Apoptosis as a mechanism of T-regulatory cell homeostasis and suppression

Immunology and Cell Biology

Volumn 86, Issue 8, 2008, Pages 650-658

  Yolcu, Esma S ^a   Ash, Shifra ^b   Kaminitz, Ayelet ^b   Sagiv, Yuval ^c   Askenasy, Nadir ^b   Yarkoni, Shai ^c  

^a University of Louisville School of Medicine   (United States)

^b SCHNEIDER CHILDREN S MEDICAL CENTER OF ISRAEL   (Israel)

^c Target In Ltd   (Israel)

Author keywords

Apoptosis; CD25; Death receptors; Immune homeostasis; T regulatory cell

Indexed keywords

CYCLOPHOSPHAMIDE; DEATH RECEPTOR; FAS LIGAND; FLUDARABINE; INTERLEUKIN 2; RAPAMYCIN;

APOPTOSIS; CELL CONTACT; CELL DEATH; CELL EXPANSION; CELL FUNCTION; HOMEOSTASIS; IMMUNE RESPONSE; IMMUNOREGULATION; IMMUNOSTIMULATION; LYMPHOCYTE; NONHUMAN; POLARIZATION; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; REGULATORY T LYMPHOCYTE; REVIEW; STEADY STATE; TURNOVER TIME;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; CYCLOPHOSPHAMIDE; CYTOKINES; FAS LIGAND PROTEIN; FAS-ASSOCIATED DEATH DOMAIN PROTEIN; HOMEOSTASIS; HUMANS; IMMUNOSUPPRESSIVE AGENTS; T-LYMPHOCYTES, CYTOTOXIC; T-LYMPHOCYTES, REGULATORY; VIDARABINE;

EID: 56249126742     PISSN: 08189641     EISSN: 14401711     Source Type: Journal    
DOI: 10.1038/icb.2008.62     Document Type: Review

References (186)

