Targeting T lymphocytes for immune monitoring and intervention in autoimmune diabetes

American Journal of Therapeutics

Volumn 12, Issue 6, 2005, Pages 534-550

  Mallone, Roberto ^a   Nepom, Gerald T ^a,b  

^a UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

^b BENAROYA RESEARCH INSTITUTE   (United States)

Author keywords

Anergy; Apoptosis; Immune tolerance; Regulatory cell; Tetramer

Indexed keywords

2,4 DINITROPHENOL; ANTIGEN; AUTOANTIBODY; AUTOANTIGEN; CD4 ANTIGEN; CD69 ANTIGEN; CD8 ANTIGEN; COLECALCIFEROL; DEXAMETHASONE; EPITOPE; FLUOROCHROME; GAMMA INTERFERON; GLIADIN; GLUTAMATE DECARBOXYLASE 65; HLA DR ANTIGEN; INTERLEUKIN 2 RECEPTOR ALPHA; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; OKT 3; PROINSULIN; RECOMBINANT PROTEIN; T LYMPHOCYTE RECEPTOR; TETRAMER;

AMINO TERMINAL SEQUENCE; ANTIGEN RECOGNITION; ANTIGEN SPECIFICITY; APOPTOSIS; AUTOIMMUNE DISEASE; AUTOIMMUNITY; BINDING AFFINITY; CELL ASSAY; CELL LABELING; CELL MATURATION; CLINICAL TRIAL; CLONAL ANERGY; CONFERENCE PAPER; CYTOKINE PRODUCTION; CYTOTOXIC T LYMPHOCYTE; DENDRITIC CELL; DIABETES MELLITUS; DRUG POTENCY; GEL PERMEATION CHROMATOGRAPHY; GENE SILENCING; HUMAN; IMMUNE RESPONSE; IMMUNOASSAY; INSULIN DEPENDENT DIABETES MELLITUS; MEMORY CELL; NONHUMAN; PANCREAS ISLET BETA CELL; PERIPHERAL BLOOD MONONUCLEAR CELL; PHENOTYPE; PRIORITY JOURNAL; SENSITIVITY AND SPECIFICITY; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; TH2 CELL; TRANSGENE;

APOPTOSIS; CD4 LYMPHOCYTE COUNT; DIABETES MELLITUS, TYPE 1; GENES, MHC CLASS II; HUMANS; IMMUNE TOLERANCE; T-LYMPHOCYTES;

EID: 27144438181     PISSN: 10752765     EISSN: None     Source Type: Journal    
DOI: 10.1097/01.mjt.0000178772.54396.38     Document Type: Conference Paper

References (144)

