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Review Article

Therapeutic potential of TGF-β-induced CD4+ Foxp3+ regulatory T cells in autoimmune diseases

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Pages 43-50 | Received 15 Mar 2010, Accepted 16 Mar 2010, Published online: 29 Jul 2010

References

  • Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004; 22:531–562.
  • Shevach EM. CD4+ CD25+ suppressor T cells: More questions than answers. Nat Rev Immunol. 2002; 2:389–400.
  • Gershon RK, Kondo K. Cell interactions in the induction of tolerance: The role of thymic lymphocytes. Immunology. 1970; 18:723–737.
  • Kojima A, Prehn RT. Genetic susceptibility to post-thymectomy autoimmune diseases in mice. Immunogenetics. 1981; 14:15–27.
  • 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. 1995; 155:1151–1164.
  • Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003; 299:1057–1061.
  • Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat Immunol. 2003; 4:330–336.
  • Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+ CD25+ T regulatory cells. Nat Immunol. 2003; 4:337–342.
  • Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 2005; 22:329–341.
  • Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+ CD25 high regulatory cells in human peripheral blood. J Immunol. 2001; 167:1245–1253.
  • Morgan ME, van Bilsen JH, Bakker AM, Heemskerk B, Schilham MW, Hartgers FC, Elferink BG, van der Zanden L, de Vries RR, Huizinga TW, Ottenhoff TH, Toes RE. Expression of FOXP3 mRNA is not confined to CD4+ CD25+ T regulatory cells in humans. Hum Immunol. 2005; 66:13–20.
  • Allan SE, Crome SQ, Crellin NK, Passerini L, Steiner TS, Bacchetta R, Roncarolo MG, Levings MK. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol. 2007; 19:345–354.
  • Yu JN, Ma JL, Wang JH, Tao XJ, Li XP, Zou HJ, Zheng SG. FOXP3, is still a specific marker for human regulatory T cells?. Chin J Allergy Clin Immunol. 2008; 2:5–10.
  • Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, Helms C, Bowcock AM. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest. 2000; 106:R75–R81.
  • Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, Levy-Lahad E, Mazzella M, Goulet O, Perroni L, Bricarelli FD, Byrne G, McEuen M, Proll S, Appleby M, Brunkow ME. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001; 27:18–20.
  • Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001; 27:20–21.
  • Tang Q, Bluestone JA. The Foxp3+ regulatory T cell: A jack of all trades, master of regulation. Nat Immunol. 2008; 9:239–244.
  • Horwitz DA, Zheng SG, Gray JD, Wang JH, Ohtsuka K, Yamagiwa S. Regulatory T cells generated ex vivo as an approach for the therapy of autoimmune disease. Semin Immunol. 2004; 16:135–143.
  • Hahn BH, Singh RP, La Cava A, Ebling FM. Tolerogenic treatment of lupus mice with consensus peptide induces Foxp3-expressing, apoptosis-resistant, TGF-β-secreting CD8+ T cell suppressors. J Immunol. 2005; 175:7728–7737.
  • Ochi H, Abraham M, Ishikawa H, Frenkel D, Yang K, Basso AS, Wu H, Chen ML, Gandhi R, Miller A, Maron R, Weiner HL. Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+ CD25 − LAP+ T cells. Nat Med. 2006; 12:627–635.
  • Kang HK, Michaels MA, Berner BR, Datta SK. Very low-dose tolerance with nucleosomal peptides controls lupus and induces potent regulatory T cell subsets. J Immunol. 2005; 174:3247–3255.
  • Brand DD, Myers LK, Whittington KB, Latham KA, Stuart JM, Kang AH, Rosloniec EF. Detection of early changes in autoimmune T cell phenotype and function following intravenous administration of type II collagen in a TCR-transgenic model. J Immunol. 2002; 168:490–498.
  • Vieira PL, Christensen JR, Minaee S, O'Neill EJ, Barrat FJ, Boonstra A, Barthlott T, Stockinger B, Wraith DC, O'Garra A. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+ CD25+ regulatory T cells. J Immunol. 2004; 172:5986–5993.
  • Zheng SG, Gray JD, Ohtsuka K, Yamagiwa S, Horwitz DA. Generation ex vivo of TGF-β producing regulatory T cells from CD4+ CD25 − precursors. J Immunol. 2002; 169:4183–4189.
  • Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM. Conversion of peripheral CD4+ CD25 − naive T cells to CD4+ CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J Exp Med. 2003; 198:1875–1886.
  • Zheng SG, Wang JH, Gray JD, Soucier H, Horwitz DA. 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. 2004; 172:5213–5221.
  • Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF. Cutting edge: TGF-β induces a regulatory phenotype in CD4+ CD25 − T cells through Foxp3 induction and downregulation of Smad7. J Immunol. 2004; 172:5149–5153.
  • Chatenoud L, Bluestone JA. CD3-specific antibodies: A portal to the treatment of autoimmunity. Nat Rev Immunol. 2007; 7:622–632.
  • Battaglia M, Gregori S, Bacchetta R, Roncarolo MG. Tr1 cells: From discovery to their clinical application. Semin Immunol. 2006; 18:120–127.
  • Horwitz DA, Zheng SG, Gray JD. Natural and TGF-β-induced Foxp3+ CD4+ CD25+ regulatory T cells are not mirror images of each other. Trends Immunol. 2008; 29:429–435.
  • Thornton AM, Shevach EM. CD4+ CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med. 1998; 188:287–296.
  • Nakamura K, Kitani A, Strober W. Cell contact-dependent immunosuppression by CD4+ CD25+ regulatory T cells is mediated by cell surface-bound transforming growth factor β. J Exp Med. 2001; 194:629–644.
  • Zheng SG, Wang J, Horwitz DA. Cutting edge: Foxp3+ CD4+ CD25+ regulatory T cells induced by IL-2 and TGF-β are resistant to Th17 conversion by IL-6. J Immunol. 2008; 180:7112–7116.
  • DiPaolo RJ, Glass DD, Bijwaard KE, Shevach EM. CD4+ CD25+ T cells prevent the development of organ-specific autoimmune disease by inhibiting the differentiation of autoreactive effector T cells. J Immunol. 2005; 175:7135–7142.
  • Read S, Malmström V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+ CD4+ regulatory cells that control intestinal inflammation. J Exp Med. 2000; 192:295–302.
  • Kohm AP, Carpentier PA, Anger HA, Miller SD. Cutting edge: CD4+ CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol. 2002; 169:4712–4716.
  • Scalapino KJ, Tang Q, Bluestone JA, Bonyhadi ML, Daikh DI. Suppression of disease in New Zealand Black/New Zealand White lupus-prone mice by adoptive transfer of ex vivo expanded regulatory T cells. J Immunol. 2006; 177:1451–1459.
  • Zheng SG, Wang JH, Koss MN, Quismorio FJr, Gray JD, Horwitz DA. CD4+ and CD8+ regulatory T cells generated ex vivo with IL-2 and TGF-β suppress a stimulatory graft versus-host disease with a lupus-like syndrome. J Immunol. 2004; 172:1531–1539.
  • Weber SE, Harbertson J, Godebu E, Mros GA, Padrick RC, Carson BD, Ziegler SF, Bradley LM. Adaptive islet-specific regulatory CD4 T cells control autoimmune diabetes and mediate the disappearance of pathogenic Th1 cells in vivo. J Immunol. 2006; 176:4730–4739.
  • Selvaraj RK, Geiger TL. Mitigation of experimental allergic encephalomyelitis by TGF-β-induced Foxp3+ regulatory T lymphocytes through the induction of anergy and infectious tolerance. J Immunol. 2008; 180:2830–2838.
  • Fahlén L, Read S, Gorelik L, Hurst SD, Coffman RL, Flavell RA, Powrie F. T cells that cannot respond to TGF-β escape control by CD4(+)CD25(+) regulatory T cells. J Exp Med. 2005; 201:737–746.
  • Hara M, Kingsley CI, Niimi M, Read S, Turvey SE, Bushell AR, Morris PJ, Powrie F, Wood KJ. IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. J Immunol. 2001; 166:3789–3796.
  • Zheng SG, Meng L, Wang JH, Watanabe M, Barr ML, Cramer DV, Gray JD, Horwitz DA. Transfer of regulatory T cells generated ex vivo modifies graft rejection through induction of tolerogenic CD4+ CD25+ cells in the recipient. Int Immunol. 2006; 18:279–289.
  • Jonuleit H, Schmitt E, Kakirman H, Stassen M, Knop J, Enk AH. Infectious tolerance: Human CD25+ regulatory T cells convey suppressor activity to conventional CD4+ T helper cells. J Exp Med. 2002; 196:255–260.
