Skip to main content
SpringerLink
Log in

Effector Lymphocytes in Islet Cell Autoimmunity

  • Published:
Reviews in Endocrine and Metabolic Disorders Aims and scope Submit manuscript

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Ji H, Korganow AS, Mangialaio S, Hoglund P, Andre I, Luhder F, Gonzalez A, Poirot L, Benoist C, Mathis D. Different modes of pathogenesis in T-cell-dependent autoimmunity: Clues from two TCR transgenic systems. Immunol Rev 1999;169:139–146.

    Google Scholar 

  2. Abiru N, Eisenbarth G. Autoantibodies and autoantigens in type 1 diabetes: Role in pathogenesis, prediction and prevention. Can Journ Diab Car 1999;23:59–65.

    Google Scholar 

  3. Henkart PA. Mechanism of lymphocyte-mediated cytotoxicity. Annu Rev Immunol 1985;3:31–58.

    Google Scholar 

  4. Ostergaard HL, Kane KP, Mescher MF, Clark WR. Cytotoxic T lymphocyte mediated lysis without release of serine esterase. Nature 1987;330:71–72.

    Google Scholar 

  5. Helgason CD, Prendergast JA, Berke G, Bleackley RC. Peritoneal exudate lymphocyte and mixed lymphocyte culture hybridomas are cytolytic in the absence of cytotoxic cell proteinases and perforin. Eur J Immunol 1992;22:3187–190.

    Google Scholar 

  6. Rouvier E, Luciani MF, Golstein P. Fas involvement in Ca(2+)-independent T cell-mediated cytotoxicity. J Exp Med 1993;177:195–200.

    Google Scholar 

  7. Katz J, Benoist C, Mathis D. Major histocompatibility complex class I molecules are required for the generation of insulitis in non-obese diabetic mice. Eur J Immunol 1993;23:3358–3360.

    Google Scholar 

  8. Serreze D, Leiter E, Christianson G, Greiner D, Roopenian D. Major histocompatibility complex class I-deficient NOD. β1mnull mice are diabetes and insulitis resistant. Diabetes 1994;43:505– 508.

    Google Scholar 

  9. Wicker L, Leiter E, Todd J, Renjilian RJ, Peterson E, Fischer PA, Podolin PL, Zijlstra M, Jaenisch R, Peterson LB. β2-microglobulin-deficient NOD mice do not develop insulitis or diabetes. Diabetes 1994;43:500–504.

    Google Scholar 

  10. Wang B, Gonzalez A, Benoist C, Mathis D. The role of CD8+ T-cells in initiation of insulin-dependent diabetes mellitus. Eur J Immunol 1996;26:1762–1769.

    Google Scholar 

  11. Nagata M, Santamaria P, Kawamura T, Utsugi T, Yoon J-W. Evidence for the role of CD8+ cytotoxic T cells in the destruction of pancreatic beta cells in NOD mice. J Immunol 1994;152:2042–2050.

    Google Scholar 

  12. Santamaria P, Utsugi T, Park B, Averill N, Kawazu S, Yoon J. Beta cell cytotoxic CD8+ T cells from non-obese diabetic mice use highly homologous T cell receptor alpha chain CDR3 sequences. J Immunol 1995;154:2494–2503.

    Google Scholar 

  13. Verdaguer J, Yoon J-W, Anderson B, Averill N, Utsugi T, Park BJ, Santamaria P. Acceleration of spontaneous diabetes in TCRβ-transgenic nonobese diabetic mice by beta cell-cytotoxic CD8+ T cells expressing identical endogenous TCRα chains. J Immunol 1996;157:4726–4735.

    Google Scholar 

  14. Verdaguer J, Schmidt D, Amrani A, Anderson B, Averill N, Santamaria P. Spontaneous autoimmune diabetes in monoclonal T cell nonobese diabetic mice. J Exp Med 1997;186:1663–1676.

    Google Scholar 

  15. DiLorenzo T, Graser T, Ono T, Christianson GJ, Chapman HD, Roopenian DC, Nathenson SG, Serreze DV. MHC class I-restricted T-cells are required for all but end stages of diabetes development and utilize a prevalent T cell receptor α chain gene rearrangement. Proc Natl Acad Sci USA 1998;95:12538–12542.

    Google Scholar 

  16. Anderson B, Park BJ, Verdaguer J, Amrani A, Santamaria P. PrevalentCD8+ T cell response against one peptide/MHC complex in autoimmune diabetes. Proc Natl Acad Sci USA 1999;96:9311–9316.

    Google Scholar 

  17. Amrani A, Verdaguer J, Serra P, Tafuro S, Tan R, Santamaria P. Progression of autoimmune diabetes driven by avidity maturation of a T-cell population. Nature 2000;406:739–742.

    Google Scholar 

  18. Christianson S, Shultz L, Leiter E. Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD. NON-thy-1a donors. Diabetes 1993;42:44–55.