1. Altman JD, Moss PA, Goulder PJ, et al. Phenotypic analysis of antigen-specific T lymphocytes. Science. 1996;274:94-96.
2. Kozono H, White J, Clements J, et al. Production of soluble MHC class II proteins with covalently bound single peptides. Nature. 1994;369:151-154.
3. Crawford F, Kozono H, White J, et al. Detection of antigen-specific T cells with multivalent soluble class II MHC covalent peptide complexes. Immunity. 1998;8:675-682.
4. Cameron TO, Norris PJ, Patel A, et al. Labeling antigen-specific CD4(+) T cells with class II MHC oligomers. J Immunol Methods. 2002;268:51-69.
5. McMichael AJ, O'Callaghan CA. A new look at T cells. J Exp Med. 1998;187:1367-1371.
6. Novak EJ, Liu AW, Nepom GT, et al. MHC class II tetramers identify peptide-specific human CD4(+) T cells proliferating in response to influenza A antigen. J Clin Invest. 1999;104:R63-R67.
7. Day CL, Seth NP, Lucas M, et al. Ex vivo analysis of human memory CD4 T cells specific for hepatitis C virus using MHC class II tetramers. J Clin Invest. 2003;112:831-842.
8. Kwok WW, Liu AW, Novak EJ, et al. HLA-DQ tetramers identify epitope-specific T cells in peripheral blood of herpes simplex virus type 2-infected individuals: direct detection of immunodominant antigen-responsive cells. J Immunol. 2000;164:4244-4249.
9. Kotzin BL, Falta MT, Crawford F, et al. Use of soluble peptide-DR4 tetramers to detect synovial T cells specific for cartilage antigens in patients with rheumatoid arthritis. Proc Natl Acad Sci U S A. 2000;97:291-296.
10. Meyer AL, Trollmo C, Crawford F, et al. Direct enumeration of Borrelia-reactive CD4 T cells ex vivo by using MHC class II tetramers. Proc Natl Acad Sci U S A. 2000;97:11433-11438.
11. Quarsten H, McAdam SN, Jensen T, et al. Staining of celiac disease-relevant T cells by peptide-DQ2 multimers. J Immunol. 2001;167:4861-4868.
12. Mallone R, Nepom GT. MHC class II tetramers and the pursuit of antigen-specific T cells: define, deviate, delete. Clin Immunol. 2004;110:232-242.
13. Haanen JB, van Oijen MG, Tirion F, et al. In situ detection of virus- and tumor-specific T-cell immunity. Nat Med. 2000;6:1056-1060.
14. Bischof F, Hofmann M, Schumacher TN, et al. Analysis of autoreactive CD4 T cells in experimental autoimmune encephalomyelitis after primary and secondary challenge using MHC class II tetramers. J Immunol. 2004;172:2878-2884.
15. Bielekova B, Sung MH, Kadom N, et al. Expansion and functional relevance of high-avidity myelin-specific CD4+ T cells in multiple sclerosis. J Immunol. 2004;172:3893-3904.
16. Trudeau JD, Kelly-Smith C, Verchere CB, et al. Prediction of spontaneous autoimmune diabetes in NOD mice by quantification of autoreactive T cells in peripheral blood. J Clin Invest. 2003;111:217-223.
17. Reijonen H, Novak EJ, Kochik S, et al. Detection of GAD65-specific T-cells by major histocompatibility complex class II tetramers in type 1 diabetic patients and at-risk subjects. Diabetes. 2002;51:1375-1382.
18. Ogg GS, Rod DP, Romero P, et al. High frequency of skin-homing melanocyte-specific cytotoxic T lymphocytes in autoimmune vitiligo. J Exp Med. 1998;188:1203-1208.
19. Danke NA, Kwok WW. HLA class II-restricted CD4+ T cell responses directed against influenza viral antigens postinfluenza vaccination. J Immunol. 2003;171:3163-3169.
20. Brooks-Worrell BM, Starkebaum GA, Greenbaum C, et al. Peripheral blood mononuclear cells of insulin-dependent diabetic patients respond to multiple islet cell proteins. J Immunol. 1996;157:5668-5674.
21. Brooks-Worrell B, Gersuk VH, Greenbaum C, et al. Intermolecular antigen spreading occurs during the preclinical period of human type 1 diabetes. J Immunol. 2001;166:5265-5270.
