Regulatory T cells as immunotherapy

Frontiers in Immunology

Volumn 5, Issue FEB, 2014, Pages

  Singer, Benjamin D ^a   King, Landon S ^a   D'Alessio, Franco R ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Adoptive transfer; Expansion; Immunotherapeutics; Inflammation; Regulatory T cells; Tolerance

Indexed keywords

ALPHA2 INTEGRIN; CD28 ANTIGEN; CD3 ANTIGEN; CD4 ANTIGEN; CD45RA ANTIGEN; CD45RO ANTIGEN; CD69 ANTIGEN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; HERMES ANTIGEN; INDUCIBLE T CELL COSTIMULATOR; INTERLEUKIN 17; INTERLEUKIN 2 RECEPTOR ALPHA; INTERLEUKIN 7 RECEPTOR; L SELECTIN; LATENCY ASSOCIATED PEPTIDE; TRANSCRIPTION FACTOR FOXP3;

ADOPTIVE TRANSFER; ATOPY; AUTOIMMUNE DISEASE; CD4+ CD25+ T LYMPHOCYTE; CELL PROLIFERATION; FLUORESCENCE ACTIVATED CELL SORTING; HIGH THROUGHPUT SCREENING; HUMAN; IMMUNOLOGICAL TOLERANCE; IMMUNOTHERAPY; INFLAMMATORY DISEASE; NONHUMAN; PROTEIN EXPRESSION; REGULATORY T LYMPHOCYTE; REVIEW; SURVIVAL RATE; TREATMENT OUTCOME;

EID: 84895560752     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2014.00046     Document Type: Review

References (145)

1. Christen U, von Herrath MG. Initiation of autoimmunity. Curr Opin Immunol (2004) 16:759-67. doi: 10.1016/j.coi.2004.09.002.
2. Rosenberg AS, Singer A. Cellular basis of skin allograft rejection: an in vivo model of immune-mediated tissue destruction. Annu Rev Immunol (1992) 10:333-58. doi:10.1146/annurev.iy.10.040192.002001.
3. Trenado A, Charlotte F, Fisson S, Yagello M, Klatzmann D, Salomon BL, et al. Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia. J Clin Invest (2003) 112:1688-96. doi:10.1172/JCI17702.
4. Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med (2003) 9:1144-50. doi:10.1038/nm915.
5. Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev (2001) 182:18-32. doi:10.1034/j.1600-065X.2001.1820102.x.
6. Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet (2001) 27:68-73. doi:10.1038/83784.
7. 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) 27:20-1. doi:10.1038/83713.
8. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol (2003) 4:330-6. doi:10.1038/ni904.
9. Josefowicz SZ, Rudensky A. Control of regulatory T cell lineage commitment and maintenance. Immunity (2009) 30:616-25. doi:10.1016/j.immuni.2009.04.009.
10. 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) 322:271-5. doi:10.1126/science.1160062.
11. Scalapino KJ, Daikh DI. CTLA-4: a key regulatory point in the control of autoimmune disease. Immunol Rev (2008) 223:143-55. doi:10.1111/j.1600-065X.2008.00639.x.
12. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science (2003) 299:1057-61. doi:10.1126/science.1079490.
13. Gandhi R, Farez MF, Wang Y, Kozoriz D, Quintana FJ, Weiner HL. Cutting edge: human latency-associated peptide+ T cells: a novel regulatory T cell subset. J Immunol (2010) 184:4620-4. doi:10.4049/jimmunol.0903329.
14. Levings MK, Sangregorio R, Sartirana C, Moschin AL, Battaglia M, Orban PC, et al. Human CD25+CD4+ T suppressor cell clones produce transforming growth factor beta, but not interleukin 10, and are distinct from type 1 T regulatory cells. J Exp Med (2002) 196:1335-46. doi:10.1084/jem.20021139.