  • Qiao M, Thornton AM, Shevach EM. CD4+ CD25+ regulatory T cells render naïve CD4+ CD25 − T cells anergic and suppressive. Immunology. 2007; 120 4: 447–455.
  • La Cava A. Tregs are regulated by cytokines: Implications for autoimmunity. Autoimmun Rev. 2008; 8:83–87.
  • Zheng SG, Wang J, Wang P, Gray JD, Horwitz DA. IL-2 is essential for TGF-β to convert naive CD4+ CD25 − cells to CD25+ Foxp3+ regulatory T cells and for expansion of these cells. J Immunol. 2007; 178:2018–2027.
  • Davidson TS, DiPaolo RJ, Andersson J, Shevach EM. Cutting Edge: IL-2 is essential for TGFβ-mediated induction of Foxp3+ T regulatory cells. J Immunol. 2007; 178:4022–4026.
  • Huber S, Stahl FR, Schrader J, Lüth S, Presser K, Carambia A, Flavell RA, Werner S, Blessing M, Herkel J, Schramm C. Activin a promotes the TGF-β-induced conversion of CD4+ CD25 − T cells into Foxp3+ induced regulatory T cells. J Immunol. 2009; 182:4633–4640.
  • Lu L, Ma J, Wang X, Wang J, Zhang F, Yu J, He G, Xu B, Brand DD, Horwitz DA, Shi W, Zheng SG. Synergistic effect of TGF-β superfamily members on the induction of Foxp3+ Treg. Eur J Immunol. 2010; 40 1: 142–152.
  • Piccirillo CA, Letterio JJ, Thornton AM, McHugh RS, Mamura M, Mizuhara H, Shevach EM. CD4+ CD25+ regulatory T cells can mediate suppressor function in the absence of transforming growth factor β1 production and responsiveness. J Exp Med. 2002; 196:237–246.
  • Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol. 2005; 6:1142–1151.
  • Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA. B7/CD28 costimulation is essential for the homeostasis of the CD4+ CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity. 2000; 12:431–440.
  • You S, Leforban B, Garcia C, Bach JF, Bluestone JA, Chatenoud L. Adaptive TGF-β-dependent regulatory T cells control autoimmune diabetes and are a privileged target of anti-CD3 antibody treatment. Proc Natl Acad Sci USA. 2007; 104:6335–6340.
  • Zheng SG, Wang JH, Stohl W, Kim KS, Gray JD, Horwitz DA. TGF-β requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+ CD25+ regulatory cells. J Immunol. 2006; 176:3321–3329.
  • Herman AE, Freeman GJ, Mathis D, Benoist C. CD4+ CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J Exp Med. 2004; 199:1479–1489.
  • So T, Croft M. Cutting edge: OX40 inhibits TGF-β- and antigen-driven conversion of naïve CD4 T cells into CD25+ Foxp3+ T cells. J Immunol. 2007; 179:1427–1430.
  • Vu MD, Xiao X, Gao W, Degauque N, Chen M, Kroemer A, Killeen N, Ishii N, Chang Li X. OX40 costimulation turns off Foxp3+Tregs. Blood. 2007; 110:2501–2510.
  • Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGF-β in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006; 24:179–189.
  • Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006; 441:235–238.
  • Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S. Type 17 T helper cells-origins, features and possible roles in rheumatic disease. Nat Rev Rheumatol. 2009; 5:325–331.
  • Lu L, Wang J, Zhang F, Chai Y, Brad DD, Wang XH, Horwitz DA, Shi W, Zheng SG. Role of Smad and non-Smad signals in the development of Th17 and regulatory T cells. J Immunol. 2010; 184 8: 4295–4306.
  • Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt. Nat Immunol. 2008; 9:641649.
  • Xu L, Kitani A, Fuss I, Strober W. Cutting edge: Regulatory T cells induce CD4+ CD25 − Foxp3 − T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-β. J Immunol. 2007; 178:6725–6729.
  • Wan YY, Flavell RA. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature. 2007; 445:766–770.
  • Tsuji M, Komatsu N, Kawamoto S, Suzuki K, Kanagawa O, Honjo T, Hori S, Fagarasan S. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science. 2009; 323:1488–1492.