22. Arif S, Tree TI, Astill TP, et al. Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J Clin Invest. 2004;113:451-463.
23. Trudeau JD, Dutz JP, Arany E, et al. Neonatal beta-cell apoptosis: a trigger for autoimmune diabetes? Diabetes. 2000;49:1-7.
24. Mathis D, Vence L, Benoist C. beta-cell death during progression to diabetes. Nature. 2001;414:792-798.
25. Turley S, Poirot L, Hattori M, et al. Physiological {beta} cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model. J Exp Med. 2003;198:1527-1537.
26. Kassem SA, Ariel I, Thornton PS, et al. Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes. 2000;49:1325-1333.
27. Katz J, Benoist C, Mathis D. Major histocompatibility complex class I molecules are required for the development of insulitis in non-obese diabetic mice. Eur J Immunol. 1993;23:3358-3360.
28. Wicker LS, Leiter EH, Todd JA, et al. Beta 2-microglobulin-deficient NOD mice do not develop insulitis or diabetes. Diabetes. 1994;43:500-504.
29. Wong FS, Visintin I, Wen L, et al. CD8 T cell clones from young nonobese diabetic (NOD) islets can transfer rapid onset of diabetes in NOD mice in the absence of CD4 cells. J Exp Med. 1996;183:67-76.
30. Graser RT, DiLorenzo TP, Wang F, et al. Identification of a CD8 T cell that can independently mediate autoimmune diabetes development in the complete absence of CD4 T cell helper functions. J Immunol. 2000;164:3913-3918.
31. Serreze DV, Chapman HD, Varnum DS, et al. Initiation of autoimmune diabetes in NOD/Lt mice is MHC class I-dependent. J Immunol. 1997;158:3978-3986.
32. Soen Y, Chen DS, Kraft DL, et al. Detection and characterization of cellular immune responses using peptide-MHC microarrays. PLoS Biol. 2003;1:E65.
33. Jordan MS, Boesteanu A, Reed AJ, et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat Immunol. 2001;2:301-306.
34. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4:330-336.
35. Sakaguchi S. Policing the regulators. Nat Immunol. 2001;2:283-284.
36. Amrani A, Verdaguer J, Serra P, et al. Progression of autoimmune diabetes driven by avidity maturation of a T-cell population. Nature. 2000;406:739-742.
37. Tian J, Gregori S, Adorini L, et al. The frequency of high avidity T cells determines the hierarchy of determinant spreading. J Immunol. 2001;166:7144-7150.
38. Rees W, Bender J, Teague TK, et al. An inverse relationship between T cell receptor affinity and antigen dose during CD4(+) T cell responses in vivo and in vitro. Proc Natl Acad Sci U S A. 1999;96:9781-9786.
39. Alexander-Miller MA, Leggatt GR, Berzofsky JA. Selective expansion of high- or low-avidity cytotoxic T lymphocytes and efficacy for adoptive immunotherapy. Proc Natl Acad Sci U S A. 1996;93:4102-4107.
40. Viglietta V, Kent SC, Orban T, et al. GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes. J Clin Invest. 2002;109:895-903.
41. Reichstetter S, Ettinger RA, Liu AW, et al. Distinct T cell interactions with HLA class II tetramers characterize a spectrum of TCR affinities in the human antigen-specific T cell response. J Immunol. 2000;165:6994-6998.
42. Savage PA, Boniface JJ, Davis MM. A kinetic basis for T cell receptor repertoire selection during an immune response. Immunity. 1999;10:485-492.
43. Gebe JA, Falk BA, Rock KA, et al. Low-avidity recognition by CD4+ T cells directed to self-antigens. Eur J Immunol. 2003;33:1409-1417.
44. Derby MA, Wang J, Margulies DH, et al. Two intermediate-avidity cytotoxic T lymphocyte clones with a disparity between functional avidity and MHC tetramer staining. Int Immunol. 2001;13:817-824.
45. Reddy J, Bettelli E, Nicholson L, et al. Detection of autoreactive myelin proteolipid protein 139-151-specific T cells by using MHC II (IAs) tetramers. J Immunol. 2003;170:870-877.