15. Bohle B, Kinaciyan T, Gerstmayr M, Radakovics A, Jahn-Schmid B, Ebner C. Sublingual immunotherapy induces IL-10-producing T regulatory cells, allergen-specific T-cell tolerance, and immune deviation. J Allergy Clin Immunol (2007) 120:707-13. doi:10.1016/j.jaci.2007.06.013.
16. Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med (2013) 19:739-46. doi:10.1038/nm.3179.
17. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol (1995) 155:1151-64.
18. Golovina TN, Mikheeva T, Suhoski MM, Aqui NA, Tai VC, Shan X, et al. CD28 costimulation is essential for human T regulatory expansion and function. J Immunol (2008) 181:2855-68.
19. Bollyky PL, Falk BA, Long SA, Preisinger A, Braun KR, Wu RP, et al. CD44 costimulation promotes FoxP3+ regulatory T cell persistence and function via production of IL-2, IL-10, and TGF-beta. J Immunol (2009) 183:2232-41. doi:10.4049/jimmunol.0900191.
20. Lange CM, Tran TYV, Farnik H, Jungblut S, Born T, Wagner TO, et al. Increased frequency of regulatory T cells and selection of highly potent CD62L+ cells during treatment of human lung transplant recipients with rapamycin. Transpl Int (2010) 23:266-76. doi:10.1111/j.1432-2277.2009.00973.x.
21. Ermann J, Hoffmann P, Edinger M, Dutt S, Blankenberg FG, Higgins JP, et al. Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD. Blood (2005) 105:2220-6. doi:10.1182/blood-2004-05-2044.
22. Han Y, Guo Q, Zhang M, Chen Z, Cao X. CD69+ CD4+ CD25-T cells, a new subset of regulatory T cells, suppress T cell proliferation through membrane-bound TGF-beta 1. J Immunol (2009) 182:111-20.
23. Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med (2006) 203:1693-700. doi:10.1084/jem.20060468.
24. Karim M, Kingsley CI, Bushell AR, Sawitzki BS, Wood KJ. Alloantigen-induced CD25+CD4+ regulatory T cells can develop in vivo from CD25-CD4+ precursors in a thymus-independent process. J Immunol (2004) 172:923-8.
25. Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S, et al. Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol (2013) 14:307-8. doi:10.1038/ni.2554.
26. Gershon RK. A disquisition on suppressor T cells. Transplant Rev (1975) 26:170-85.
27. June CH, Blazar BR. Clinical application of expanded CD4+25+ cells. Semin Immunol (2006) 18:78-88. doi:10.1016/j.smim.2006.01.006.
28. Riley JL, June CH, Blazar BR. Human T regulatory cell therapy: take a billion or so and call me in the morning. Immunity (2009) 30:656-65. doi:10.1016/j.immuni.2009.04.006.
29. Kukreja A, Cost G, Marker J, Zhang C, Sun Z, Lin-Su K, et al. Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest (2002) 109:131-40. doi:10.1172/JCI13605.
30. Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TIM. Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes (2005) 54:92-9. doi:10.2337/diabetes.54.1.92.
31. 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) 22:329-41. doi:10.1016/j.immuni.2005.01.016.
32. Allan SE, Crome SQ, Crellin NK, Passerini L, Steiner TS, Bacchetta R, et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol (2007) 19:345-54. doi:10.1093/intimm/dxm014.
33. Trzonkowski P, Bieniaszewska M, Juscinska J, Dobyszuk A, Krzystyniak A, Marek N, et al. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127-T regulatory cells. Clin Immunol (2009) 133:22-6. doi:10.1016/j.clim.2009.06.001.
34. Earle KE, Tang Q, Zhou X, Liu W, Zhu S, Bonyhadi ML, et al. In vitro expanded human CD4+CD25+ regulatory T cells suppress effector T cell proliferation. Clin Immunol (2005) 115:3-9. doi:10.1016/j.clim.2005.02.017.
35. Golshayan D, Jiang S, Tsang J, Garin MI, Mottet C, Lechler RI. In vitro-expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance. Blood (2007) 109:827-35. doi:10.1182/blood-2006-05-025460.