1. Shevach EM. Regulatory T cells in autoimmmunity. Annu Rev Immunol 2000; 18: 423-449.
2. Maloy KJ, Powrie F. Regulatory T cells in the control of immune pathology. Nat Immunol 2001; 2: 816-822.
3. + suppressor T cells: more questions than answers. Nat Rev Immunol 2002; 2: 389-400.
4. Bach JF. Regulatory T cells under scrutiny. Nat Rev Immunol 2003; 3: 189-198.
5. Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol 2003; 3: 253-257.
6. Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol 2003; 3: 199-210.
7. Fehervari Z, Sakaguchi S. CD4 Tregs and immune control. J Clin Invest 2004; 114: 1209-1217.
8. Paust S, Cantor H. Regulatory T cells and autoimmune disease. Immunol Rev 2005; 204: 195-207.
9. Sakaguchi S, Sakaguchi N. Regulatory T cells in immunologic selftolerance and autoimmune disease. Int Rev Immunol 2005; 24: 211-226.
10. Schwartz RH. Natural regulatory T cells and self-tolerance. Nat Immunol 2005; 6: 327-330.
11. + regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004; 22: 531-562.
12. Sakaguchi S. Naturally arising Foxp3-expressing CD25 CD4 regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 2005; 6: 345-352.
13. + natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 2006; 212: 8-27.
14. Shevach EM. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 2006; 25: 195-201.
15. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 Receptor a-Chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155: 1151-1164.
16. + regulatory T cells. Nat Immunol 2003; 4: 330-336.
17. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299: 1057-1106.
18. Walker MR, Kasprowicz DJ, Gersuk VH, Be'nard A, Van Landeghen M, Buckner JH 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.
19. + regulatory T cells. Curr Opin Immunol 2004; 16: 203-208.
20. Kabelitz D, Pohl T, Pechhold K. Activation-induced cell death (apoptosis) of mature peripheral T lymphocytes. Immunol Today 1993; 14: 338-339.
21. Nagata S. Apoptosis by death factor. Cell 1997; 88: 355-365.
22. Lenardo M, Chan KM, Hornung F, McFarland H, Siegel R, Wang J et al. Mature T lymphocyte apoptosis - immune regulation in a dynamic and unpredictable antigenic environment. Ann Rev Immunol 1999; 17: 221-253.
23. Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 2003; 3: 745-756.
24. Dempsey PW, Doyle SE, He JQ, Cheng G. The signalling adaptors and pathways activated by TNF superfamily. Cytokine Growth Factor Rev 2003; 14: 193-209.
25. Gaur U, Aggarwal BB. Regulation of proliferation, survival and apoptosis by members of the TNF superfamily. Biochem Pharmacol 2003; 66: 1403-1408.
26. Ware CF. The TNF superfamily. Cytokine Growth Factor Rev 2003; 14: 181-184.
27. Gavin MA, Clarke SR, Negrou E, Gallegos A, Rudensky A. Homeostasis and anergy of CD4(+)CD25(+) suppressor T cells in vivo. Nat Immunol 2002; 3: 33-41.
28. McHugh RS, Whitters MJ, Piccirillo CA, Young DA, Shevach EM, Collins M et al. CD4(+) CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002; 16: 311-323.
29. + regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 2002; 3: 135-142.
30. + T cells. J Immunol 2007; 179: 1427-1430.
31. Nocentini G, Riccardi C. GITR: a multifaceted regulator of immunity belonging to the tumor necrosis factor receptor superfamily. Eur J Immunol 2005; 35: 1016-1022.
32. + T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR. Blood 2005; 105: 2845-2851.
33. + T cells. Nature 1995; 376: 181-184.
34. + T cells induced by cross-presentation of self-antigens involves signaling through CD95 (Fas, Apo-1). J Exp Med 1998; 188: 415-420.
35. Green DR, Ferguson TA. The role of Fas ligand in immune privilege. Nat Rev Mol Cell Biol 2001; 2: 917-924.
36. Bohana-Kashtan O, Civin CI. Fas ligand as a tool for immunsuppression and generation of immune tolerance. Stem Cells 2004; 22: 908-924.
37. Askenasy N, Yolcu ES, Yaniv I, Shirwan H. Fas-ligand as a double-edged immunomodulator to induce transplantation tolerance. Blood 2005; 105: 1396-1404.
38. Zhang ZX, Yang L, Young KJ, DuTemple B, Zhang L. Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression. Nat Med 2000; 6: 782-789.