    Google Scholar 

  19. Tisch R, McDevitt H. Insulin-dependent diabetes mellitus. Cell 1996;85:291–297.

    Google Scholar 

  20. Schmidt D, Verdaguer J, Averill N, Santamaria P. A mechanism for the major histocompatibility complex-linked resistance to autoimmunity. J Exp Med 1997;186:1059–1075.

    Google Scholar 

  21. Schmidt D, Amrani A, Verdaguer J, Bou S, Santamaria P. Autoantigen-independent deletion of diabetogenic CD4+ thymocytes by protective MHC class II molecules. J Immunol 1999;162:4627–4636.

    Google Scholar 

  22. Delovitch T, Singh B. The nonobese diabetic mouse as a model of autoimmune diabetes: Immune disregulation gets the NOD. Immunity 1997;7:727–738.

    Google Scholar 

  23. Peterson J, Haskins K. Transfer of diabetes in the NOD-scid mouse by CD4+ T cell clones. Differential requirement for CD8+ T cells. Diabetes 1996;45:328–336.

    Google Scholar 

  24. Kurrer M, Pakala S, Hanson H, Katz J. Beta cell apoptosis in T cell-mediated autoimmune diabetes. Proc Natl Acad Sci USA 1997;94:213–218.

    Google Scholar 

  25. Liblau R, Wong F, Mars L, Santamaria P. Autoreactive CD8+ T cells in organ-specific autoimmunity: Emerging targets for therapeutic intervention. Immunity 2002;17:1–20.

    Google Scholar 

  26. Fennessy M, Metcalfe K, Hitman GA, Niven M, Biro PA, Tuomilehto J, Tuomilehto-Wolf E. A gene in the HLA class I region contributes to susceptibility to IDDM in the Finnish population. Childhood Diabetes in Finland (DiMe) Study Group. Diabetologia 1994;37:937–944.

    Google Scholar 

  27. Honeyman M, Harrison L, Drummond B, Colman P, Tait B. Analysis of families at risk for insulin-dependent diabetes mellitus reveals that HLA antigens influence progression to clinical disease. Mol Med 1995;1:576–582.

    Google Scholar 

  28. Tait B, Harrison L, Drummond B, Stewart V, Varney M, Honeyman M. HLA antigens and age at diagnosis of insulin-dependent diabetes mellitus. Hum Immunol 1995;42:116–122.

    Google Scholar 

  29. Nejentsev S, Reijonen H, Adojaan B, Kovalchuk L, Sochnevs A, Schwartz EI, Akerblom HK, Ilonen J. The effect of HLA-B allele on the IDDM risk defined by DRB1*04 subtypes and DQB1*0302. Diabetes 1997;46:1888–1892.

    Google Scholar 

  30. Nakanishi K, Kobayashi T, Murase T, Naruse T, Nose Y, Inoko H. HLA-A24 and-DQA1*0301 in Japanese insulin-dependent diabetes mellitus: Independent contributions to susceptibility to the disease and additive contributions to acceleration of beta cell destruction. J Clin Endocrinol Metab 1999;84:3721–3725.

    Google Scholar 

  31. Bottazzo GF, Dean BM, McNally JM, McKay EH, Swift PGF, Gamble DR. In situ characterization of autoimmune phenomenon: An expression of HLA molecules in the pancreas of diabetic insulinitis. N Engl J Med 1985;313:353–360.

    Google Scholar 

  32. Hanninen A, Jalkanen S, Salmi M, Toikkanen S, Nikolakaros G, Simell O. Macrophages, T cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulin-dependent diabetes mellitus. J Clin Invest 1992;90:1901–1908.

    Google Scholar 

  33. Itoh N, Hanafusa T, Miyazaki A, Miyagawa J, Yamagata K, Yamamoto K, Waguri M, Imagawa A, Tamura S, Inada M, et al. Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients. J Clin Invest 1993;92:2313–2322.

    Google Scholar 

  34. Somoza N, Vargas F, Roura-Mir C, Vives-Pi M, Fernandez-Figueras MT, Ariza A, Gomis R, Bragado R, Marti M, Jaraquemada D. Pancreas in recent onset insulin-dependent diabetes mellitus. J Immunol 1994;153:1360–1377.

    Google Scholar 

  35. Sibley RK, Sutherland DER, Goetz F, Michael AF. Recurrent diabetes mellitus in the pancreas iso-and allograft. Lab Invest 1985;53:132–144.

    Google Scholar 

  36. Santamaria P, Lewis C, Sutherland D, Barbosa J. CD8+ T cells from isletitis of graft-recurrent type I diabetes are oligoclonal and showrestricted TCR usage. Diabetes 1992;41(suppl. 1): 97A.

    Google Scholar 

  37. Santamaria P, Nakhleh RE, Sutherland DER, Barbosa JJ. Isolation and characterization of T lymphocytes infiltrating a human pancreas allograft affected by isletitis and recurrent diabetes. Diabetes 1992;41:53–61.