  • Kong N, Zhou XH, Fan HM, Liu ZM, Brand DD, Zou HJ, Zheng SG. TGF-β-induced CD4+ Foxp3+ Cells but not natural CD4+ CD25+ cells suppress established collagen-induced arthritis. Arthritis Rheum. 2009; 60:S4.
  • Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, Schlawe K, Chang HD, Bopp T, Schmitt E, Klein-Hessling S, Serfling E, Hamann A, Huehn J. Epigenetic control of the Foxp3 locus in regulatory T cells. PLoS Biol. 2007; 5:e38.
  • Lal G, Zhang N, van der Touw W, Ding Y, Ju W, Bottinger EP, Reid SP, Levy DE, Bromberg JS. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol. 2009; 182:259–273.
  • Zhou XH, Kong N, Wang J, Zou HJ, Fan HM, Brand DD, Liu ZM, Zheng SG. All-trans retinoid acid restores the stability and functionality of nTregs in the Inflammatory milieu. Arthritis Rheum. 2009; 60:S736.
  • Polansky JK, Kretschmer K, Freyer J, Floess S, Garbe A, Baron U, Olek S, Hamann A, von Boehmer H, Huehn J. DNA methylation controls Foxp3 gene expression. Eur J Immunol. 2008; 38:1654–1663.
  • Mottet C, Uhlig HH, Powrie F. Cutting edge: Cure of colitis by CD4+ CD25+ regulatory T cells. J Immunol. 2003; 170:3939–3943.
  • Morgan ME, Flierman R, van Duivenvoorde LM, Witteveen HJ, van Ewijk W, van Laar JM, de Vries RR, Toes RE. Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis Rheum. 2005; 52:2212–2221.
  • Bardos T, Czipri M, Vermes C, Finnegan A, Mikecz K, Zhang J. CD4+ CD25+ immunoregulatory T cells may not be involved in controlling autoimmune arthritis. Arthritis Res Ther. 2003; 5:R106–113.
  • Huter EN, Stummvoll GH, DiPaolo RJ, Glass DD, Shevach EM. Cutting edge: Antigen-specific TGF-β-induced regulatory T cells suppress Th17-mediated autoimmune disease. J Immunol. 2008; 181:8209–8213.
  • Chai JG, Tsang JY, Lechler R, Simpson E, Dyson J, Scott D. CD4+ CD25+ T cells as immunoregulatory T cells in vitro. Eur J Immunol. 2002; 32:2365–2375.
  • Monk CR, Spachidou M, Rovis F, Leung E, Botto M, Lechler RI, Garden OA. MRL/Mp CD4+ CD25 − T cells show reduced sensitivity to suppression by CD4+ CD25+ regulatory T cells in vitro: A novel defect of T cell regulation in systemic lupus erythematosus. Arthritis Rheum. 2005; 52:1180–1184.
  • Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+ CD25+ T cell-mediated suppression by dendritic cells. Science. 2003; 299:1033–1036.
  • Valencia X, Stephens G, Goldbach-Mansky R, Wilson M, Shevach EM, Lipsky PE. TNF downmodulates the function of human CD4+ CD25hi T-regulatory cells. Blood. 2006; 108:253–261.
  • Linker-Israeli M, Deans RJ, Wallace DJ, Prehn J, Ozeri-Chen T, Klinenberg JR. Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis. J Immunol. 1991; 147:117–123.
  • Aricha R, Feferman T, Fuchs S, Souroujon MC. Ex vivo generated regulatory T cells modulate experimental autoimmune myasthenia gravis. J Immunol. 2008; 180:2132–2139.
  • Su H, Ye DQ, Wang BL, Fang XH, Chen J, Wang Q, Li WX, Zhang N. Transforming growth factor-β1-induced CD4+ CD25+ regulatory T cells in vitro reverse and prevent a murine lupus-like syndrome of chronic graft-versus-host disease. Br J Dermatol. 2008; 158:1197–1209.
  • 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-β dependent but does not confer a regulatory phenotype. Blood. 2007; 110:2983–2990.
  • Yamagiwa S, Gray JD, Hashimoto S, Horwitz DA. A role for TGF-β in the generation and expansion of CD4+ CD25+ regulatory T cells from human peripheral blood. J Immunol. 2001; 166:7282–7289.
  • Riley JL, June CH, Blazar BR. Human T regulatory cell therapy: Take a billion or so and call me in the morning. Immunity. 2009; 30:656–665.

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