. Immunol. 166, 4216–4222 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Stephens, L. A., Malpass, K. H. & Anderton, S. M. Curing CNS autoimmune disease with myelin-reactive Foxp3+ TREG . Eur. J. Immunol. 39, 1108–1117 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. 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 

  105. 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 

  106. Godebu, E., Summers-Torres, D., Lin, M. M., Baaten, B. J. & Bradley, L. M. Polyclonal adaptive regulatory CD4 cells that can reverse type I diabetes become oligoclonal long-term protective memory cells. J. Immunol. 181, 1798–1805 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. McGeachy, M. J., Stephens, L. A. & Anderton, S. M. Natural recovery and protection from autoimmune encephalomyelitis: contribution of CD4+CD25+ regulatory cells within the central nervous system. J. Immunol. 175, 3025–3032 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Korn, T. et al. Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat. Med. 13, 423–431 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 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 

  110. Zhou, X. et al. Cutting edge: all-trans retinoic acid sustains the stability and function of natural regulatory T cells in an inflammatory milieu. J. Immunol. 185, 2675–2679 (2010).

    Article  CAS  PubMed  Google Scholar 

  111. Kong, N. et al. Antigen-specific transforming growth factor beta-induced TREG cells, but not natural TREG cells, ameliorate autoimmune arthritis in mice by shifting the TH17/TREG cell balance from TH17 predominance to TREG cell predominance. Arthritis Rheum. 64, 2548–2558 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. van Herwijnen, M. J. et al. Regulatory T cells that recognize a ubiquitous stress-inducible self-antigen are long-lived suppressors of autoimmune arthritis. Proc. Natl Acad. Sci. USA 109, 14134–14139 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Sakaguchi, N. et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426, 454–460 (2003).

    Article  CAS  PubMed  Google Scholar 

  114. Humrich, J. Y. et al. Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus. Proc. Natl Acad. Sci. USA 107, 204–209 (2010).

    Article  CAS  PubMed  Google Scholar 

  115. Weigert, O. et al. CD4+Foxp3+ regulatory T cells prolong drug-induced disease remission in (NZB×NZW) F1 lupus mice. Arthritis Res. Ther. 15, R35 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Hasegawa, H. et al. Therapy for pneumonitis and sialadenitis by accumulation of CCR2-expressing CD4+CD25+ regulatory T cells in MRL/lpr mice. Arthritis Res. Ther. 9, R15 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Wright, G. P. et al. Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis. Proc. Natl Acad. Sci. USA 106, 19078–19083 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Zhang, J. L. et al. CD3 mAb treatment ameliorated the severity of the cGVHD-induced lupus nephritis in mice by up-regulation of Foxp3+ regulatory T cells in the target tissue: kidney. Transpl. Immunol. 24, 17–25 (2010).

    Article  PubMed  CAS  Google Scholar 

  119. Battaglia, M., Stabilini, A. & Roncarolo, M. G. Rapamycin selectively expands CD4+CD25+Foxp3+ regulatory T cells. Blood 105, 4743–4748 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. 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 

  121. Strauss, L. et al. Selective survival of naturally occurring human CD4+CD25+Foxp3+ regulatory T cells cultured with rapamycin. J. Immunol. 178, 320–329 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Smolen, J. S., Aletaha, D. & Redlich, K. The pathogenesis of rheumatoid arthritis: new insights from old clinical data? Nat. Rev. Rheumatol. 8, 235–243 (2012).

    Article  CAS  PubMed  Google Scholar 

  123. Koreth, J. et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N. Engl. J. Med. 365, 2055–2066 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Saadoun, D. et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N. Engl. J. Med. 365, 2067–2077 (2011).

    Article  CAS  PubMed  Google Scholar 

  125. Long, S. A. et al. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments TREGS yet transiently impairs beta-cell function. Diabetes 61, 2340–2348 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Hippen, K. L., Riley, J. L., June, C. H. & Blazar, B. R. Clinical perspectives for regulatory T cells in transplantation tolerance. Semin. Immunol. 23, 462–468 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. 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 

  128. Benson, M. J., Pino-Lagos, K., Rosemblatt, M. & Noelle, R. J. All-trans retinoic acid mediates enhanced T REG cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J. Exp. Med. 204, 1765–1774 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. 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 

  130. Polansky, J. K. et al. DNA methylation controls Foxp3 gene expression. Eur. J. Immunol. 38, 1654–1663 (2008).

    Article  CAS  PubMed  Google Scholar 

  131. Floess, S. et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 5, e38 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Kim, H. P. & Leonard, W. J. CREB/ATF-dependent T cell receptor-induced Foxp3 gene expression: a role for DNA methylation. J. Exp. Med. 204, 1543–1551 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ohkura, N. et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for TREG cell development. Immunity 37, 785–799 (2012).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

M.M. was supported by Association Lupus France, SNFMI, Association Francophone contre la Polychondrite Chronique Atrophiante and by Fondation ARTHRITIS Courtin. S.S. was supported by Grants-in-Aid for Specially Promoted Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by Core Research for Evolutional Science and Technology (CREST) from Japan Science and Technology Agency.

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Authors and Affiliations

  1. Department of Immunology, Department of Internal Medicine, Pitié-Salpêtrière Hospital, APHP, 83 Boulevard de l'Hôpital, Paris, 75013, France

    Makoto Miyara

  2. Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan

    Yoshinaga Ito

  3. Department of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Shimon Sakaguchi

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  1. Makoto Miyara
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  2. Yoshinaga Ito
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All authors researched the data for the article, provided substantial contribution to discussions of the content, contributed to writing the article and to reviewing and editing the manuscript before submission.

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Correspondence to Shimon Sakaguchi.

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Miyara, M., Ito, Y. & Sakaguchi, S. TREG-cell therapies for autoimmune rheumatic diseases. Nat Rev Rheumatol 10, 543–551 (2014). https://doi.org/10.1038/nrrheum.2014.105

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