    Google Scholar 

  38. Ohashi P, Oehen S, Buerki K, Pircher H, Ohashi CT, Odermatt B, Malissen B, Zinkernagel RM, Hengartner H. Ablation of tolerance and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 1991;65:305–317.

    Google Scholar 

  39. Morgan D, Liblau R, Scott B, Fleck S, McDevitt HO, Sarvetnick N, Lo D, Sherman LA. CD8+ T-cell-mediated spontaneous diabetes in neonatal mice. J Immunol 1996;157:978–983.

    Google Scholar 

  40. Blanas E, Carbone F, Allison J, Miller J, Heath W. Induction of autoimmune diabetesby oral administration of autoantigen. Science 1996;274:1707–1709.

    Google Scholar 

  41. Wong F, Karttunen J, Dumont C, Wen L, Visintin I, Pilip IM, Shastri N, Pamer EG, Janeway CA. Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organspecific cDNA library. Nat Med 1999;9:1026–1031.

    Google Scholar 

  42. Amrani A, Serra P, Yamanouchi J, Trudeau JD, Tan R, Elliott JF, Santamaria P. Expansion of the antigenic repertoire of a single T cell receptor upon T-cell activation. J Immunol 2001;167:655–666.

    Google Scholar 

  43. Trudeau J, Kelly-Smith C, Verchere B, Finegood D, Santamaria P, Tan R. AutoreactiveTcells in peripheral blood predict development of type 1 diabetes. J Clin Invest 2003;111:217–223.

    Google Scholar 

  44. Graser R, DiLorenzo T, Wang F, Christianson GJ, Chapman HD, Roopenian DC, Nathenson SG, Serreze DV. 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.

    Google Scholar 

  45. Kanagawa O, Shimizu J, Vaupel BA. Thymic and postthymic regulation of diabetogenicCD8+ T cell development in TCR Transgenic Nonobese Diabetic (NOD) mice. J Immunol 2000;164:5466–5473.

    Google Scholar 

  46. Heath W, Carbone F. Cross-presentation, dendritic cells, tolerance and immunity. Annu Rev Immunol 2001;19:47–64.

    Google Scholar 

  47. Carbone F, Bevan M. Class I-restricted processing and presentation of exogenous cell-associated antigen in vivo. J Exp Med 1990;171:377–387.

    Google Scholar 

  48. Huang A, Golumbeck P, Ahmadzadeh E, Jaffee E, Pardoll D, Levitsky H. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 1994;264:961–965.

    Google Scholar 

  49. Sigal L, Crotty S, Andino R, Rock K. Cytotoxic T-cell immunity to virus-infected non-haemotopoietic cells requires presentation of exogenous antigen. Nature 1999;398:77–80.

    Google Scholar 

  50. Kurts C, Heath W, Carbone F, Allison J, Miller J, Kosaka H. Constitutive class I-restricted exogenous presentation of self-antigens in vivo. J Exp Med 1996;184:923–930.

    Google Scholar 

  51. Albert M, Pearce S, Francisco LM, Sauter B, Roy P, Silverstein RL, Bhardwaj N. Immature dendritic cells phagocytose apoptotic cells via alphaV-beta-5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J Exp Med 1998;188:1359–1368.

    Google Scholar 

  52. Albert M, Sauter B, Bhardwaj N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 1998;392:86–89.

    Google Scholar 

  53. Rovere P, Vallinoto C, Bondanza A, Crosti MC, Rescigno M, Ricciardi-Castagnoli P, Rugarli C, Manfredi AA. Cutting-edge: Bystander apoptosis triggers dendritic cell maturation and antigenpresenting function. J Immunol 1998;161:4467–4471.

    Google Scholar 

  54. Sauter B, Albert M, Francisco L, Larsson M, Somersan S, Bhardwaj N. Consequences of cell death: Exposure to necrotic tumor cells, but not primary tissue or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J Exp Med 2000;191:423–434.

    Google Scholar 

  55. Zhang Y, O'Brien B, Trudeau J, Tan R, Santamaria P, Dutz J. In situ beta cell death promotes priming of diabetogenic CD8+ T lymphocytes. J Immunol 2001;168:1466–1472.

    Google Scholar 

  56. Trudeau J, Dutz J, Arany E, Hill D, Fieldus W, Finegood D. Neonatal beta-cell apoptosis: A trigger for autoimmune diabetes? Diabetes 2000;49:1–7.

    Google Scholar 

  57. Finegood D, Scaglia L, Bonner-Weir S. Dynamics of beta cell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes 1995;44:249–256.

    Google Scholar 

  58. Graser RT, DiLorenzo TP, Wang F, Christianson GJ, Chapman HD, Roopenian DC, Nathenson SG, Serreze DV. 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.

    Google Scholar 

  59. Stuhler G, Walden P. Collaboration of helper and cytotoxic T lymphocytes. Eur J Immunol 1993;23:2279–2286.

    Google Scholar 

  60. Grewal I, Xu J, Flavell R. Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand. Nature 1995;378:617–620.

    Google Scholar 

  61. Essen Dv, Kikutani H, Gray D. CD40 ligand-transduced costimulation of T-cells in the development of helper function. Nature 1995;378:620–623.