39. Ford MS, Young KJ, Zhang Z, Ohashi PS, Zhang L. The immune regulatory function of lymphoproliferative double negative T cells in vitro and in vivo. J Exp Med 2002; 196: 261-267.
40. Weber SE, Harbertson J, Godebu E, Mros GA, Padrick RC, Carson BD et al. Adaptive islet-specific regulatory CD4T cells control autoimmune diabetes and mediate the disappearance of pathogenic Th1 cells in vivo. J Immunol 2006; 176: 4730-4739.
41. Pearl-Yafe M, Yolcu ES, Yaniv I, Stein J, Shirwan H, Askenasy N. The dual role of Fasligand as an injury effector and defense strategy in diabetes and islet transplantation. BioEssays 2006; 28: 211-222.
42. Alderson MR, Armitage RJ, Maraskovsky E, Tough TW, Roux E, Schooley K et al. Fas transduces activation signals in normal human T lymphocytes. J Exp Med 1993; 178: 2231-2235.
43. + T cells. Nat Med 1998; 4: 1377-1382.
44. Alam A, Cohen LY, Aouad S, Sekaly RP. Early activation of caspases during T lymphocyte stimulation results in selective substrate cleavage in nonapoptotic cells. J Exp Med 1999; 190: 1879-1890.
45. Kennedy NJ, Kataoka T, Tschopp J, Budd RC. Caspase activation is required for T cell proliferation. J Exp Med 1999; 190: 1891-1896.
46. Pimentel-Muinos FX, Seed B. Regulated commitment of TNF receptor signaling: a molecular switch for death or activation. Immunity 1999; 11: 783-793.
47. Wallach D, Varfolomeev EE, Malinin NL, Goltsev YV, Kovalenko AV, Boldin MP. Tumor necrosis factor receptor and Fas signaling mechanisms. Annu Rev Immunol 1999; 17: 331-367.
48. + T cells. Proc Natl Acad Sci USA 2000; 97: 1707-1712.
49. + T cells. J Immunol 2000; 165: 5537-5543.
50. Hohlbaum AM, Gregory MS, Ju ST, Marshak-Rothstein A. Fas ligand engagement of resident peritoneal macrophages in vivo induces apoptosis and the production of neutrophil chemotactic factors. J Immunol 2001; 167: 6217-6224.
51. Budd RC. Death receptors couple to both cell proliferation and apoptosis. J Clin Invest 2002; 109: 437-441.
52. Peter ME, Budd RC, Desbarats J, Hedrick SM, Hueber AO, Newell MK et al. The CD95 receptor: apoptosis revisited. Cell 2007; 129: 447-450.
53. + T cells expressing CD95 ligand and secreting IL-4 in the liver. J Immunol 2002; 168: 2188-2199.
54. Chen Y, Kuchroo VK, Inobe J, Hafler DA, Weiner HL. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 1994; 265: 1237-1240.
55. Chen Y, Inobe J, Marks R, Gonnella P, Kuchroo VK, Weiner HL. Peripheral deletion of antigen-reactive T cells in oral tolerance. Nature 1995; 376: 177-180.
56. Weiner HL. Oral tolerance: immune mechanisms and the generation of Th3-type TGF-secreting regulatory cells. Microbes Infect 2001; 3: 947-954.
57. Schwarz A, Grabbe S, Grosse-Heitmeyer K, Roters B, Riemann H, Luger TA et al. Ultraviolet light-induced immune tolerance is mediated via the Fas/Fas-ligand system. J Immunol 1998; 160: 4262-4270.
58. + T cells as a functionally and phenotypically distinct immunoregulatory T cell subpopulation. Int Immunol 2000; 12: 1145-1155.
59. Kramer S, Schimpl A, Hunig T. Immunopathology of interleukin (IL) 2-deficient mice: thymus dependence and suppression by thymus-dependent cells with an intact IL-2 gene. J Exp Med 1995; 182: 1769-1776.
60. + lymphocytes convert to anergic or memory-like cells in T cell-deprived recipients. Eur J Immunol 2001; 31: 2256-2265.
61. + regulatory T cell function. Eur J Immunol 2004; 34: 2480-2488.
62. Taams LS, Smith J, Rustin MH, Salmon M, Poulter LW, Akbar AN. Human anergic/ suppressive CD4(+)CD25(+) T cells: a highly differentiated and apoptosis-prone population. Eur J Immunol 2001; 31: 1122-1131.
63. Banz A, Pontoux C, Papiernik M. Modulation of Fas-dependent apoptosis: a dynamic process controlling both the persistence and death of CD4 regulatory T cells and effector T cells. J Immunol 2002; 169: 750-757.
64. + regulatory T cells in the steady state. J Exp Med 2003; 198: 737-746.
65. Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J et al. In vitro-expanded antigenspecific regulatory T cells suppress autoimmune diabetes. J Exp Med 2004; 199: 1455-1465.
66. + regulatory T cells are highly susceptible to CD95 ligand- but not to TCR-mediated cell death. J Immunol 2005; 175: 32-36.