36. Sagoo P, Ali N, Garg G, Nestle FO, Lechler RI, Lombardi G. Human regulatory T cells with alloantigen specificity are more potent inhibitors of alloimmune skin graft damage than polyclonal regulatory T cells. Sci Transl Med (2011) 3:83ra42. doi:10.1126/scitranslmed.3002076.
37. Jiang S, Tsang J, Game DS, Stevenson S, Lombardi G, Lechler RI. Generation and expansion of human CD4+ CD25+ regulatory T cells with indirect allospecificity: potential reagents to promote donor-specific transplantation tolerance. Transplantation (2006) 82:1738-43. doi:10.1097/01.tp.0000244932.29542.9e.
38. Hippen KL, Harker-Murray P, Porter SB, Merkel SC, Londer A, Taylor DK, et al. Umbilical cord blood regulatory T-cell expansion and functional effects of tumor necrosis factor receptor family members OX40 and 4-1BB expressed on artificial antigen-presenting cells. Blood (2008) 112:2847-57. doi:10.1182/blood-2008-01-132951.
39. Hippen KL, Merkel SC, Schirm DK, Sieben CM, Sumstad D, Kadidlo DM, et al. Massive ex vivo expansion of human natural regulatory T cells (T(regs)) with minimal loss of in vivo functional activity. Sci Transl Med (2011) 3:83ra41. doi:10.1126/scitranslmed.3001809.
40. Suhoski MM, Golovina TN, Aqui NA, Tai VC, Varela-Rohena A, Milone MC, et al. Engineering artificial antigen-presenting cells to express a diverse array of co-stimulatory molecules. Mol Ther (2007) 15:981-8. doi:10.1038/mt.sj.6300134.
41. 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) 199:1455-65. doi:10.1084/jem.20040139.
42. Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood (2011) 117:1061-70. doi:10.1182/blood-2010-07-293795.
43. Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood (2011) 117:3921-8. doi:10.1182/blood-2010-10-311894.
44. Tang Q, Lee K. Regulatory T-cell therapy for transplantation: how many cells do we need? Curr Opin Organ Transplant (2012) 17:349-54. doi:10.1097/MOT.0b013e328355a992.
45. Hoffmann P, Eder R, Kunz-Schughart LA, Andreesen R, Edinger M. Large-scale in vitro expansion of polyclonal human CD4(+)CD25high regulatory T cells. Blood (2004) 104:895-903. doi:10.1182/blood-2004-01-0086.
46. Curotto de Lafaille MA, Lafaille JJ. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity (2009) 30:626-35. doi:10.1016/j.immuni.2009.05.002.
47. Chen W, Jin W, Hardegen N, Lei K-J, Li L, Marinos N, et al. Conversion of peripheral CD4+CD25-naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med (2003) 198:1875-86. doi:10.1084/jem.20030152.
48. Barrat FJ, Cua DJ, Boonstra A, Richards DF, Crain C, Savelkoul HF, et al. In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)-and Th2-inducing cytokines. J Exp Med (2002) 195:603-16. doi:10.1084/jem.20011629.
49. Chen W, Liang X, Peterson AJ, Munn DH, Blazar BR. The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J Immunol (2008) 181:5396-404.
50. Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med (2007) 204:1765-74. doi:10.1084/jem.20070719.
51. Moon C, Kim SH, Park KS, Choi BK, Lee HS, Park JB, et al. Use of epigenetic modification to induce FOXP3 expression in naïve T cells. Transplant Proc (2009) 41:1848-54. doi:10.1016/j.transproceed.2009.02.101.
52. Lan Q, Fan H, Quesniaux V, Ryffel B, Liu Z, Zheng SG. Induced Foxp3(+) regulatory T cells: a potential new weapon to treat autoimmune and inflammatory diseases? J Mol Cell Biol (2012) 4:22-8. doi:10.1093/jmcb/mjr039.
53. Ohkura N, Kitagawa Y, Sakaguchi S. Development and Maintenance of Regulatory T cells. Immunity (2013) 38:414-23. doi:10.1016/j.immuni.2013.03.002.