    Google Scholar 

  62. Yang Y, Wilson J. CD40 ligand-dependent T-cell activation: Requirement of B7-CD28 signalling through CD40. Science 1996;273:1862–1865.

    Google Scholar 

  63. Grewal I, Foellmer H, Grewal K, Xu J, Hardardottir F, Baron JL, Janeway CA Jr, Flavell RA. Requirement for CD40 ligand in costimulation induction, T-cell activation, and experimental allergic encephalomyelitis. Science 1996;273:1864–1868.

    Google Scholar 

  64. Ridge J, Rosa FD, Matzinger P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 1998;393:474–478.

    Google Scholar 

  65. Bennett S, Carbone F, Karamalis F, Flavell R, Miller J, Heath W. Help for cytotoxicT-cell responses is mediated by CD40 signalling. Nature 1998;393:478–480.

    Google Scholar 

  66. Schoenberger S, Toes R, Voort Evd, Offringa R, Melief C. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 1998;393:480–483.

    Google Scholar 

  67. Grewal I, Flavell R. CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol 1998;16:111–135.

    Google Scholar 

  68. Amrani A, Serra P, Yamanouchi J, Han B, Thiessen S, Verdaguer J, Santamaria P. CD154-dependent priming of diabetogenic CD4+ T cells dissociated from activation of antigen-presenting cells. Immunity 2002;16:719–732.

    Google Scholar 

  69. Balasa B, Krahl T, Pastone G, Lee J, Tisch R, McDevitt HO, Sarvetnick N. CD40 ligand-CD40 interactions are necessary for the initiation of insulitis and diabetes in nonobese diabetic mice. J Immunol 1997;159:4620–4627.

    Google Scholar 

  70. Green EA, Wong FS, Eshima K, Mora C, Flavell RA. Neonatal tumor necrosis factor alpha promotes diabetes in nonobese diabetic mice by CD154-independent antigen presentation to CD8+ T cells. J Exp Med 2000;191:225–238.

    Google Scholar 

  71. Kenyon NS, Chatzipetrou M, Masetti M, Ranuncoli A, Oliveira M, Wagner JL, Kirk AD, Harlan DM, Burkly LC, Ricordi C. Longterm survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154. Proc Natl Acad Sci USA 1999;96:8132–8137.

    Google Scholar 

  72. Blair PJ, Riley JL, Harlan DM, Abe R, Tadaki DK, Hoffmann SC, White L, Francomano T, Perfetto SJ, Kirk AD, June CH. CD40 ligand (CD154) triggers a short-term CD4+ T cell activation response that results in secretion of immunomodulatory cytokines and apoptosis. J Exp Med 2000;191:651–660.

    Google Scholar 

  73. Brenner B, Koppenhoefer U, Grassme H, Kun J, Lang F, Gulbins E. Evidence for a novel function of the CD40 ligand as a signaling molecule in T lymphocytes. FEBBS Lett 1997;417:301–306.

    Google Scholar 

  74. Shi L, Kraut RP, Aebersold R, Greenberg AH. A natural killer cell granule protein that induces DNA fragmentation and apoptosis. J Exp Med 1992;175:553–566.

    Google Scholar 

  75. Kagi D, Ledermann B, Burki K, Seiler P, Odermatt B, Olsen KJ, Podack ER, Zinkernagel RM, Hengartner H. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforindeficient mice. Nature 1994;369:31–37.

    Google Scholar 

  76. Lowin B, Beermann F, Schmidt A, Tschopp J. A null mutation in the perforin gene impairs cytolytic T lymphocyte-and natural killer cell-mediated cytotoxicity. Proc Natl Acad Sci USA 1994;91:11571–11575.

    Google Scholar 

  77. Heusel J, Wesselschmidt R, Shresta S, Russell J, Ley T. Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells. Cell 1994;76:977–987.

    Google Scholar 

  78. Froelich C, Orth K, Turbov J, Seth P, Gottlieb R, Babior B, Shah GM, Bleackley RC, Dixit VM, Hanna W. New paradigm for lymphocyte granule-mediated cytotoxicity. Target cells bind and internalize granzyme B, but an endosomolytic agent is necessary for cytosolic delivery and apoptosis. J Biol Chem 1996;271:29073–29079.

    Google Scholar 

  79. Shi L, Mai S, Israels S, Browne K, Trapani J, Greenberg A. Granzyme B (GraB) autonomously crosses the cell membrane and perforin initiates apoptosis and GraB nuclear localization. J Exp Med 1997;185:855–866.

    Google Scholar 

  80. Pinkoski MJ, Hobman M, Heibein JA, Tomaselli K, Li F, Seth P, Froelich CJ, Bleackley RC. Entry and trafficking of granzyme B in target cells during granzyme B-perforin-mediated apoptosis. Blood 1998;92:1044–1054.