67. + TR cells. Int Immunol 2006; 18: 1265-1277.
68. Franke DD, Yolcu ES, Alard P, Kosiewicz MM, Shirwan H. A novel multimeric form of FasL modulates the ability of diabetogenic T cells to mediate type 1 diabetes in an adoptive transfer model. Mol Immunol 2007; 44: 2884-2892.
69. Taylor SR, Alexander DR, Cooper JC, Higgins CF, Elliott JI. Regulatory T cells are resistant to apoptosis via TCR but not P2X7. J Immunol 2007; 178: 3474-3482.
70. Fritzsching B, Oberle N, Pauly E, Geffers R, Buer J, Poschl J et al. Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death. Blood 2006; 108: 3371-3378.
71. + T cell responses to Fas engagement. Proc Natl Acad Sci USA 1999; 96: 8104-8109.
72. Inaba M, Kurasawa K, Mamura M, Kumano K, Saito Y, Iwamoto I. Primed T cells are more resistant to Fas-mediated activation-induced cell death than naive T cells. J Immunol 1999; 163: 1315-1320.
73. Ramsdell F, Seaman MS, Miller RE, Picha KS, Kennedy MK, Lynch DH. Differential ability of th1 and th2 t cells to express fas ligand and to undergo activation-induced cell death. Int Immunol 1994; 6: 1545-1553.
74. Zhang X, Brunner T, Carter L, Dutton RW, Rogers P, Bradley L et al. Unequal death in T helper cell (Th)1 and Th2 effectors: Th1, but not Th2, effectors undergo rapid Fas/ FasL-mediated apoptosis. J Exp Med 1997; 185: 1837-1849.
75. Varadhachary AS, Perdow SN, Hu C, Ramanarayanan M, Salgame P. Differential ability of T cell subsets to undergo activation-induced cell death. Proc Natl Acad Sci USA 1997; 94: 5778-5783.
76. Young KJ, Yang L, Phillips MJ, Zhang L. Donor-lymphocyte infusion induces transplantation tolerance by activating systemic and graft-infiltrating double-negative regulatory T cells. Blood 2002; 100: 3408-3414.
77. + T cells: IL-2 and IL-7 differentially regulate the balance between proliferation and Fas-mediated apoptosis. J Immunol 2003; 171: 61-68.
78. Suchin EJ, Langmuir PB, Palmer E, Sayegh MH, Wells AD, Turka LA. Quantifying the frequency of alloreactive T cells in vivo: new answers to an old question. J Immunol 2001; 166: 973-981.
79. Yu XZ, Martin PJ, Anasetti C. CD28 signal enhances apoptosis of CD8T cells after strong TCR ligation. J Immunol 2003; 170: 3002-3006.
80. Miyara M, Sakaguchi S. Natural regulatory T cells: mechanisms of suppression. Trends Mol Med 2007; 13: 108-116.
81. Askenasy N, Kaminitz A, Yarkoni S. Mechanisms of T regulatory cell function. Autommun Rev 2008; 7: 370-375.
82. + splenocytes that delays adoptive transfer of diabetes expresses 1-selectin and high levels of CCR7. J Immunol 2002; 169: 2461-2465.
83. Yarkoni S, Kaminitz A, Sagiv Y, Yaniv I, Askenasy N. Involvement of IL-2 in homeostasis of regulatory T cells: the IL-2 cycle. BioEssays 2008; 30: 875-888.
84. + regulatory T cells. J Autoimmun 2003; 21: 261-271.
85. + T-regulatory cell subset has optimal suppressive and proliferative potential. Am J Transplant 2004; 4: 65-78.
86. Kim CH. The greater chemotactic network for lymphocyte trafficking: chemokines and beyond. Curr Opin Hematol 2005; 12: 298-304.
87. Wei S, Kryczek I, Zou W. Regulatory T cell compartmentalization and trafficking. Blood 2006; 108: 426-431.
88. + T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J Exp Med 2004; 199: 1479-1489.
89. Green EA, Choi Y, Flavell RA. Pancreatic lymph node-derived CD4 (+) CD25 (+) Treg cells: highly potent regulators of diabetes that require TRANCE-RANK signals. Immunity 2002; 16: 183-191.
90. Peng Y, Laouar Y, Li MO, Green EA, Flavell RA. TGF-beta regulates in vivo expansion of Foxp3-expressing CD4?CD25? regulatory T cells responsible for protection against diabetes. Proc Natl Acad Sci USA 2004; 101: 4572-4577.
91. Siegmund K, Feuerer M, Siewert C, Ghani S, Haubold U, Dankof A et al. Migration matters: regulatory T-cell compartmentalization determines suppressive activity in vivo. Blood 2005; 106: 3097-3104.
92. 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.
93. Knoechel B, Lohr J, Kahn E, Bluestone JA, Abbas AK. Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen. J Exp Med 2005; 202: 1375-1386.