46. Turcanu V, Maleki SJ, Lack G. Characterization of lymphocyte responses to peanuts in normal children, peanut-allergic children, and allergic children who acquired tolerance to peanuts. J Clin Invest. 2003;111:1065-1072.
47. Tarbell KV, Lee M, Ranheim E, et al. CD4(+) T cells from glutamic acid decarboxylase (GAD)65-specific T cell receptor transgenic mice are not diabetogenic and can delay diabetes transfer. J Exp Med. 2002;196:481-492.
48. Hamad AR, O'Herrin SM, Lebowitz MS, et al. Potent T cell activation with dimeric peptide-major histocompatibility complex class II ligand: the role of CD4 coreceptor. J Exp Med. 1998;188:1633-1640.
49. Appel H, Gauthier L, Pyrdol J, et al. Kinetics of T-cell receptor binding by bivalent HLA-DR. Peptide complexes that activate antigen-specific human T-cells. J Biol Chem. 2000;75:312-321.
50. Valitutti S, Muller S, Cella M, et al. Serial triggering of many T-cell receptors by a few peptide-MHC complexes. Nature. 1995;375:148-151.
51. Valitutti S, Lanzavecchia A. Serial triggering of TCRs: a basis for the sensitivity and specificity of antigen recognition. Immunol Today. 1997;18:299-304.
52. Boniface JJ, Rabinowitz JD, Wulfing C, et al. Initiation of signal transduction through the T cell receptor requires the multivalent engagement of peptide/MHC ligands. Immunity. 1998;9:459-466.
53. Cochran JR, Cameron TO, Stern LJ. The relationship of MHC-peptide binding and T cell activation probed using chemically defined MHC class II oligomers. Immunity. 2000;12:241-250.
54. Kim JV, Latouche JB, Riviere I, et al. The ABCs of artificial antigen presentation. Nat Biotechnol. 2004;22:403-410.
55. Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346:1692-1698.
56. Herold KC, Burton JB, Francois F, et al. Activation of human T cells by FcR nonbinding anti-CD3 mAb, hOKT3gamma1(Ala-Ala). J Clin Invest. 2003;111:409-418.
57. Belghith M, Bluestone JA, Barriot S, et al. TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat Med. 2003;9:1202-1208.
58. Masteller EL, Bluestone JA. Immunotherapy of insulin-dependent diabetes mellitus. Curr Opin Immunol. 2002;14:652-659.
59. Chatenoud L. CD3-specific antibody-induced active tolerance: from bench to bedside. Nat Rev Immunol. 2003;3:123-132.
60. Casares S, Zong CS, Radu DL, et al. Antigen-specific signaling by a soluble, dimeric peptide/major histocompatibility complex class II/Fc chimera leading to T helper cell type 2 differentiation. J Exp Med. 1999;190:543-553.
61. Casares S, Hurtado A, McEvoy RC, et al. Down-regulation of diabetogenic CD4+ T cells by a soluble dimeric peptide-MHC class II chimera. Nat Immunol. 2002;3:383-391.
62. Appel H, Seth NP, Gauthier L, et al. Anergy induction by dimeric TCR ligands. J Immunol. 2001;166:5279-5285.
63. Zuo L, Cullen CM, DeLay ML, et al. A single-chain class II MHC-IgG3 fusion protein inhibits autoimmune arthritis by induction of antigen-specific hyporesponsiveness. J Immunol. 2002;168:2554-2559.
64. Huan J, Subramanian S, Jones R, et al. Monomeric recombinant TCR ligand reduces relapse rate and severity of experimental autoimmune encephalomyelitis in SJL/J mice through cytokine switch. J Immunol. 2004;172:4556-1566.
65. O'Herrin SM, Slansky JE, Tang Q, et al. Antigen-specific blockade of T cells in vivo using dimeric MHC peptide. J Immunol. 2001;167:2555-2560.
66. Masteller EL, Warner MR, Ferlin W, et al. Peptide-MHC class II dimers as therapeutics to modulate antigen-specific T cell responses in autoimmune diabetes. J Immunol. 2003;171:5587-5595.
67. Mallone R, Kochik SA, Laughlin EM, et al. Differential recognition and activation thresholds in human autoreactive GAD-specific T-cells. Diabetes. 2004;53:971-977.