    Google Scholar 

  81. Browne KA, Blink E, Sutton VR, Froelich CJ, Jans DA, Trapani JA. Cytosolic delivery of granzyme B by bacterial toxins: Evidence that endosomal disruption, in addition to transmembrane pore formation, is an important function of perforin. Mol Cell Biol 1999;19:8604–8615.

    Google Scholar 

  82. Motyka B, Korbutt G, Pinkoski MJ, Heibein JA, Caputo A, Hobman M, Barry M, Shostak I, Sawchuk T, Holmes CF, Gauldie J, Bleackley RC. Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Cell 2000;103:491–500.

    Google Scholar 

  83. Darmon A, Nicholson D, Bleackley R. Activation of the apoptotic protease CPP32 by cytotoxic T-cell-derived granzyme B. Nature 1995;377:446–488.

    Google Scholar 

  84. Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S. Acaspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 1998;391:43–50.

    Google Scholar 

  85. Barry M, Heibein JA, Pinkoski MJ, Lee SF, Moyer RW, Green DR, Bleackley RC. Granzyme B short-circuits the need for caspase 8 activity during granule-mediated cytotoxic T-lymphocyte killing by directly cleaving Bid. Mol Cell Biol 2000;20:3781–3794.

    Google Scholar 

  86. Pinkoski MJ, Waterhouse NJ, Heibein JA, Wolf BB, Kuwana T, Goldstein JC, Newmeyer DD, Bleackley RC, Green DR. Granzyme B-mediated apoptosis proceeds predominantly through a Bcl-2-inhibitable mitochondrial pathway. J Biol Chem 2001;276:12060–12067.

    Google Scholar 

  87. Heibein JA, Goping IS, Barry M, Pinkoski MJ, Shore GC, Green DR, Bleakley RC. Granzyme B-mediated cytochrome c release is regulated by the Bcl-2 family members bid and Bax. J Exp Med 2000;192:1391–1402.

    Google Scholar 

  88. Sutton VR, Davis JE, Cancilla M, Johnstone RW, Ruefli AA, Sedelies K, Browne KA, Trapani JA. Initiation of apoptosis by granzymeBrequires direct cleavage of bid, but not direct granzyme B-mediated caspase activation. J Exp Med 2000;192:1403–1414.

    Google Scholar 

  89. Alimonti JB, Shi L, Baijal PK, Greenberg AH. GranzymeBinduces BID-mediated cytochrome c release and mitochondrial permeability transition. J Biol Chem 2001;276:6974–6982.

    Google Scholar 

  90. Thomas DA, Scorrano L, Putcha GV, Korsmeyer SJ, Ley TJ. Granzyme B can cause mitochondrial depolarization and cell death in the absence of BID, BAX, and BAK. Proc Natl Acad Sci USA 2001;98:14985–14990.

    Google Scholar 

  91. Thomas DA, Du C, Xu M, Wang X, Ley TJ. DFF45/ICAD can be directly processed by granzyme B during the induction of apoptosis. Immunity 2000;12:621–632.

    Google Scholar 

  92. Sharif-Askari E, Alam A, Rheaume E, Beresford PJ, Scotto C, Sharma K, Lee D, DeWolf WE, Nuttall ME, Lieberman J, Sekaly RP. Direct cleavage of the human DNA fragmentation factor-45 by granzyme B induces caspase-activated DNase release and DNA fragmentation. Embo J 2001;20:3101–3113.

    Google Scholar 

  93. Zhang D, Pasternack MS, Beresford PJ, Wagner L, Greenberg AH, Lieberman J. Induction of rapid histone degradation by the cytotoxic T lymphocyte protease Granzyme A. J Biol Chem 2001;276:3683–3690.

    Google Scholar 

  94. Zhang D, Beresford PJ, Greenberg AH, Lieberman J. Granzymes A and B directly cleave lamins and disrupt the nuclear lamina during granule-mediated cytolysis. Proc Natl Acad Sci USA 2001;98:5746–5751.

    Google Scholar 

  95. Shresta S, Graubert TA, Thomas DA, Raptis SZ, Ley TJ. Granzyme A initiates an alternative pathway for granule-mediated apoptosis. Immunity 1999;10:595–605.

    Google Scholar 

  96. Simon M, Hausmann M, Tran T, Ebnet K, Tschopp J, ThaHla R, Mullbacher A. In vitro-and Ex-derived cytolytic leukocytes from granzyme A X B double knockout mice are defective in granule-mediated apoptosis but not lysis of target cells. J Exp Med 1997;186:1781–1786.

    Google Scholar 

  97. Krensky AM. Granulysin: A novel antimicrobial peptide of cytolytic T lymphocytes and natural killer cells. Biochem Pharmacol 2000;59:317–320.

    Google Scholar 

  98. Kaspar AA, Okada S, Kumar J, Poulain FR, Drouvalakis KA, Kelekar A, Hanson DA, Kluck RM, Hitoshi Y, Johnson DE, Froelich CJ, Thompson CB, Newmeyer DD, Anel A, Clayberger C, Krensky AM. A distinct pathway of cell-mediated apoptosis initiated by granulysin. J Immunol 2001;167:350–356.