94. Raimondi G, Turner MS, Thomson AW, Morel PA. Naturally occurring regulatory T cells: recent insights in health and disease. Crit Rev Immunol 2007; 27: 61-95.
95. + T cells with regulatory properties from human blood. J Exp Med 2001; 193: 1303-1310.
96. + T cells with regulatory properties isolated from peripheral blood. J Exp Med 2001; 193: 1285-1294.
97. + 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: 1295-1302.
98. + T reg cells impinge on autoimmune diabetes. J Exp Med 2005; 202: 1387-1397.
99. + regulatory T cells abrogates their function in vivo. J Immunol 2006; 177: 4376-4383.
100. Malissen M, Gillet A, Ardouin L, Bouvier G, Trucy J, Ferrier P et al. Altered T cell development in mice with a targeted mutation of the CD3-{epsilon} gene. EMBO J 1995; 14: 4641-4653.
101. + T cell numbers. J Immunol 2002; 169: 4850-4860.
102. Malek TR, Bayer AL. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol 2004; 4: 665-674.
103. Nelson BH. IL-2, regulatory T cells, and tolerance. J Immunol 2004; 172: 3983-3988.
104. Fehervari Z, Yamaguchi T, Sakaguchi S. The dichotomous role of IL-2: tolerance versus immunity. Trends Immunol 2006; 27: 109-111.
105. Kung JT, Beller D, Ju S-T. Lymphokine regulation of activation-induced apoptosis in T cells of IL-2 and IL-2R_ knockout mice. Cell Immunol 1998; 185: 158-163.
106. Leung DT, Morefield S, Willerford DM. Regulation of lymphoid homeostasis by IL-2 receptor signals in vivo. J Immunol 2000; 164: 3527-3534.
107. Lenardo MJ. Interleukin-2 programs mouse T lymphocytes for apoptosis. Nature 1991; 353: 858-861.
108. Refaeli Y, Van Parijs L, London CA, Tschopp J, Abbas AK. Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. Immunity 1998; 8: 615-623.
109. Zheng L, Trageser CL, Willerford DM, Lenardo MJ. T cell growth cytokines cause the superinduction of molecules mediating antigen-induced T lymphocyte death. J Immunol 1998; 160: 763-769.
110. + T cells: evidence for two distinct regulatory mechanisms. Eur J Immunol 2001; 31: 1637-1645.
111. + T cells. Nat Immunol 2007; 8: 1353-1362.
112. + regulatory T cell survival. Biol Direct 2008; 3: 6.
113. Liston A, Siggs OM, Goodnow CC. Tracing the action of IL-2 in tolerance to isletspecific antigen. Immunol Cell Biol 2007; 85: 338-342.
114. Tang Q, Adams JY, Penaranda C, Melli K, Piaggio E, Sgouroudis E et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 2008; 28: 687-697.
115. + immunoregulatory T cells is antigen nonspecific. J Immunol 2000; 164: 183-190.
116. + immunoregulatory cells. J Immunol 2001; 167: 1137-1140.
117. + regulatory T cells and for expansion of these cells. J Immunol 2007; 178: 2018-2027.
118. + regulatory T cells. J Exp Med 2005; 201: 1061-1067.
119. + Th1/Th2 cells. Eur J Immunol 2000; 30: 2101-2111.
120. Cottrez F, Groux H. Regulation of TGF-beta response during T cell activation is modulated by IL-10. J Immunol 2001; 167: 773-778.
121. Taylor PA, Lees CJ, Blazar BR. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood 2002; 99: 3493-3499.
122. - cells to develop suppressive activity: the role of IL-2, TGF-, and IL-10. J Immunol 2004; 172: 5213-5221.
123. + T regulatory cells. J Immunol 2007; 178: 4022-4026.
124. + T cells. J Immunol 1999; 163: 1817-1826.
125. + T lymphocytes from MHC class II-deficient mice exhibit regulatory activity. J Immunol 2005; 175: 246-253.
126. Khoruts A, Mondino A, Pape KA, Reiner SL, Jenkins MK. A natural immunological adjuvant enhances T cell clonal expansion through a CD28-dependent, interleukin (IL)-2-independent mechanism. J Exp Med 1998; 187: 225-236.
127. + regulatory T cells for cellular immunotherapy in patients with graft-versus-host disease. J Immunother 2006; 29: 336-349.
128. + regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med 2002; 196: 389-399.
129. + regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 2003; 9: 1144-1150.
130. + Treg cells. Exp Hematol 2006; 34: 66-71.
131. Nagata S, Suda T. Fas and Fas ligand: lpr and gld mutations. Immunol Today 1995; 16: 39-43.
132. Radvanyi LG, Raju K, Spaner D, Mills GB, Miller RG. Interleukin-2 reverses the defect in activation-induced apoptosis in T cells from autoimmune lpr mice. Cell Immunol 1998; 183: 1-12.
