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Therapeutic Potential of Regulatory T cells in Autoimmune Disorders

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Abstract

Regulatory T cells (Tregs) play a dominant role in the regulation of immune responses. Quantitative and/or qualitative abnormalities of Tregs were observed in patients with autoimmune diseases and therapeutic interventions focusing Tregs are an attractive new target with the potential to cure these disorders. Biological agents approved for treatment of inflammatory rheumatic diseases transiently influence Treg prevalences and function and experimental therapies including novel biological agents, gene therapy, activation and ex vivo expansion of purified Tregs as well as substances influencing tolerogenic dendritic cells will be developed for selective Treg therapy. Although many of these interventions are effective in vitro, in animal models as well as in early clinical trials, significant concerns exist regarding the stability of Treg modifications as well as the long-term safety of Treg-based therapies.

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References

  1. Danke NA, Koelle DM, Yee C, Beheray S, Kwok WW. Autoreactive T cells in healthy individuals. J Immunol. 2004;172(10):5967–72.

    PubMed  CAS  Google Scholar 

  2. Dejaco C, Duftner C, Grubeck-Loebenstein B, Schirmer M. Imbalance of regulatory T cells in human autoimmune diseases. Immunology. 2006;117(3):289–300.

    Article  PubMed  CAS  Google Scholar 

  3. Piccirillo CA, Letterio JJ, Thornton AM, McHugh RS, Mamura M, Mizuhara H, et al. CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness. J Exp Med. 2002;196(2):237–46.

    Article  PubMed  CAS  Google Scholar 

  4. Zheng SG, Wang J, Wang P, Gray JD, Horwitz DA. IL-2 is essential for TGF-beta to convert naive CD4+CD25− cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells. J Immunol. 2007;178(4):2018–27.

    PubMed  CAS  Google Scholar 

  5. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27(1):20–1.

    Article  PubMed  CAS  Google Scholar 

  6. Tran DQ, Ramsey H, Shevach EM. 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. 2007;110(8):2983–90.

    Article  PubMed  CAS  Google Scholar 

  7. Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol. 2010;184(7):3433–41.

    Article  PubMed  CAS  Google Scholar 

  8. Akimova T, Beier UH, Wang L, Levine MH, Hancock WW. Helios expression is a marker of T cell activation and proliferation. PLoS One. 2011;6(8):e24226.

    Article  PubMed  CAS  Google Scholar 

  9. Thornton AM, Piccirillo CA, Shevach EM. Activation requirements for the induction of CD4+CD25+ T cell suppressor function. Eur J Immunol. 2004;34(2):366–76.

    Article  PubMed  CAS  Google Scholar 

  10. Qin S, Cobbold SP, Pope H, Elliott J, Kioussis D, Davies J, et al. “Infectious” transplantation tolerance. Science. 1993;259(5097):974–7.

    Article  PubMed  CAS  Google Scholar 

  11. Walunas TL, Bakker CY, Bluestone JA. CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med. 1996;183(6):2541–50.

    Article  PubMed  CAS  Google Scholar 

  12. Misra N, Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Kaveri SV. Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells. J Immunol. 2004;172(8):4676–80.

    PubMed  CAS  Google Scholar 

  13. Grossman WJ, Verbsky JW, Barchet W, Colonna M, Atkinson JP, Ley TJ. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity. 2004;21(4):589–601.

    Article  PubMed  CAS  Google Scholar 

  14. Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450(7169):566–9.

    Article  PubMed  CAS  Google Scholar 

  15. Collison LW, Pillai MR, Chaturvedi V, Vignali DA. Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner. J Immunol. 2009;182(10):6121–8.

    Article  PubMed  CAS  Google Scholar 

  16. Murai M, Turovskaya O, Kim G, Madan R, Karp CL, Cheroutre H, et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol. 2009;10(11):1178–84.

    Article  PubMed  CAS  Google Scholar 

  17. Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X, et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity. 2008;28(4):546–58.

    Article  PubMed  CAS  Google Scholar 

  18. Sundstedt A, O’Neill EJ, Nicolson KS, Wraith DC. Role for IL-10 in suppression mediated by peptide-induced regulatory T cells in vivo. J Immunol. 2003;170(3):1240–8.

    PubMed  CAS  Google Scholar 

  19. Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet. 2002;39(8):537–45.