    Google Scholar 

  99. Irmler M, Thorme M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J. Inhibition of death receptor signals by cellular FLIP. Nature 1997;388:190–195.

    Google Scholar 

  100. Li H, Zhu H, Xu C, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998; 94:491–501.

    Google Scholar 

  101. Kim T, Zhao Y, Barber M, Kuharsky D, Yin X. Bid-induced cytochrome c release is mediated by a pathway independent of mitochondrial permeability transition pore and Bax. J Biol Chem 2000;275:39474–39481.

    Google Scholar 

  102. Deveraux Q, Reed T. IAP family proteins—suppressors of apoptosis. Genes Dev 1999;13:239–252.

    Google Scholar 

  103. Wang J, Zheng L, Lobito A, Chan FK, Dale J, Sneller M, Yao X, Puck JM, Straus SE, Lenardo MJ. Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell 1999;98:47–58.

    Google Scholar 

  104. Kayagaki N, Yamaguchi N, Nakayama M, Kawasaki A, Akiba H, Okumura K, Yagita H. Involvement of TNF-related apoptosisinducing ligand in human CD4+ T cell-mediated cytotoxicity. J Immunol 1999;162:2639–2647.

    Google Scholar 

  105. Gura T. How TRAIL kills cancer cells, but not normal cells. Science 1997;277:768.

    Google Scholar 

  106. Jiang Y, Woronicz J, Liu W, Goeddel D. Prevention of constitutive TNF receptor 1 signaling by silence of death domains. Science 1999;283:543–546.

    Google Scholar 

  107. Siegel R, Chang F, Chun H, Lenardo M. The multifaceted role of fas signaling in immune cell homeostasis and autoimmunity. Nat Immunol 2000;1:469–474.

    Google Scholar 

  108. Kawahara A, YOhsawa, Matsumura H, Uchiyama Y, Nagata S. Caspase-independent cell killing by Fas-associated protein with death domain. J Cell Biol 1998;143:1353–1360.

    Google Scholar 

  109. Vercammen D, Brouckaert G, Denecker G, Van de Craen M, Declercq W, Fiers W, Vandenabeele P. Dual signaling of the Fas receptor: Initiation of both apoptotic and necrotic cell death pathways. J Exp Med 1998;188:919–930.

    Google Scholar 

  110. Villunger A, Huang D, Holler N, Tschopp J, Strasser A. Fas ligandinduced c-Jun kinase activation in lymphoid cells requires extensive receptor aggregation but is independent of DAXX, and Fas-mediated cell death does not involve DAXX, RIP or RAIDD. J Immunol 2000;165:1337–1343.

    Google Scholar 

  111. Li M, Berg A. Induction of necrotic-like cell death by tumor necrosis factor alpha and caspase inhibitors:Novel mechanism for killing virus-infected cells. J Virol 2000;74:7470–7477.

    Google Scholar 

  112. Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 1996;85:817–827.

    Google Scholar 

  113. Boldin MP, Goncharov TM, Goltsev YV, Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1-and TNF receptor-induced cell death. Cell 1996;85:803–815.

    Google Scholar 

  114. Chinnaiyan AM, Tepper CG, Seldin MF, O'Rourke K, Kischkel FC, Hellbardt S, Krammer PH, Peter ME, Dixit VM. FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis. J Biol Chem 1996;271:4961–4965.

    Google Scholar 

  115. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME. Two CD95 (APO-1/Fas) signaling pathways. Embo J 1998;17:1675–1687.

    Google Scholar 

  116. Luo X, Budihardjo I, Zou H, Slaughter C, Wang X. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 1998;94:481–490.

    Google Scholar 

  117. Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 2000;102:43–53.

    Google Scholar 

  118. Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000;102:33–42.

    Google Scholar 

  119. Hegde R, Srinivasula SM, Zhang Z, Wassell R, Mukattash R, Cilenti L, DuBois G, Lazebnik Y, Zervos AS, Fernandes-Alnemri T, Alnemri ES. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J Biol Chem 2002;277:432–438.

    Google Scholar 

  120. Kagi D, Odermatt B, Ohashi P, Zinkernagel R, Hengartner H. Development of insulitis without diabetes in transgenic mice lacking perforin-dependent cytotoxicity. J Exp Med 1996;183:2143–2152.

    Google Scholar 

  121. Seewaldt S, Thomas HE, Ejrnaes M, Christen U, Wolfe T, Rodrigo E, Coon B, Michelsen B, Kay TW, von Herrath MG. Virus-induced autoimmune diabetes: Most beta-cells die through inflammatory cytokines and not perforin from autoreactive (anti-viral) cytotoxic T-lymphocytes. Diabetes 2000;49:1801–1809.

    Google Scholar 

  122. Kreuwel HT, Morgan DJ, Krahl T, Ko A, Sarvetnick N, Sherman LA. Comparing the relative role of Perforin/Granzyme versus Fas/Fas ligand cytotoxic pathways in CD8+ T cell-mediated insulin-dependent diabetes mellitus. J Immunol 1999;163:4335–4341.