54. Francis RS, Feng G, Tha-In T, Lyons IS, Wood KJ, Bushell A. Induction of transplantation tolerance converts potential effector T cells into graft-protective regulatory T cells. Eur J Immunol (2011) 41:726-38. doi:10.1002/eji.201040509.
55. Wood KJ, Bushell AR, Darby CR, Pearson TC, West L, Morris PJ. Mechanism of induction of transplantation tolerance using donor antigen and anti-CD4 monoclonal antibody. Transplant Proc (1991) 23:133-4.
56. Bushell A, Morris PJ, Wood KJ. Induction of operational tolerance by random blood transfusion combined with anti-CD4 antibody therapy. A protocol with significant clinical potential. Transplantation (1994) 58:133-9. doi:10.1097/00007890-199405820-00002.
57. Bushell A, Morris PJ, Wood KJ. Transplantation tolerance induced by antigen pretreatment and depleting anti-CD4 antibody depends on CD4+ T cell regulation during the induction phase of the response. Eur J Immunol (1995) 25:2643-9. doi:10.1002/eji.1830250936.
58. Saitovitch D, Bushell A, Morris PJ, Wood KJ. Modulation of the CD4 molecule is a major event in the induction of transplantation tolerance with anti-CD4 monoclonal antibodies. Transplant Proc (1997) 29:1159. doi:10.1016/S0041-1345(96)00504-0.
59. Hara M, Kingsley CI, Niimi M, Read S, Turvey SE, Bushell AR, et al. IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. J Immunol (2001) 166:3789-96.
60. Graca L, Thompson S, Lin C-Y, Adams E, Cobbold SP, Waldmann H. Both CD4(+)CD25(+) and CD4(+)CD25(-) regulatory cells mediate dominant transplantation tolerance. J Immunol (2002) 168:5558-65.
61. Webster KE, Walters S, Kohler RE, Mrkvan T, Boyman O, Surh CD, et al. In vivo expansion of T reg cells with IL-2-mAb complexes: induction of resistance to EAE and long-term acceptance of isletallografts without immunosuppression. J Exp Med (2009) 206:751-60. doi:10.1084/jem.20082824.
62. Adeegbe D, Serafini P, Bronte V, Zoso A, Ricordi C, Inverardi L. In vivo induction of myeloid suppressor cells and CD4(+)Foxp3(+) T regulatory cells prolongs skin allograft survival in mice. Cell Transplant (2011) 20:941-54. doi:10.3727/096368910X540621.
63. Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea EP III, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med (2011) 365:2055-66. doi:10.1056/NEJMoa1108188.
64. Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA. IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J Immunol (2007) 178:280-90.
65. Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity (2009) 30:832-44. doi:10.1016/j.immuni.2009.04.014.
66. Zeiser R, Leveson-Gower DB, Zambricki EA, Kambham N, Beilhack A, Loh J, et al. Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood (2008) 111:453-62. doi:10.1182/blood-2007-06-094482.
67. Battaglia M, Stabilini A, Roncarolo M-G. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood (2005) 105:4743-8. doi:10.1182/blood-2004-10-3932.
68. Zhang P, Tey S-K, Koyama M, Kuns RD, Olver SD, Lineburg KE, et al. Induced regulatory T cells promote tolerance when stabilized by rapamycin and IL-2 in vivo. J Immunol (2013) 191:5291-303. doi:10.4049/jimmunol.1301181.
69. Hendrikx TK, Velthuis JHL, Klepper M, van Gurp E, Geel A, Schoordijk W, et al. Monotherapy rapamycin allows an increase of CD4 CD25 FoxP3 T cells in renal recipients. Transpl Int (2009) 22:884-91. doi:10.1111/j.1432-2277.2009.00890.x.
70. Lopez M, Clarkson MR, Albin M, Sayegh MH, Najafian N. A novel mechanism of action for anti-thymocyte globulin: induction of CD4+CD25+Foxp3+ regulatory T cells. J Am Soc Nephrol (2006) 17:2844-53. doi:10.1681/ASN.2006050422.