    Article  PubMed  CAS  Google Scholar 

  20. Lawson CA, Brown AK, Bejarano V, Douglas SH, Burgoyne CH, Greenstein AS, et al. Early rheumatoid arthritis is associated with a deficit in the CD4+CD25high regulatory T cell population in peripheral blood. Rheumatology (Oxford). 2006;45(10):1210–7.

    Article  CAS  Google Scholar 

  21. Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med. 2004;200(3):277–85.

    Article  PubMed  CAS  Google Scholar 

  22. van Amelsfort JM, Jacobs KM, Bijlsma JW, Lafeber FP, Taams LS. CD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum. 2004;50(9):2775–85.

    Article  PubMed  Google Scholar 

  23. Han GM, O’Neil-Andersen NJ, Zurier RB, Lawrence DA. CD4+CD25high T cell numbers are enriched in the peripheral blood of patients with rheumatoid arthritis. Cell Immunol. 2008;253(1–2):92–101.

    Article  PubMed  CAS  Google Scholar 

  24. Mottonen M, Heikkinen J, Mustonen L, Isomaki P, Luukkainen R, Lassila O. 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. 2005;140(2):360–7.

    Article  PubMed  CAS  Google Scholar 

  25. Wang Y, Liu XP, Zhao ZB, Chen JH, Yu CG. Expression of CD4+ forkhead box P3 (FOXP3)+ regulatory T cells in inflammatory bowel disease. J Dig Dis. 2011;12(4):286–94.

    Article  PubMed  CAS  Google Scholar 

  26. Reddy J, Waldner H, Zhang X, Illes Z, Wucherpfennig KW, Sobel RA, et al. Cutting edge: CD4+CD25+ regulatory T cells contribute to gender differences in susceptibility to experimental autoimmune encephalomyelitis. J Immunol. 2005;175(9):5591–5.

    PubMed  CAS  Google Scholar 

  27. Marwaha AK, Crome SQ, Panagiotopoulos C, Berg KB, Qin H, Ouyang Q, et al. Cutting edge: Increased IL-17-secreting T cells in children with new-onset type 1 diabetes. J Immunol. 2010;185(7):3814–8.

    Article  PubMed  CAS  Google Scholar 

  28. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30(6):899–911.

    Article  PubMed  CAS  Google Scholar 

  29. Long SA, Cerosaletti K, Bollyky PL, Tatum M, Shilling H, Zhang S, et al. Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4(+)CD25(+) regulatory T-cells of type 1 diabetic subjects. Diabetes. 2010;59(2):407–15.

    Article  PubMed  CAS  Google Scholar 

  30. Brusko TM, Wasserfall CH, Clare-Salzler MJ, Schatz DA, Atkinson MA. Functional defects and the influence of age on the frequency of CD4+CD25+ T-cells in type 1 diabetes. Diabetes. 2005;54(5):1407–14.

    Article  PubMed  CAS  Google Scholar 

  31. Putnam AL, Vendrame F, Dotta F, Gottlieb PA. CD4+CD25high regulatory T cells in human autoimmune diabetes. J Autoimmun. 2005;24(1):55–62.

    Article  PubMed  CAS  Google Scholar 

  32. Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004;199(7):971–9.

    Article  PubMed  CAS  Google Scholar 

  33. Huan J, Culbertson N, Spencer L, Bartholomew R, Burrows GG, Chou YK, et al. Decreased FOXP3 levels in multiple sclerosis patients. J Neurosci Res. 2005;81(1):45–52.

    Article  PubMed  CAS  Google Scholar 

  34. Valencia X, Yarboro C, Illei G, Lipsky PE. Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol. 2007;178(4):2579–88.

    PubMed  CAS  Google Scholar 

  35. Zhang B, Zhang X, Tang F, Zhu L, Liu Y. Reduction of forkhead box P3 levels in CD4+CD25high T cells in patients with new-onset systemic lupus erythematosus. Clin Exp Immunol. 2008;153(2):182–7.

    Article  PubMed  CAS  Google Scholar 

  36. Han S, Li Y, Mao Y, Xie Y. Meta-analysis of the association of CTLA-4 exon-1 +49A/G polymorphism with rheumatoid arthritis. Hum Genet. 2005;118(1):123–32.