68. Fasso M, Anandasabapathy N, Crawford F, et al. T cell receptor (TCR)-mediated repertoire selection and loss of TCR vbeta diversity during the initiation of a CD4(+) T cell response in vivo. J Exp Med. 2000;192:1719-1730.
69. Anderton SM, Wraith DC. Selection and fine-tuning of the autoimmune T-cell repertoire. Nat Rev Immunol. 2002;2:487-498.
70. Rellahan BL, Jones LA, Kruisbeek AM, et al. In vivo induction of anergy in peripheral V beta 8+ T cells by staphylococcal enterotoxin B. J Exp Med. 1990;172:1091-1100.
71. Oxenius A, Zinkernagel RM, Hengartner H. Comparison of activation versus induction of unresponsiveness of virus-specific CD4+ and CD8+ T cells upon acute versus persistent viral infection. Immunity. 1998;9:449-457.
72. Rocha B, von Boehmer H. Peripheral selection of the T cell repertoire. Science. 1991;251:1225-1228.
73. Lanoue A, Bona C, von Boehmer H, et al. Conditions that induce tolerance in mature CD4+ T cells. J Exp Med. 1997;185:405-414.
74. Pape KA, Merica R, Mondino A, et al. Direct evidence that functionally impaired CD4+ T cells persist in vivo following induction of peripheral tolerance. J Immunol. 1998;160:4719-4729.
75. Schwartz RH. T cell anergy. Annu Rev Immunol. 2003;21:305-334.
76. Macian F, Im SH, Garcia-Cozar FJ, et al. T-cell anergy. Curr Opin Immunol. 2004;16:209-216.
77. Zhang L, Miller RG, Zhang J. Characterization of apoptosis-resistant antigen-specific T cells in vivo. J Exp Med. 1996;183:2065-2073.
78. Nicolle MW, Nag B, Sharma SD, et al. Specific tolerance to an acetylcholine receptor epitope induced in vitro in myasthenia gravis CD4+ lymphocytes by soluble major histocompatibility complex class II-peptide complexes. J Clin Invest. 1994;93:1361-1369.
79. Walker LS, Abbas AK. The enemy within: keeping self-reactive T cells at bay in the periphery. Nat Rev Immunol. 2002;2:11-19.
80. Shevach EM. CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol. 2002;2:389-400.
81. Jonuleit H, Schmitt E. The regulatory T cell family: distinct subsets and their interrelations. J Immunol. 2003;171:6323-6327.
82. von Herrath MG, Harrison LC. Antigen-induced regulatory T cells in autoimmunity. Nat Rev Immunol. 2003;3:223-232.
83. Fehervari Z, Sakaguchi S. Development and function of CD25(+)CD4(+) regulatory T cells. Curr Opin Immunol. 2004;16:203-208.
84. Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol. 2003;3:253-257.
85. Thornton AM, Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol. 2000;164:183-190.
86. Ng WF, Duggan PJ, Ponchel F, et al. Human CD4(+)CD25(+) cells: a naturally occurring population of regulatory T cells. Blood. 2001;98:2736-2744.
87. Piccirillo CA, Shevach EM. Cutting edge: control of CD8+ T cell activation by CD4+CD25+ immunoregulatory cells. J Immunol. 2001;167:1137-1140.
88. Cederbom L, Hall H, Ivars F. CD4+CD25+ regulatory T cells down-regulate costimulatory molecules on antigen-presenting cells. Eur J Immunol. 2000;30:1538-1543.
89. Misra N, Bayry J, Lacroix-Desmazes S, et al. Cutting edge: human CD4(+)CD25(+) T cells restrain the maturation and antigen-presenting function of dendritic cells. J Immunol. 2004;172:4676-4680.
90. Sporri R. Reis e Sousa: newly activated T cells promote maturation of bystander dendritic cells but not IL-12 production. J Immunol. 2003;171:6406-6413.
91. Caux C, Massacrier C, Vanbervliet B, et al. Activation of human dendritic cells through CD40 cross-linking. J Exp Med. 1994;180:1263-1272.
92. Serra P, Amrani A, Yamanouchi J, et al. CD40 ligation releases immature dendritic cells from the control of regulatory CD4+CD25+ T cells. Immunity. 2003;19:877-889.
93. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057-1061.