133. + regulatory T cells in the absence of interleukin 2 signaling. Nat Immunol 2005; 6: 1151-1158.
134. D'Souza WN, Schluns KS, Masopust D, Lefrancois L. Essential role for IL-2 in the regulation of antiviral extralymphoid CD8T cell responses. J Immunol 2002; 168: 5566-5572.
135. Kneitz B, Herrmann T, Yonehara S, Schimpl A. Normal clonal expansion but impaired Fas-mediated cell death and anergy induction in interleukin-2-deficient mice. Eur J Immunol 1995; 25: 2572-2577.
136. Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW. Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 1995; 3: 521-530.
137. Van Parijs L, Biuckians A, Ibragimov A, Alt FW, Willerford DM, Abbas AK. Functional responses and apoptosis of CD25 (IL-2R)-deficient T cells expressing a transgenic antigen receptor. J Immunol 1997; 158: 3738-3745.
138. Van Parijs L, Refaeli Y, Lord JD, Nelson BH, Abbas AK, Baltimore D. Uncoupling IL-2 signals that regulate T cell proliferation, survival, and Fas-mediated activationinduced cell death. Immunity 1999; 11: 281-288.
139. Wrenshall LE, Platt JL. Regulation of T cell homeostasis by heparan sulfate-bound IL-2. J Immunol 1999; 163: 3793-3800.
140. Malek TR, Porter BO, Codias EK, Scibelli P, Yu A. Normal lymphoid homeostasis and lack of lethal autoimmunity in mice containing mature T cells with severely impaired IL-2 receptors. J Immunol 2000; 164: 2905-2914.
141. Suzuki H, Zhou YW, Kato M, Mak TW, Nakashima I. Normal regulatory alpha/beta T cells effectively eliminate abnormally activated T cells lacking the interleukin 2 receptor beta in vivo. J Exp Med 1999; 190: 1561-1572.
142. Xiao S, Sung S-SJ, Fu SM, Ju S-T. Combining Fas mutation with interleukin-2 deficiency prevents colitis and lupus. J Biol Chem 2003; 278: 52730-52738.
143. Sharma R, Bagavant H, Jarjour WN, Sung SS, Ju ST. The role of Fas in the immune system biology of IL-2R alpha knockout mice: interplay among regulatory T cells, inflammation, hemopoiesis, and apoptosis. J Immunol 2005; 175: 1965-1973.
144. Zheng L, Sharma R, Gaskin F, Fu SM, Ju ST. A novel role of IL-2 in organ-specific autoimmune inflammation beyond regulatory T cell checkpoint: both IL-2 knockout and Fas mutation prolong lifespan of Scurfy mice but by different mechanisms. J Immunol 2007; 179: 8035-8041.
145. + regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 2004; 34: 336-344.
146. +CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood 2005; 106: 2018-2025.
147. + regulatory T cells, which suppress induction of contact hypersensitivity. J Dermatol Sci 2005; 39: 105-112.
148. Di Paolo NC, Tuve S, Ni S, Hellstrom KE, Hellstrom I, Lieber A. Effect of adenovirusmediated heat shock protein expression and oncolysis in combination with low-dose cyclophosphamide treatment on antitumor immune responses. Cancer Res 2006; 66: 960-969.
149. Taieb J, Chaput N, Schartz N, Roux S, Novault S, Ménard C et al. Chemoimmunotherapy of tumors: cyclophosphamide synergizes with exosome based vaccines. J Immunol 2006; 176: 2722-2729.
150. Polak L, Geleick H, Turk JL. Reversal by cyclophosphamide of tolerance in contact sensitization: tolerance induced by prior feeding with DNCB. Immunology 1975; 28: 939-942.
151. Mitsuoka A, Baba M, Morikawa S. Enhancement of delayed hypersensitivity by depletion of suppressor T cells with cyclophosphamide in mice. Nature 1976; 262: 77-78.
152. Rollinghoff M, Starzinski-Powitz A, Pfizenmaier K, Wagner H. Cyclophosphamidesensitive T lymphocytes suppress the in vivo generation of antigen-specific cytotoxic T lymphocytes. J Exp Med 1977; 145: 455-459.
153. Yasunami R, Bach JF. Anti-suppressor effect of cyclophosphamide on the development of spontaneous diabetes in NOD mice. Eur J Immunol 1988; 18: 481-484.
154. Harada M, Makino S. Promotion of spontaneous diabetes in non-obese diabetes-prone mice by cyclophosphamide. Diabetologia 1984; 27: 604-606.
155. + regulatory T cells. J Immunol 2006; 177: 6603-6612.
156. Charlton B, Bacelj A, Slattery RM, Mandel TE. Cyclophosphamide-induced diabetes in NOD/WEHI mice: evidence for suppression in spontaneous autoimmune diabetes mellitus. Diabetes 1989; 38: 441-447.