    Article  PubMed  CAS  Google Scholar 

  37. Barreto M, Santos E, Ferreira R, Fesel C, Fontes MF, Pereira C, et al. Evidence for CTLA4 as a susceptibility gene for systemic lupus erythematosus. Eur J Hum Genet. 2004;12(8):620–6.

    Article  PubMed  CAS  Google Scholar 

  38. Flores-Borja F, Jury EC, Mauri C, Ehrenstein MR. Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis. Proc Natl Acad Sci USA. 2008;105(49):19396–401.

    Article  PubMed  CAS  Google Scholar 

  39. Bonelli M, Savitskaya A, Steiner CW, Rath E, Smolen JS, Scheinecker C. Phenotypic and functional analysis of CD4+CD25− Foxp3+ T cells in patients with systemic lupus erythematosus. J Immunol. 2009;182(3):1689–95.

    PubMed  CAS  Google Scholar 

  40. Suen JL, Li HT, Jong YJ, Chiang BL, Yen JH. Altered homeostasis of CD4(+) FoxP3(+) regulatory T-cell subpopulations in systemic lupus erythematosus. Immunology. 2009;127(2):196–205.

    Article  PubMed  CAS  Google Scholar 

  41. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421(6924):744–8.

    Article  PubMed  CAS  Google Scholar 

  42. Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med. 2003;198(12):1951–7.

    Article  PubMed  CAS  Google Scholar 

  43. Wong CK, Lit LC, Tam LS, Li EK, Wong PT, Lam CW. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin Immunol. 2008;127(3):385–93.

    Article  PubMed  CAS  Google Scholar 

  44. Aringer M, Stummvoll GH, Steiner G, Koller M, Steiner CW, Hofler E, et al. Serum interleukin-15 is elevated in systemic lupus erythematosus. Rheumatology (Oxford). 2001;40(8):876–81.

    Article  CAS  Google Scholar 

  45. Gonzalez-Alvaro I, Ortiz AM, Garcia-Vicuna R, Balsa A, Pascual-Salcedo D, Laffon A. Increased serum levels of interleukin-15 in rheumatoid arthritis with long- term disease. Clin Exp Rheumatol. 2003;21(5):639–42.

    PubMed  CAS  Google Scholar 

  46. Ziolkowska M, Koc A, Luszczykiewicz G, Ksiezopolska-Pietrzak K, Klimczak E, Chwalinska-Sadowska H, et al. High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J Immunol. 2000;164(5):2832–8.

    PubMed  CAS  Google Scholar 

  47. Rossol M, Kraus S, Pierer M, Baerwald C, Wagner U. The CD14(bright) CD16+ monocyte subset is expanded in rheumatoid arthritis and promotes expansion of the Th17 cell population. Arthritis Rheum. 2012;64(3):671–7.

    Article  PubMed  CAS  Google Scholar 

  48. Beriou G, Costantino CM, Ashley CW, Yang L, Kuchroo VK, Baecher-Allan C, et al. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood. 2009;113(18):4240–9.

    Article  PubMed  CAS  Google Scholar 

  49. Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP, et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity. 2008;29(1):44–56.

    Article  PubMed  CAS  Google Scholar 

  50. Lal G, Zhang N, van der Touw W, Ding Y, Ju W, Bottinger EP, et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol. 2009;182(1):259–73.

    PubMed  CAS  Google Scholar 

  51. Lal G, Bromberg JS. Epigenetic mechanisms of regulation of Foxp3 expression. Blood. 2009;114(18):3727–35.

    Article  PubMed  CAS  Google Scholar 

  52. Huber S, Gagliani N, Esplugues E, O’Connor W Jr, Huber FJ, Chaudhry A, et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3(-) and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity. 2011;34(4):554–65.

    Article  PubMed  CAS  Google Scholar 

  53. Alvarez-Quiroga C, Abud-Mendoza C, Doniz-Padilla L, Juarez-Reyes A, Monsivais-Urenda A, Baranda L, et al. CTLA-4-Ig therapy diminishes the frequency but enhances the function of Treg cells in patients with rheumatoid arthritis. J Clin Immunol. 2011;31(4):588–95.

    Article  PubMed  CAS  Google Scholar 

  54. Shen H, Xia L, Lu J, Xiao W. Infliximab reduces the frequency of interleukin 17-producing cells and the amounts of interleukin 17 in patients with rheumatoid arthritis. J Investig Med. 2010;58(7):905–8.

