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Published in: BioDrugs 4/2013

01-08-2013 | Leading Article

Therapeutic Potential of Regulatory T cells in Autoimmune Disorders

Authors: Johannes Fessler, Anja Felber, Christina Duftner, Christian Dejaco

Published in: BioDrugs | Issue 4/2013

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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.
Literature
1.
go back to reference Danke NA, Koelle DM, Yee C, Beheray S, Kwok WW. Autoreactive T cells in healthy individuals. J Immunol. 2004;172(10):5967–72.PubMed Danke NA, Koelle DM, Yee C, Beheray S, Kwok WW. Autoreactive T cells in healthy individuals. J Immunol. 2004;172(10):5967–72.PubMed
2.
go back to reference Dejaco C, Duftner C, Grubeck-Loebenstein B, Schirmer M. Imbalance of regulatory T cells in human autoimmune diseases. Immunology. 2006;117(3):289–300.PubMedCrossRef Dejaco C, Duftner C, Grubeck-Loebenstein B, Schirmer M. Imbalance of regulatory T cells in human autoimmune diseases. Immunology. 2006;117(3):289–300.PubMedCrossRef
3.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
4.
go back to reference 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 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
5.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
6.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
7.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
8.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
9.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
10.
go back to reference Qin S, Cobbold SP, Pope H, Elliott J, Kioussis D, Davies J, et al. “Infectious” transplantation tolerance. Science. 1993;259(5097):974–7.PubMedCrossRef Qin S, Cobbold SP, Pope H, Elliott J, Kioussis D, Davies J, et al. “Infectious” transplantation tolerance. Science. 1993;259(5097):974–7.PubMedCrossRef
11.
go back to reference Walunas TL, Bakker CY, Bluestone JA. CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med. 1996;183(6):2541–50.PubMedCrossRef Walunas TL, Bakker CY, Bluestone JA. CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med. 1996;183(6):2541–50.PubMedCrossRef
12.
go back to reference 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 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
13.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
14.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
15.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
16.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
17.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
18.
go back to reference 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 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
19.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
20.
go back to reference 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.CrossRef 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.CrossRef
21.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
22.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
23.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
24.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
25.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
26.
go back to reference 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 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
27.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
28.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
29.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
30.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
31.
go back to reference Putnam AL, Vendrame F, Dotta F, Gottlieb PA. CD4+CD25high regulatory T cells in human autoimmune diabetes. J Autoimmun. 2005;24(1):55–62.PubMedCrossRef Putnam AL, Vendrame F, Dotta F, Gottlieb PA. CD4+CD25high regulatory T cells in human autoimmune diabetes. J Autoimmun. 2005;24(1):55–62.PubMedCrossRef
32.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
33.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
34.
go back to reference 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 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
35.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
36.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
37.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
38.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
39.
go back to reference 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 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
40.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
41.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
42.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
43.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
44.
go back to reference 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.CrossRef 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.CrossRef
45.
go back to reference 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 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
46.
go back to reference 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 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
47.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
48.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
49.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
50.
go back to reference 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 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
51.
go back to reference Lal G, Bromberg JS. Epigenetic mechanisms of regulation of Foxp3 expression. Blood. 2009;114(18):3727–35.PubMedCrossRef Lal G, Bromberg JS. Epigenetic mechanisms of regulation of Foxp3 expression. Blood. 2009;114(18):3727–35.PubMedCrossRef
52.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
53.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
54.
go back to reference 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 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
55.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
56.
go back to reference 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.CrossRef 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.CrossRef
57.
go back to reference 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.CrossRef 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.CrossRef
58.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
59.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
60.
go back to reference 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.CrossRef 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.CrossRef
61.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
62.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
63.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
64.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
65.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
66.
go back to reference 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. 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.
67.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
68.
go back to reference 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 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
69.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
70.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
71.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
72.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
73.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
74.
go back to reference 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 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
75.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
76.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
77.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
78.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
79.
go back to reference Thornton AM, Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol. 2000;164(1):183–90.PubMed Thornton AM, Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol. 2000;164(1):183–90.PubMed
80.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
81.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
82.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
83.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
84.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
85.
go back to reference 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. 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.
86.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
87.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
88.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
89.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
90.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
91.
go back to reference 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. 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.
92.
go back to reference 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. 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.
93.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
94.
go back to reference 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. 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.
95.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
96.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
97.
go back to reference Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–61.PubMedCrossRef Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–61.PubMedCrossRef
98.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
99.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
100.
go back to reference 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. 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.
101.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
102.
go back to reference 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 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
103.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
104.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
105.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
106.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
107.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
108.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
109.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
110.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
111.
go back to reference 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. 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.
112.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
113.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
114.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
115.
go back to reference 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. 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.
116.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
117.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
Metadata
Title
Therapeutic Potential of Regulatory T cells in Autoimmune Disorders
Authors
Johannes Fessler
Anja Felber
Christina Duftner
Christian Dejaco
Publication date
01-08-2013
Publisher
Springer International Publishing
Published in
BioDrugs / Issue 4/2013
Print ISSN: 1173-8804
Electronic ISSN: 1179-190X
DOI
https://doi.org/10.1007/s40259-013-0026-5

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