    Google Scholar 

  123. Chervonsky A, Wang Y, Wong FS, Visintin I, Flavell RA, Janeway CA Jr, Matis LA. The role of Fas in autoimmune diabetes. Cell 1997;89:17–24.

    Google Scholar 

  124. Kagi D, Odermatt B, Seiler P, Zinkernagel R, Mak T, Hengartner H. Reduced incidence and delayed onset of diabetes in perforindeficient nonobese diabetic mice. J Exp Med 1997;186:989–997.

    Google Scholar 

  125. Itoh N, Imagawa A, Hanafusa T, Waguri M, Yamamoto K, Iwahashi H, Moriwaki M, Nakajima H, Miyagawa J, Namba M, Makino S, Nagata S, Kono N, Matsuzawa Y. Requirement of Fas for the development of autoimmune diabetes in nonobese diabetic mice. J Exp Med 1997;186:613–618.

    Google Scholar 

  126. Amrani A, Verdaguer J, Anderson B, Utsugi T, Bou S. Perforinindependent beta cell destruction by diabetogenic CD8+ T lymphocytes in transgenic nonobese diabetic mice. J Clin Invest 1999;103:1201–1209.

    Google Scholar 

  127. Amrani A, Verdaguer J, Thiessen S, Bou S, Santamaria P. IL-1α, IL-1β, and IFN-γ mark beta cells for Fas-dependent destruction by diabetogenic CD4+ T-lymphocytes. J Clin Invest 2000;105:459– 468.

    Google Scholar 

  128. Stassi G, De Maria R, Trucco G, Rudert W, Testi R, Galluzzo A, Giordano C, Trucco M. Nitric oxide primes pancreatic beta cells for Fas-mediated destruction in insulin-dependent diabetes mellitus. J Exp Med 1997;186:1193–1200.

    Google Scholar 

  129. Heitmeier M, Scarim A, Corbett J. IFN-γ increases the sensitivity of islets of Langerhans for inducible nitric oxide synthase expression induced by interleukin 1. J Biol Chem 1997;272:13697–13704.

    Google Scholar 

  130. Moriwaki M, Itoh N, Miyagawa J, Yamamoto K, Imagawa A, Yamagata K, Iwahashi H, Nakajima H, Namba M, Nagata S, Hanafusa T, Matsuzawa Y. Fas and Fas ligand expression in in-flamed islets in pancreas sections of patients with recent-onset Type I diabetes mellitus. Diabetologia 1999;42:1332–1340.

    Google Scholar 

  131. Garban H, Bonavida B. Nitroc Oxide inhibits the transcription repressor yin-yang 1 binding activity at the silencer region of the Fas promoter: A pivotal role for nitric oxide in the up-regulation of Fas gene expression in human tumor cells. J Immunol 2001;167:75–81.

    Google Scholar 

  132. Cao W, Tykodi S, Esser M, Braciale V, Braciale T. Partial activation of CD8+ T cells by a self-derived peptide. Nature (Lond.) 1995;378:295–298.

    Google Scholar 

  133. Brossart P, Bevan M. Selective activation of Fas/Fas ligandmediated cytotoxicity by a self peptide. J Exp Med 1996;183:2449–2458.

    Google Scholar 

  134. Esser M, Krishnamurphy B, Braciale V. Distinct T cell receptor signaling requirements for perforin-or FasL-mediated cytotoxicity. J Exp Med 1996;183:1697–1706.

    Google Scholar 

  135. Lehmann C, Zeis M, Schmitz N, Uharek L. Impaired binding of perforin on the surface of tumor cells is a cause of target cell resistance against cytotoxic effector cells. Blood 2000;96:594–600.

    Google Scholar 

  136. Medana I, Li Z, Flugel A, Tschopp J, Wekerle H, Neumann H. Fas ligand (CD95L) protects neurons against perforin-mediated T-lymphocyte cytotoxicity. J Immunol 2001;167:674–681.

    Google Scholar 

  137. Allison J, Strasser A. Mechanisms of beta cell death in diabetes: A minor role for CD95. Proc Natl Acad Sci USA 1998;95:13818–13822.

    Google Scholar 

  138. Pakala S, Chivetta M, Kelly C, Katz J. In autoimmune diabetes the transition from benighn to pernicious insulitis requires an inslet cell response to tumor necrosis factor x. J Exp Med 1999;189:1053–1062.

    Google Scholar 

  139. Thomas HE, Darwiche R, Corbett JA, Kay TW. Evidence that beta cell death in the nonobese diabetic mouse is Fas independent. J Immunol 1999;163:1562–1569.

    Google Scholar 

  140. Kim S, Kim KA, Hwang DY, Lee TH, Kayagaki N, Yagita H, Lee MS. Inhibition of autoimmune diabetes by Fas ligand: The paradox is solved. J Immunol 2000;164:2931–2936.