    PubMed  CAS  Google Scholar 

  55. Boschetti G, Nancey S, Sardi F, Roblin X, Flourie B, Kaiserlian D. Therapy with anti-TNFalpha antibody enhances number and function of Foxp3(+) regulatory T cells in inflammatory bowel diseases. Inflamm Bowel Dis. 2011;17(1):160–70.

    Article  PubMed  Google Scholar 

  56. Blache C, Lequerre T, Roucheux A, Beutheu S, Dedreux I, Jacquot S, et al. Number and phenotype of rheumatoid arthritis patients’ CD4+CD25hi regulatory T cells are not affected by adalimumab or etanercept. Rheumatology (Oxford). 2011;50(10):1814–22.

    Article  CAS  Google Scholar 

  57. Calleja S, Cordero-Coma M, Rodriguez E, Llorente M, Franco M, Ruiz de Morales JG. Adalimumab specifically induces CD3(+) CD4(+) CD25(high) Foxp3(+) CD127(−) T-regulatory cells and decreases vascular endothelial growth factor plasma levels in refractory immuno-mediated uveitis: a non-randomized pilot intervention study. Eye (Lond). 2012;26(3):468–77.

    Article  CAS  Google Scholar 

  58. Samson M, Audia S, Janikashvili N, Ciudad M, Trad M, Fraszczak J, et al. Brief Report: Inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. Arthritis Rheum. 2012;64(8):2499–503.

    Article  PubMed  CAS  Google Scholar 

  59. Orban T, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, et al. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet. 2011;378(9789):412–9.

    Article  PubMed  CAS  Google Scholar 

  60. Emery P. Optimizing outcomes in patients with rheumatoid arthritis and an inadequate response to anti-TNF treatment. Rheumatology (Oxford). 2012;51(Suppl 5):v22–30.

    Article  CAS  Google Scholar 

  61. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000;192(2):303–10.

    Article  PubMed  CAS  Google Scholar 

  62. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271–5.

    Article  PubMed  CAS  Google Scholar 

  63. Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol. 2003;4(12):1206–12.

    Article  PubMed  CAS  Google Scholar 

  64. Sansom DM, Walker LS. The role of CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) in regulatory T-cell biology. Immunol Rev. 2006;212:131–48.

    Article  PubMed  CAS  Google Scholar 

  65. Tang Q, Boden EK, Henriksen KJ, Bour-Jordan H, Bi M, Bluestone JA. Distinct roles of CTLA-4 and TGF-beta in CD4+CD25+ regulatory T cell function. Eur J Immunol. 2004;34(11):2996–3005.

    Article  PubMed  CAS  Google Scholar 

  66. Huang B, Wang QT, Song SS, Wu YJ, Ma YK, Zhang LL, et al. Combined use of etanercept and MTX restores CD4(+)/CD8 (+) ratio and Tregs in spleen and thymus in collagen-induced arthritis. Inflamm Res. 2012;61(11):1229–39.

    Google Scholar 

  67. Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature. 2008;453(7192):236–40.

    Article  PubMed  CAS  Google Scholar 

  68. Prietl B, Pilz S, Wolf M, Tomaschitz A, Obermayer-Pietsch B, Graninger W, et al. Vitamin D supplementation and regulatory T cells in apparently healthy subjects: vitamin D treatment for autoimmune diseases? Isr Med Assoc J. 2010;12(3):136–9.

    PubMed  Google Scholar 

  69. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296(23):2832–8.

    Article  PubMed  CAS  Google Scholar 

  70. Smolders J, Thewissen M, Peelen E, Menheere P, Tervaert JW, Damoiseaux J, et al. Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis. PLoS One. 2009;4(8):e6635.

    Article  PubMed  CAS  Google Scholar 

  71. Terrier B, Derian N, Schoindre Y, Chaara W, Geri G, Zahr N, et al. Restoration of regulatory and effector T cell balance and B cell homeostasis in systemic lupus erythematosus patients through vitamin D supplementation. Arthritis Res Ther. 2012;14(5):R221.