157. + T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 2005; 105: 2862-2868.
158. Steiner D, Brunicki N, Bachar-Lustig E, Taylor PA, Blazar BR, Reisner Y. Overcoming T cell-mediated rejection of bone marrow allografts by T-regulatory cells: synergism with veto cells and rapamycin. Exp Hematol 2006; 34: 802-808.
159. + regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood 2006; 108: 390-399.
160. Li Y, Li XC, Zheng XX, Wells AD, Turka LA, Strom TB. Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nat Med 1999; 5: 1298-1302.
161. Wells AD, Li XC, Li Y, Walsh MC, Zheng XX, Wu Z et al. Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance. Nat Med 1999; 5: 1303-1307.
162. Baan CC, van der Mast BJ, Klepper M, Mol WM, Peeters AM, Korevaar SS et al. Differential effect of calcineurin inhibitors, anti-CD25 antibodies and Rapamycin on the induction of FOXP3 in human T cells. Transplantation 2005; 80: 110-117.
163. + naturally anergic and suppressive T cells. Int Immunol 1998; 10: 1969-1980.
164. + immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 1998; 188: 287-296.
165. + cells in vivo. J Immunol 2004; 172: 3391-3398.
166. + CD25- T cells anergic and suppressive. Immunology 2007; 120: 447-455.
167. + naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol 1999; 162: 5317-5326.
168. Asseman C, Mauze S, Leach MW, Coffman RL, Powrie F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 1999; 190: 995-1004.
169. + T cells through TGF-beta-TGF-beta receptor interactions in type 1 diabetes. Proc Natl Acad Sci USA 2003; 100: 10878-10883.
170. Stock P, Akbari O, Berry G, Freeman GJ, Dekruyff RH, Umetsu DT. Induction of T helper type 1-like regulatory cells that express Foxp3 and protect against airway hyper-reactivity. Nat Immunol 2004; 5: 1149-1156.
171. Thompson C, Powrie F. Regulatory T cells. Curr Opin Pharmacol 2004; 4: 408-414.
172. Mahiou J, Walter U, Lepault F, Godeau F, Bach JF, Chatenoud L. In vivo blockade of the Fas-Fas ligand pathway inhibits cyclophosphamide- induced diabetes in NOD mice. J Autoimmun 2001; 16: 431-440.
173. + T cells lyse antigen-presenting B cells by Fas-Fas ligand interaction in an epitope-specific manner. J Immunol 2003; 171: 4604-4612.
174. + T cells and their ability to prevent not only diabetes but also insulitis in an adoptive transfer model in BB rats. Scand J Immunol 2006; 64: 17-29.
175. + regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism. J Immunol 2006; 177: 6540-6547..
176. 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: 589-601.
177. + regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J Immunol 2005; 174: 1783-1786.
178. + regulatory T-cells. Diabetes 2005; 54: 78-84.
179. Hadaya K, Kared H, Masson A, Chatenoud L, Zavala F. G-CSF treatment prevents cyclophosphamide acceleration of autoimmune diabetes in the NOD mouse. J Autoimmun 2005; 24: 125-134.
180. + double-negative T cells suppress polyclonal T cell activation by a Fas-independent mechanism that involves inhibition of IL-2 production. J Immunol 2003; 171: 2421-2426.
181. Hill LL, Shreedhar VK, Kripke ML, Owen-Schaub LB. A critical role for Fas ligand in the active suppression of systemic immune responses by ultraviolet radiation. J Exp Med 1999; 189: 1285-1294.
182. Bottino R, Lemarchand P, Trucco M, Giannoukakis N. Gene- and cell-based therapeutics for type I diabetes mellitus. Gene Ther 2003; 10: 875-889.
183. Martin E, O'Sullivan B, Low P, Thomas R. Antigen-specific suppression of a primed immune response by dendritic cells mediated by regulatory T cells secreting interleukin-10. Immunity 2003; 18: 155-167.
184. Zheng XX, Sanchez-Fueyo A, Sho M, Domenig C, Sayegh MH, Strom TB. Favorably tipping the balance between cytopathic and regulatory T cells to create transplantation tolerance. Immunity 2003; 19: 503-514.
185. + CD4T cells in vivo after CD25-directed recombinant immunotoxin administration. J Immunother 2008; 31: 189-198.
186. + regulatory T cells via FasL protein transfer enhances the therapeutic efficacy of adoptive T cell transfer. Cancer Res 2007; 67: 1291-1298.