    Google Scholar 

  141. Su X, Hu Q, Kristan JM, Costa C, Shen Y, Gero D, Matis LA, Wang Y. Significant role for Fas in the pathogenesis of autoimmune diabetes. J Immunol 2000;164:2523–2532.

    Google Scholar 

  142. Green EA, Flavell RA. The temporal importance of TNF-alpha expression in the development of diabetes. Immunity 2000;12:459– 469.

    Google Scholar 

  143. Walter U, Frantzke A, Sarukhan A, Zober C, von Boehmer H, Buer J, Lechner O. Monitoring gene expression of TNFR family members by beta-cells during development of autoimmune diabetes. Eur J Immunol 2000;30:1224–1232.

    Google Scholar 

  144. Yamada K, Takane-Gyotoku N, Ichikawa F, Inada C, Nokada K. Mouse islet cell lysis mediated by interleukin-1-induced Fas. Diabetologia 1996;39:1306–1312.

    Google Scholar 

  145. Bretz JD, Arscott PL, Myc A, Baker JR. Inflammatory cytokine regulation of Fas-mediated apoptosis in thyroid follicular cells. J Biol Chem 1999;274:25433–25438.

    Google Scholar 

  146. Heitmeier MR, Arnush M, Scarim AL, Corbett JA. Pancreatic beta-Cell Damage Mediated by beta-Cell Production of Interleukin-1. A novel mechanism for virus-induced diabetes. J Biol Chem 2001;276:11151–11158.

    Google Scholar 

  147. Arnush M, Hitmeier M, Scarim A, Marino M, Manning P, Corbett J. IL-1 produced and released endogenously within human islets inhibits beta cell function. J Clin Invest 1998;102:516–526.

    Google Scholar 

  148. Arnush M, Scarim A, Hitmeier M, Kelly C, Corbett J. Potential role of resident islet macrophage activation in the initiation of of autoimmune diabetes. J Immunol 1998; 160:2684–2691.

    Google Scholar 

  149. Dupraz P, Rinsch C, Pralong WF, Rolland E, Zufferey R, Trono D, Thorens B. Lentivirus-mediated Bcl-2 expression in beta TC-tet cells improves resistance to hypoxia and cytokine-induced apoptosi while preserving in vitro and in vivo control of insulin secretio. Gene Ther 1999;6:1160–1169.

    Google Scholar 

  150. Dupraz P, Cottet S, Hamburger F, Dolci W, Felley-Bosco E, Thorens B. Dominant negative MyD88 proteins inhibit interleukin-1beta/interferon-gamma-mediated induction of nuclear factor kap B-dependent nitrite production and apoptosis in beta cells. J Biol Chem 2000;275:37672–37678.

    Google Scholar 

  151. Thomas H, Darwiche R, Corbett J, Kay T. Interleukin-1 plus γ-interferon-induced pancreatic beta cell dysfunction is mediated by beta cell nitric oxide production. Diabetes 2002;51:311–316.

    Google Scholar 

  152. Cottet S, Dupraz P, Hamburger F, Dolci W, Jaquet M, Thorens B. SOCS-1 protein prevents Janus Kinase/STAT-dependent inhibition of beta cell insulin gene transcription and secretion in response to interferon-γ. J Biol Chem 2001;276:25862–25870.

    Google Scholar 

  153. Hoorens A, Stange G, Pavlovic D, Pipeleers D. Distinction between interleukin-1-induced necrosis and apoptosis of islet cells. Diabetes 2001;50:551–557.

    Google Scholar 

  154. Liu D, Pavlovic D, Chen MC, Flodstrom M, Sandler S, Eizirik DL. Cytokines induce apoptosis in beta-cells isolated from mice lacking the inducible isoform of nitric oxide synthase (iNOS-/-). Diabetes 2000;49:1116–1122.

    Google Scholar 

  155. Mathews CE, Graser RT, Savinov A, Serreze DV, Leiter EH. Unusual resistance of ALRLt mouse beta cells to autoimmune destruction: Role for beta cell-expressed resistance determinants. Proc Natl Acad Sci USA 2001;98:235–240.

    Google Scholar 

  156. Hotta M, Tashiro F, Ikegami H, Niwa H, Ogihara T, Yodoi J, Miyazaki J. PancreaticBcell-specific expression of thioredoxin, an antioxidative and antiapoptotoc protein, prevents autoimmune and streptozotocin-induced diabetes. J Exp Med 1998;188:1445–1451.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Microbiology and Infectious Diseases and Julia McFarlane Diabetes Research Centre, Faculty of Medicine, The University of Calgary, 3330 Hospital Drive N.W., Calgary, T2N 4N1, Canada

    Pere Santamaria

Authors
  1. Pere Santamaria
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Santamaria, P. Effector Lymphocytes in Islet Cell Autoimmunity. Rev Endocr Metab Disord 4, 271–280 (2003). https://doi.org/10.1023/A:1025156413404

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1025156413404

Search

Navigation