    Article  PubMed  CAS  Google Scholar 

  72. Gabbay MA, Sato MN, Finazzo C, Duarte AJ, Dib SA. Effect of cholecalciferol as adjunctive therapy with insulin on protective immunologic profile and decline of residual beta-cell function in new-onset type 1 diabetes mellitus. Arch Pediatr Adolesc Med. 2012;166(7):601–7.

    Article  PubMed  Google Scholar 

  73. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355(10):1018–28.

    Article  PubMed  CAS  Google Scholar 

  74. Chatenoud L, Primo J, Bach JF. CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J Immunol. 1997;158(6):2947–54.

    PubMed  CAS  Google Scholar 

  75. Sherry N, Hagopian W, Ludvigsson J, Jain SM, Wahlen J, Ferry RJ Jr, et al. Teplizumab for treatment of type 1 diabetes (Protege study): 1-year results from a randomised, placebo-controlled trial. Lancet. 2011;378(9790):487–97.

    Article  PubMed  CAS  Google Scholar 

  76. Ochi H, Abraham M, Ishikawa H, Frenkel D, Yang K, Basso A, et al. New immunosuppressive approaches: oral administration of CD3-specific antibody to treat autoimmunity. J Neurol Sci. 2008;274(1–2):9–12.

    Article  PubMed  CAS  Google Scholar 

  77. Ilan Y, Zigmond E, Lalazar G, Dembinsky A, Ben Ya’acov A, Hemed N, et al. Oral administration of OKT3 monoclonal antibody to human subjects induces a dose-dependent immunologic effect in T cells and dendritic cells. J Clin Immunol. 2010;30(1):167–77.

    Article  PubMed  CAS  Google Scholar 

  78. Notley CA, McCann FE, Inglis JJ, Williams RO. ANTI-CD3 therapy expands the numbers of CD4+ and CD8+ Treg cells and induces sustained amelioration of collagen-induced arthritis. Arthritis Rheum. 2010;62(1):171–8.

    Article  PubMed  CAS  Google Scholar 

  79. Thornton AM, Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol. 2000;164(1):183–90.

    PubMed  CAS  Google Scholar 

  80. Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med. 2004;199(11):1455–65.

    Article  PubMed  CAS  Google Scholar 

  81. Bresson D, Fradkin M, Manenkova Y, Rottembourg D, von Herrath M. Genetic-induced variations in the GAD65 T-cell repertoire governs efficacy of anti-CD3/GAD65 combination therapy in new-onset type 1 diabetes. Mol Ther. 2010;18(2):307–16.

    Article  PubMed  CAS  Google Scholar 

  82. Rabinovitch A, Suarez-Pinzon WL, Shapiro AM, Rajotte RV, Power R. Combination therapy with sirolimus and interleukin-2 prevents spontaneous and recurrent autoimmune diabetes in NOD mice. Diabetes. 2002;51(3):638–45.

    Article  PubMed  CAS  Google Scholar 

  83. Shin HJ, Baker J, Leveson-Gower DB, Smith AT, Sega EI, Negrin RS. Rapamycin and IL-2 reduce lethal acute graft-versus-host disease associated with increased expansion of donor type CD4+CD25+Foxp3+ regulatory T cells. Blood. 2011;118(8):2342–50.

    Article  PubMed  CAS  Google Scholar 

  84. Golovina TN, Mikheeva T, Brusko TM, Blazar BR, Bluestone JA, Riley JL. Retinoic acid and rapamycin differentially affect and synergistically promote the ex vivo expansion of natural human T regulatory cells. PLoS One. 2011;6(1):e15868.

    Article  PubMed  CAS  Google Scholar 

  85. Long SA, Rieck M, Sanda S, Bollyky JB, Samuels PL, Goland R, et al. Rapamycin/IL-2 Combination Therapy in Patients with Type 1 Diabetes Augments Tregs yet Transiently Impairs beta-Cell Function. Diabetes. 2012;61(9):2340–8.

    Google Scholar 

  86. Bresson D, Fousteri G, Manenkova Y, Croft M, von Herrath M. Antigen-specific prevention of type 1 diabetes in NOD mice is ameliorated by OX40 agonist treatment. J Autoimmun. 2011;37(4):342–51.

    Article  PubMed  CAS  Google Scholar 

  87. Valzasina B, Guiducci C, Dislich H, Killeen N, Weinberg AD, Colombo MP. Triggering of OX40 (CD134) on CD4(+)CD25 + T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR. Blood. 2005;105(7):2845–51.