71. D'Addio F, Yuan X, Habicht A, Williams J, Ruzek M, Iacomini J, et al. A novel clinically relevant approach to tip the balance toward regulation in stringent transplant model. Transplantation (2010) 90:260-9. doi:10.1097/TP.0b013e3181e64217.
72. Stary G, Klein I, Bauer W, Koszik F, Reininger B, Kohlhofer S, et al. Glucocorticosteroids modify Langerhans cells to produce TGF-beta and expand regulatory T cells. J Immunol (2011) 186:103-12. doi:10.4049/jimmunol.1002485.
73. Bloom DD, Chang Z, Fechner JH, Dar W, Polster SP, Pascual J, et al. CD4+ CD25+ FOXP3+ regulatory T cells increase de novo in kidney transplant patients after immunodepletion with Campath-1H. Am J Transplant (2008) 8:793-802. doi:10.1111/j.1600-6143.2007.02134.x.
74. Presser D, Sester U, Mohrbach J, Janssen M, Köhler H, Sester M. Differential kinetics of effector and regulatory T cells in patients on calcineurin inhibitor-based drug regimens. Kidney Int (2009) 76:557-66. doi:10.1038/ki.2009.198.
75. Brandt C, Pavlovic V, Radbruch A, Worm M, Baumgrass R. Low-dose cyclosporine A therapy increases the regulatory T cell population in patients with atopic dermatitis. Allergy (2009) 64:1588-96. doi:10.1111/j.1398-9995.2009.02054.x.
76. Baumgrass R, Brandt C, Wegner F, Abdollahnia M, Worm M. Low-dose, but not high-dose, cyclosporin A promotes regulatory T-cell induction, expansion, or both. J Allergy Clin Immunol (2010) 126:183-4. doi:10.1016/j.jaci.2010.04.032.
77. Brandt C, Liman P, Bendfeldt H, Mueller K, Reinke P, Radbruch A, et al. Whole blood flow cytometric measurement of NFATc1 and IL-2 expression to analyze cyclosporine A-mediated effects in T cells. Cytometry A (2010) 77:607-13. doi:10.1002/cyto.a.20928.
78. Weng J, Lai P, Lv M, Lin S, Ling W, Geng S, et al. Bortezomib modulates regulatory T cell subpopulations in the process of acute graft-versus-host disease. Clin Lab (2013) 59:51-8.
79. Mao R, Xiao W, Liu H, Chen B, Yi B, Kraj P, et al. Systematic evaluation of 640 FDA drugs for their effect on CD4(+)Foxp3(+) regulatory T cells using a novel cell-based high throughput screening assay. Biochem Pharmacol (2013) 85:1513-24. doi:10.1016/j.bcp.2013.03.013.
80. Zhou X, Bailey-Bucktrout SL, Jeker LT, Penaranda C, Martínez-Llordella M, Ashby M, et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol (2009) 10:1000-7. doi:10.1038/ni.1774.
81. 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 U S A (2009) 106:8635-40. doi:10.1073/pnas.0900621106.
82. 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 U S A (2009) 106:1903-8. doi:10.1073/pnas.0811556106.
83. Voo KS, Wang Y-H, Santori FR, Boggiano C, Wang Y-H, Arima K, et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci U S A (2009) 106:4793-8. doi:10.1073/pnas.0900408106.
84. Duarte JH, Zelenay S, Bergman M-L, Martins AC, Demengeot J. Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. Eur J Immunol (2009) 39:948-55. doi:10.1002/eji.200839196.
85. Miyao T, Floess S, Setoguchi R, Luche H, Fehling HJ, Waldmann H, et al. Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity (2012) 36:262-75. doi:10.1016/j.immuni.2011.12.012.
86. Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity (2012) 37:785-99. doi:10.1016/j.immuni.2012.09.010.