94. Khattri R, Cox T, Yasayko SA, et al. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 2003;4:337-342.
95. Ramsdell F. Foxp3 and natural regulatory T cells: key to a cell lineage? Immunity. 2003;19:165-168.
96. Jonuleit H, Schmitt E, Kakirman H, et al. Infectious tolerance: human CD25(+) regulatory T cells convey suppressor activity to conventional CD4(+) T helper cells. J Exp Med. 2002;196:255-260.
97. 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.
98. Takahashi T, Tagami T, Yamazaki S, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000;192:303-310.
99. Read S, Malmstrom 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.
100. Baecher-Allan C, Brown JA, Freeman GJ, et al. CD4+CD25 high regulatory cells in human peripheral blood. J Immunol. 2001;167:1245-1253.
101. Chen W, Jin W, Wahl SM. Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells. J Exp Med. 1998;188:1849-1857.
102. 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 beta. J Exp Med. 2001;194:629-644.
103. Piccirillo CA, Letterio JJ, Thornton AM, et al. CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor betal production and responsiveness. J Exp Med. 2002;196:237-246.
104. Groux H, Bigler M, de Vries JE, et al. Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. J Exp Med. 1996;184:19-29.
105. Levings MK, Sangregorio R, Galbiati F, et al. IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol. 2001;166:5530-5539.
106. Groux H, O'Garra A, Bigler M, et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature. 1997;389:737-742.
107. Roncarolo MG, Bacchetta R, Bordignon C, et al. Type 1 T regulatory cells. Immunol Rev. 2001;182:68-79.
108. Jonuleit H, Schmitt E, Schuler G, et al. Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med. 2000;192:1213-1222.
109. Buer J, Lanoue A, Franzke A, et al. Interleukin 10 secretion and impaired effector function of major histocompatibility complex class II-restricted T cells anergized in vivo. J Exp Med. 1998;187:177-183.
110. Kemper C, Chan AC, Green JM, et al. Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature. 2003;421:388-392.
111. Barrat FJ, Cua DJ, Boonstra A, 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;195:603-616.
112. Chen Y, Kuchroo VK, Inobe J, et al. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science. 1994;265:1237-1240.
113. Walker R, Kasprowicz DJ, Gersuk VH, et al. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25- T cells. J Clin Invest. 2003;112:1437-1443.
114. Chen W, Jin W, Hardegen 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;198:1875-1886.
115. Fantini MC, Becker C, Monteleone G, et al. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+. J Immunol. 2004;172:5149-5153.
116. Lombardi G, Sidhu S, Batchelor R, et al. Anergic T cells as suppressor cells in vitro. Science. 1994;264:1587-1589.
117. Scott B, Kaye J, Lo D. T cells and suppression in vitro. Science. 1994;266:464-465.
118. Taams LS, van Rensen AJ, Poelen MC, et al. Anergic T cells actively suppress T cell responses via the antigen-presenting cell. Eur J Immunol. 1998;28:2902-2912.
119. Taams LS, Boot EP, van Eden W, et al. 'Anergic' T cells modulate the T-cell activating capacity of antigen-presenting cells. J Autoimmun. 2000;14:335-341.
120. Vendetti S, Chai JG, Dyson J, et al. Anergic T cells inhibit the antigen-presenting function of dendritic cells. J Immunol. 2000;165:1175-1181.
121. Frasca L, Scotta C, Lombardi G, et al. Human anergic CD4+ T cells can act as suppressor cells by affecting autologous dendritic cell conditioning and survival. J Immunol. 2002;168:1060-1068.
122. Janssens W, Carlier V, Wu B, et al. CD4+CD25+ T cells lyse antigen-presenting B cells by Fas-Fas ligand interaction in an epitope-specific manner. J Immunol. 2003;171:4604-4612.