    Article  PubMed  CAS  Google Scholar 

  88. Vu MD, Xiao X, Gao W, Degauque N, Chen M, Kroemer A, et al. OX40 costimulation turns off Foxp3+ Tregs. Blood. 2007;110(7):2501–10.

    Article  PubMed  CAS  Google Scholar 

  89. Kelchtermans H, Geboes L, Mitera T, Huskens D, Leclercq G, Matthys P. Activated CD4+CD25+ regulatory T cells inhibit osteoclastogenesis and collagen-induced arthritis. Ann Rheum Dis. 2009;68(5):744–50.

    Article  PubMed  CAS  Google Scholar 

  90. Morgan ME, Flierman R, van Duivenvoorde LM, Witteveen HJ, van Ewijk W, van Laar JM, et al. Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis Rheum. 2005;52(7):2212–21.

    Article  PubMed  CAS  Google Scholar 

  91. Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, Grabowska M, Techmanska I, Juscinska J, et al. Administration of CD4+CD25highCD127− regulatory T cells preserves beta-cell function in type 1 diabetes in children. Diabetes Care. 2012;35(9):1817–20.

    Google Scholar 

  92. Kong N, Lan Q, Chen M, Wang J, Shi W, Horwitz DA, et al. Antigen-specific TGF-beta-induced regulatory T cells but not natural Tregs ameliorate autoimmune arthritis by shifting the balance of Th17 toward Treg cells. Arthritis Rheum. 2012;64(8):2548–58.

    Google Scholar 

  93. Haribhai D, Williams JB, Jia S, Nickerson D, Schmitt EG, Edwards B, et al. A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity. 2011;35(1):109–22.

    Article  PubMed  CAS  Google Scholar 

  94. Jeon EJ, Yoon BY, Lim JY, Oh HJ, Park HS, Park MJ, et al. Adoptive transfer of all-trans-retinal-induced regulatory T cells ameliorates experimental autoimmune arthritis in an interferon-gamma knockout model. Autoimmunity. 2012;45(6):460–9.

    Google Scholar 

  95. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4(4):330–6.

    Article  PubMed  CAS  Google Scholar 

  96. Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 2003;4(4):337–42.

    Article  PubMed  CAS  Google Scholar 

  97. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–61.

    Article  PubMed  CAS  Google Scholar 

  98. Ohata J, Miura T, Johnson TA, Hori S, Ziegler SF, Kohsaka H. Enhanced efficacy of regulatory T cell transfer against increasing resistance, by elevated Foxp3 expression induced in arthritic murine hosts. Arthritis Rheum. 2007;56(9):2947–56.

    Article  PubMed  CAS  Google Scholar 

  99. Wright GP, Notley CA, Xue SA, Bendle GM, Holler A, Schumacher TN, et al. Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis. Proc Natl Acad Sci USA. 2009;106(45):19078–83.

    Article  PubMed  CAS  Google Scholar 

  100. Liu X, Xu X, Lin X, Tian Y, Ji B, Xia S, et al. PTD-hFOXP3 protein acts as an immune regulator to convert human CD4(+) CD25(−) T cells to regulatory T-like cells. J Cell Biochem. 2012;113(12):3797–809.

    Google Scholar 

  101. Brusko TM, Koya RC, Zhu S, Lee MR, Putnam AL, McClymont SA, et al. Human antigen-specific regulatory T cells generated by T cell receptor gene transfer. PLoS One. 2010;5(7):e11726.

    Article  PubMed  CAS  Google Scholar 

  102. Corinti S, Albanesi C, la Sala A, Pastore S, Girolomoni G. Regulatory activity of autocrine IL-10 on dendritic cell functions. J Immunol. 2001;166(7):4312–8.

    PubMed  CAS  Google Scholar 

  103. Manicassamy S, Ravindran R, Deng J, Oluoch H, Denning TL, Kasturi SP, et al. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nat Med. 2009;15(4):401–9.

    Article  PubMed  CAS  Google Scholar 

  104. Ilarregui JM, Croci DO, Bianco GA, Toscano MA, Salatino M, Vermeulen ME, et al. Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10. Nat Immunol. 2009;10(9):981–91.