87. Sharma MD, Huang L, Choi J-H, Lee E-J, Wilson JM, Lemos H, et al. An inherently bifunctional subset of Foxp3+ T helper cells is controlled by the transcription factor eos. Immunity (2013) 38:998-1012. doi:10.1016/j.immuni.2013.01.013.
88. Kim H-P, Leonard WJ. CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med (2007) 204:1543-51. doi:10.1084/jem.20070109.
89. Tao R, de Zoeten EF, Ozkaynak E, Chen C, Wang L, Porrett PM, et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med (2007) 13:1299-307. doi:10.1038/nm1652.
90. Riley JL, June CH. The CD28 family: a T-cell rheostat for therapeutic control of T-cell activation. Blood (2005) 105:13-21. doi:10.1182/blood-2004-04-1596.
91. 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) 355:1018-28. doi:10.1056/NEJMoa063842.
92. Lal G, Bromberg JS. Epigenetic mechanisms of regulation of Foxp3 expression. Blood (2009) 114:3727-35. doi:10.1182/blood-2009-05-219584.
93. 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) 182:259-73.
94. Hancock WW, Akimova T, Beier UH, Liu Y, Wang L. HDAC inhibitor therapy in autoimmunity and transplantation. Ann Rheum Dis (2012) 71(Suppl 2):i46-54. doi:10.1136/annrheumdis-2011-200593.
95. Ford ML, Larsen CP. Transplantation tolerance: memories that haunt us. Sci Transl Med (2011) 3:86s22. doi:10.1126/scitranslmed.3002504.
96. Lee K, Nguyen V, Lee K-M, Kang S-M, Tang Q. Attenuation of donor-reactive T cells allows effective control of allograft rejection using regulatory T cell therapy. Am J Transplant (2014) 14:27-38. doi:10.1111/ajt.12509.
97. Weaver TA, Charafeddine AH, Agarwal A, Turner AP, Russell M, Leopardi FV, et al. Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates. Nat Med (2009) 15:746-9. doi:10.1038/nm.1993.
98. Posselt AM, Bellin MD, Tavakol M, Szot GL, Frassetto LA, Masharani U, et al. Islet transplantation in type 1 diabetics using an immunosuppressive protocol based on the anti-LFA-1 antibody efalizumab. Am J Transplant (2010) 10:1870-80. doi:10.1111/j.1600-6143.2010.03073.x.
99. Tavazzi E, Ferrante P, Khalili K. Progressive multifocal leukoencephalopathy: an unexpected complication of modern therapeutic monoclonal antibody therapies. Clin Microbiol Infect (2011) 17:1776-80. doi:10.1111/j.1469-0691.2011.03653.x.
100. Levings MK, Sangregorio R, Roncarolo MG. Human cd25(+)cd4(+) T regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med (2001) 193:1295-302. doi:10.1084/jem.193.11.1295.
101. Tang Q, Bluestone JA. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol (2008) 9:239-44. doi:10.1038/ni1572.
102. Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity (2009) 30:636-45. doi:10.1016/j.immuni.2009.04.010.
103. Lechler RI, Sykes M, Thomson AW, Turka LA. Organ transplantation-how much of the promise has been realized? Nat Med (2005) 11:605-13. doi:10.1038/nm1251.
104. Schraven B, Kalinke U. CD28 superagonists: what makes the difference in humans? Immunity (2008) 28:591-5. doi:10.1016/j.immuni.2008.04.003.
105. Golab K, Leveson-Gower D, Wang X-J, Grzanka J, Marek-Trzonkowska N, Krzystyniak A, et al. Challenges in cryopreservation of regulatory T cells (Tregs) for clinical therapeutic applications. Int Immunopharmacol (2013) 16:371-5. doi:10.1016/j.intimp.2013.02.001.
106. Peters JH, Preijers FW, Woestenenk R, Hilbrands LB, Koenen HJPM, Joosten I. Clinical grade Treg: GMP isolation, improvement of purity by CD127 depletion, Treg expansion, and Treg cryopreservation. PLoS One (2008) 3:e3161. doi:10.1371/journal.pone.0003161.