123. Fleischer B. Acquisition of specific cytotoxic activity by human T4+ T lymphocytes in culture. Nature. 1984;308:365-367.
124. Appay V, Zaunders JJ, Papagno L, et al. Characterization of CD4(+) CTLs ex vivo. J Immunol. 2002;168:5954-5958.
125. Hahn S, Gehri R, Erb P. Mechanism and biological significance of CD4-mediated cytotoxicity. Immunol Rev. 1995;146:57-79.
126. Otten GR, Germain RN. Split anergy in a CD8+ T cell: receptor-dependent cytolysis in the absence of interleukin-2 production. Science. 1991;251:1228-1231.
127. Qin S, Cobbold SP, Pope H, et al. "Infectious" transplantation tolerance. Science. 1993;259:974-977.
128. Dieckmann D, Bruett CH, Ploettner H, et al. Human CD4(+)CD25(+) regulatory, contact-dependent T cells induce interleukin 10-producing, contact-independent type 1-like regulatory T cells. J Exp Med. 2002;196:247-253.
129. Kitani A, Fuss I, Nakamura K, et al. Transforming growth factor (TGF)-beta1-producing regulatory T cells induce Smad-mediated interleukin 10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGF-beta1-mediated fibrosis. J Exp Med. 2003;198:1179-1188.
130. Francois BJ. Regulatory T cells under scrutiny. Nat Rev Immunol. 2003;3:189-198.
131. MacDonald HR, Baschieri S, Lees RK. Clonal expansion precedes anergy and death of V beta 8+ peripheral Tcells responding to staphylococcal enterotoxin B in vivo. Eur J Immunol. 1991;21:1963-1966.
132. Ucker DS, Meyers J, Obermiller PS. Activation-driven T cell death. II. Quantitative differences alone distinguish stimuli triggering nontransformed T cell proliferation or death. J Immunol. 1992;149:1583-1592.
133. Kabelitz D, Wesselborg S. Life and death of a super-antigen-reactive human CD4+ T cell done: staphylococcal enterotoxins induce death by apoptosis but simultaneously trigger a proliferative response in the presence of HLA-DR+ antigen-presenting cells. Int Immunol. 1992;4:1381-1388.
134. Wesselborg S, Janssen O, Kabelitz D. Induction of activation-driven death (apoptosis) in activated but not resting peripheral blood T cells. J Immunol. 1993;150:4338-4345.
135. Renno T, Hahne M, MacDonald HR. Proliferation is a prerequisite for bacterial superantigen-induced T cell apoptosis in vivo. J Exp Med. 1995;181:2283-2287.
136. Renno T, Attinger A, Locatelli S, et al. Cutting edge: apoptosis of superantigen-activated T cells occurs preferentially after a discrete number of cell divisions in vivo. J Immunol. 1999;162:6312-6315.
137. Perez VL, Van Parijs L, Biuckians A, et al. Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. Immunity. 1997;6:411-417.
138. Huang CT, Huso DL, Lu Z, et al. CD4+ T cells pass through an effector phase during the process of in vivo tolerance induction. J Immunol. 2003;170:3945-3953.
139. Taams LS, van Eden W, Wauben MH. Dose-dependent induction of distinct anergic phenotypes: multiple levels of T cell anergy. J Immunol. 1999;162:1974-1981.
140. Kukreja A, Cost G, Marker J, et al. Multiple immunoregulatory defects in type-1 diabetes. J Clin Invest. 2002;109:131-140.
141. Viglietta V, Baecher-Allan C, Weiner HL, et al. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004;199:971-979.
142. Ishioka GY, Adorini L, Guery JC, et al. Failure to demonstrate long-lived MHC saturation both in vitro and in vivo. Implications for therapeutic potential of MHC-blocking peptides. J Immunol. 1994;152:4310-4319.
143. Casares S, Bona CA, Brumeanu TD. Enzymatically mediated engineering of multivalent MHC class II-peptide chimeras. Protein Eng. 2001;14:195-200.
144. Pugliese A. Peptide-based treatment for autoimmune diseases: learning how to handle a double-edged sword. J Clin Invest. 2003;111:1280-1282.