    Article  PubMed  CAS  Google Scholar 

  105. Arce F, Breckpot K, Stephenson H, Karwacz K, Ehrenstein MR, Collins M, et al. Selective ERK activation differentiates mouse and human tolerogenic dendritic cells, expands antigen-specific regulatory T cells, and suppresses experimental inflammatory arthritis. Arthritis Rheum. 2011;63(1):84–95.

    Article  PubMed  CAS  Google Scholar 

  106. Mahnke K, Qian Y, Knop J, Enk AH. Induction of CD4+/CD25+ regulatory T cells by targeting of antigens to immature dendritic cells. Blood. 2003;101(12):4862–9.

    Article  PubMed  CAS  Google Scholar 

  107. Hawiger D, Inaba K, Dorsett Y, Guo M, Mahnke K, Rivera M, et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med. 2001;194(6):769–79.

    Article  PubMed  CAS  Google Scholar 

  108. Ayyoub M, Deknuydt F, Raimbaud I, Dousset C, Leveque L, Bioley G, et al. Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the T(H)17 lineage-specific transcription factor RORgamma t. Proc Natl Acad Sci USA. 2009;106(21):8635–40.

    Article  PubMed  CAS  Google Scholar 

  109. Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 2007;5(2):e38.

    Article  PubMed  CAS  Google Scholar 

  110. Wang L, Tao R, Hancock WW. Using histone deacetylase inhibitors to enhance Foxp3(+) regulatory T-cell function and induce allograft tolerance. Immunol Cell Biol. 2009;87(3):195–202.

    Article  PubMed  CAS  Google Scholar 

  111. Ju JH, Heo YJ, Cho ML, Jhun JY, Park JS, Oh HJ, et al. Modulation of STAT3 in rheumatoid Synovial T cells suppresses Th17 differentiation and increases the proportion of regulatory T cells. Arthritis Rheum. 2012;64(11):3543–52.

    Google Scholar 

  112. Richer MJ, Straka N, Fang D, Shanina I, Horwitz MS. Regulatory T-cells protect from type 1 diabetes after induction by coxsackievirus infection in the context of transforming growth factor-beta. Diabetes. 2008;57(5):1302–11.

    Article  PubMed  CAS  Google Scholar 

  113. Mendez S, Reckling SK, Piccirillo CA, Sacks D, Belkaid Y. Role for CD4(+) CD25(+) regulatory T cells in reactivation of persistent leishmaniasis and control of concomitant immunity. J Exp Med. 2004;200(2):201–10.

    Article  PubMed  CAS  Google Scholar 

  114. Cabrera R, Tu Z, Xu Y, Firpi RJ, Rosen HR, Liu C, et al. An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection. Hepatology. 2004;40(5):1062–71.

    Article  PubMed  CAS  Google Scholar 

  115. Pedroza-Gonzalez A, Verhoef C, Ijzermans JN, Peppelenbosch MP, Kwekkeboom J, Verheij J, et al. Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer. Hepatology. 2013;57(1):183–94.

    Google Scholar 

  116. Adurthi S, Mukherjee G, Krishnamurthy H, Sudhir K, Bafna UD, Umadevi K, et al. Functional tumor infiltrating TH1 and TH2 effectors in large early-stage cervical cancer are suppressed by regulatory T cells. Int J Gynecol Cancer. 2012;22(7):1130–7.

    Article  PubMed  Google Scholar 

  117. Komatsu N, Mariotti-Ferrandiz ME, Wang Y, Malissen B, Waldmann H, Hori S. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci USA. 2009;106(6):1903–8.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Prof. Dr. Winfried Graninger (Medical University of Graz) for critical review of the manuscript.

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Authors and Affiliations

  1. Department of Rheumatology and Immunology, Medical University Graz, Auenbruggerplatz 15, 8036, Graz, Austria

    Johannes Fessler, Anja Felber & Christian Dejaco

  2. Department of Internal Medicine, General Hospital Kufstein, Kufstein, Austria

    Christina Duftner

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  1. Johannes Fessler
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  2. Anja Felber
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  3. Christina Duftner
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  4. Christian Dejaco
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Correspondence to Christian Dejaco.

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Fessler, J., Felber, A., Duftner, C. et al. Therapeutic Potential of Regulatory T cells in Autoimmune Disorders. BioDrugs 27, 281–291 (2013). https://doi.org/10.1007/s40259-013-0026-5

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