107. Mougiakakos D, Choudhury A, Lladser A, Kiessling R, Johansson CC. Regulatory T cells in cancer. Adv Cancer Res (2010) 107:57-117. doi:10.1016/S0065-230X(10)07003-X.
108. Socié G, Blazar BR. Acute graft-versus-host disease: from the bench to the bedside. Blood (2009) 114:4327-36. doi:10.1182/blood-2009-06-204669.
109. Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med (2002) 196:389-99. doi:10.1084/jem.20020399.
110. Edinger M, Hoffmann P. Regulatory T cells in stem cell transplantation: strategies and first clinical experiences. Curr Opin Immunol (2011) 23:679-84. doi:10.1016/j.coi.2011.06.006.
111. Issa F, Wood KJ. Translating tolerogenic therapies to the clinic-where do we stand? Front Immunol (2012) 3:254. doi:10.3389/fimmu.2012.00254.
112. Taylor PA, Noelle RJ, Blazar BR. CD4(+)CD25(+) immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade. J Exp Med (2001) 193:1311-8. doi:10.1084/jem.193.11.1311.
113. Dodd-o JM, Lendermon EA, Miller HL, Zhong Q, John ER, Jungraithmayr WM, et al. CD154 blockade abrogates allospecific responses and enhances CD4(+) regulatory T-cells in mouse orthotopic lung transplant. Am J Transplant (2011) 11:1815-24. doi:10.1111/j.1600-6143.2011.03623.x.
114. Nadig SN, Wieckiewicz J, Wu DC, Warnecke G, Zhang W, Luo S, et al. In vivo prevention of transplant arteriosclerosis by ex vivo-expanded human regulatory T cells. Nat Med (2010) 16:809-13. doi:10.1038/nm.2154.
115. Schliesser U, Streitz M, Sawitzki B. Tregs: application for solid-organ transplantation. Curr Opin Organ Transplant (2012) 17:34-41. doi:10.1097/MOT.0b013e32834ee69f.
116. Soyka MB, Holzmann D, Akdis CA. Regulatory cells in allergen-specific immunotherapy. Immunotherapy (2012) 4:389-96. doi:10.2217/imt.12.10.
117. Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri R, et al. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med (2004) 199:1567-75. doi:10.1084/jem.20032058.
118. Jin H-S, Park Y, Elly C, Liu Y-C. Itch expression by Treg cells controls Th2 inflammatory responses. J Clin Invest (2013) 123:4923-34. doi:10.1172/JCI69355.
119. Rolland JM, Gardner LM, O'Hehir RE. Functional regulatory T cells and allergen immunotherapy. Curr Opin Allergy Clin Immunol (2010) 10:559-66. doi:10.1097/ACI.0b013e32833ff2b2.
120. Zhang Y, Zhen H, Yao W, Bian F, Mao X, Yang X, et al. Antidepressant drug, desipramine, alleviates allergic rhinitis by regulating Treg and Th17 cells. Int J Immunopathol Pharmacol (2013) 26:107-15.
121. Tritt M, Sgouroudis E, D'Hennezel E, Albanese A, Piccirillo CA. Functional waning of naturally occurring CD4+ regulatory T-cells contributes to the onset of autoimmune diabetes. Diabetes (2008) 57:113-23. doi:10.2337/db06-1700.
122. Miyara M, Amoura Z, Parizot C, Badoual C, Dorgham K, Trad S, et al. Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol (2005) 175:8392-400.
123. 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) 108:253-61. doi:10.1182/blood-2005-11-4567.
124. 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) 199:971-9. doi:10.1084/jem.20031579.
125. Baecher-Allan C, Hafler DA. Human regulatory T cells and their role in autoimmune disease. Immunol Rev (2006) 212:203-16. doi:10.1111/j.0105-2896.2006.00417.x.
126. Tarbell KV, Petit L, Zuo X, Toy P, Luo X, Mqadmi A, et al. Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J Exp Med (2007) 204:191-201. doi:10.1084/jem.20061631.
127. Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev (2006) 212:8-27. doi:10.1111/j.0105-2896.2006.00427.x.
128. 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) 35:1817-20. doi:10.2337/dc12-0038.
129. Souroujon MC, Aricha R, Feferman T, Mizrachi K, Reuveni D, Fuchs S. Regulatory T cell-based immunotherapies in experimental autoimmune myasthenia gravis. Ann N Y Acad Sci (2012) 1274:120-6. doi:10.1111/j.1749-6632.2012.06844.x.
130. Zhou X, Kong N, Wang J, Fan H, Zou H, Horwitz D, et al. Cutting edge: all-trans retinoic acid sustains the stability and function of natural regulatory T cells in an inflammatory milieu. J Immunol (2010) 185:2675-9. doi:10.4049/jimmunol.1000598.
131. Bagavant H, Tung KSK. Failure of CD25+ T cells from lupus-prone mice to suppress lupus glomerulonephritis and sialadenitis. J Immunol (2005) 175:944-50.
132. Huter EN, Stummvoll GH, DiPaolo RJ, Glass DD, Shevach EM. Cutting edge: antigen-specific TGF beta-induced regulatory T cells suppress Th17-mediated autoimmune disease. J Immunol (2008) 181:8209-13.
133. Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science (2003) 299:1033-6. doi:10.1126/science.1078231.
134. D'Alessio FR, Tsushima K, Aggarwal NR, West EE, Willett MH, Britos MF, et al. CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. J Clin Invest (2009) 119:2898-913. doi:10.1172/JCI36498.
135. Garibaldi BT, D'Alessio FR, Mock JR, Files DC, Chau E, Eto Y, et al. Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment. Am J Respir Cell Mol Biol (2013) 48:35-43. doi:10.1165/rcmb.2012-0198OC.
136. Gandolfo MT, Jang HR, Bagnasco SM, Ko G-J, Agreda P, Satpute SR, et al. Foxp3+ regulatory T cells participate in repair of ischemic acute kidney injury. Kidney Int (2009) 76:717-29. doi:10.1038/ki.2009.259.
137. Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S, et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med (2009) 15:192-9. doi:10.1038/nm.1927.
138. Ito T, Hanabuchi S, Wang Y-H, Park WR, Arima K, Bover L, et al. Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity (2008) 28:870-80. doi:10.1016/j.immuni.2008.03.018.
139. 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 U S A (2008) 105:19396-401. doi:10.1073/pnas.0806855105.
140. Wei S, Kryczek I, Zou W. Regulatory T-cell compartmentalization and trafficking. Blood (2006) 108:426-31. doi:10.1182/blood-2006-01-0177.
141. Levine BL, Humeau LM, Boyer J, MacGregor R-R, Rebello T, Lu X, et al. Gene transfer in humans using a conditionally replicating lentiviral vector. Proc Natl Acad Sci U S A (2006) 103:17372-7. doi:10.1073/pnas.0608138103.
142. Mekala DJ, Geiger TL. Immunotherapy of autoimmune encephalomyelitis with redirected CD4+CD25+ T lymphocytes. Blood (2005) 105:2090-2. doi:10.1182/blood-2004-09-3579.
143. Elinav E, Adam N, Waks T, Eshhar Z. Amelioration of colitis by genetically engineered murine regulatory T cells redirected by antigen-specific chimeric receptor. Gastroenterology (2009) 136:1721-31. doi:10.1053/j.gastro.2009.01.049.
144. Hori S, Haury M, Coutinho A, Demengeot J. Specificity requirements for selection and effector functions of CD25+4+ regulatory T cells in anti-myelin basic protein T cell receptor transgenic mice. Proc Natl Acad Sci U S A (2002) 99:8213-8. doi:10.1073/pnas.122224799.
145. Varela-Rohena A, Molloy PE, Dunn SM, Li Y, Suhoski MM, Carroll RG, et al. Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor. Nat Med (2008) 14:1390-5. doi:10.1038/nm.1779.