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Apoptosis, cross-presentation, and the fate of the antigen specific immune response

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Abstract

Induction of cell death by apoptosis, also called programmed cell death, and clearance of apoptotic bodies by scavenger cells has long thought to be an efficient means to dispose of unwanted cells without causing inflammatory responses able to mediate specific reactions. However, a number of evidences have been accumulated suggesting that apoptotic cell death is implicated in the pathogenesis of systemic and organ specific autoimmune diseases. In addition, recognition and engulfement of apoptotic cells by professional antigen presenting cells, such as dendritic cells, and their interaction with effector immune cells have been recently described to result in apoptotic cell-derived antigen specific tolerance. This review will summarise the most recent findings on the immunogenic potential of cells undergoing programmed death.

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References

  1. Kerr JFR, Wyllie AH, Currie AR. Apoptosis, Abasic biological phenomenon with wide-ranging application in tissue kinetics. Br J Cancer 1972; 26: 239–257.

    PubMed  Google Scholar 

  2. Wyllie AH, Kerr JFR, Currie AR. Cell death: The significance of apoptosis. Int Rev Cytol 1980; 68: 251–306.

    PubMed  Google Scholar 

  3. Savill J. Apoptosis. Phagocytic docking without shoking. Nature 1998; 392: 442–443.

    PubMed  Google Scholar 

  4. Fadok VA, Bratton DL, Frasch SC, Warner ML, Henson PM. The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. Cell Death Differ 1998; 5: 551–562.

    Article  PubMed  Google Scholar 

  5. Ren Y, Savill J. Apoptosis, the importance of being eaten. Cell Death Differ 1998; 5: 563–568.

    PubMed  Google Scholar 

  6. Cohen JJ. Apoptosis Immunol Today 1993; 14: 126–130.

  7. Vaux DL. Towards an understanding of the mocular mechanisms of physiological cell death. Proc Natl Acad Sci USA 1993; 90: 786–789.

    Google Scholar 

  8. Green DR, Scott DW. Activation-induced apoptosis in lymphocytes. Curr Opin Immunol 1994; 6: 476.

    Google Scholar 

  9. Cohen JJ, Duke RC, Fadok VA, Sellins KS. Apoptosis and programmed cell death in immunity. Annu Rev Immunol 1992; 10: 267–293.

    Article  PubMed  Google Scholar 

  10. Savill JS, Fadok V, Henson P, Haslett C. Phagocyte recognition of cells undergoing apoptosis. Immunol Today 1993; 14: 131–136.

    Article  PubMed  Google Scholar 

  11. Rubartelli A, Poggi A, Zocchi MR. The selective engulfment of apoptotic bodies by dendritic cells is mediated by the alpha(v)beta3 intergin and requires intracellular and extracellular calcium. Eur J Immunol 1997; 27: 1893–1900.

    PubMed  Google Scholar 

  12. Albert ML, Sauter B, Bhardwaj N. Dendritic cells acquire antigen form apoptotic cells and induce class I-restricted CTL. Nature 1998; 392: 86–89.

    PubMed  Google Scholar 

  13. Rovere P, Vallinoto C, Bondanza A, et al. Cutting edge: Bystander apoptosis triggers dendritic cell maturation and antigen-presenting function. J Immunol 1998; 161: 4467–4471.

    PubMed  Google Scholar 

  14. Inaba K, Turley S, Yamaide F, et al. Efficient presentation of phagocytosed cellular fragments on the major histocompatibility complex class II products of dendritic cells. J Exp Med 1998; 188: 2163–2173.

    PubMed  Google Scholar 

  15. Chiodoni C, Paglia P, Stoppacciaro A, et al. Dendritic cells infiltrating tumors cotransduced with granulocyte/macrophage colony-stimulating factor (GM-CSF) and CD40 ligand genes take up and present endogenous tumor-associated antigens, and prime naive mice for a cytotoxic T lymphocyte response. J Exp Med 1999; 190: 125–133.

    PubMed  Google Scholar 

  16. Yrlid U, Wick MJ. Salmonella-induced apoptosis of infected macrophages results in presentation of bacteria-encoded antigen after uptake by bystander dendritic cells. J Exp Med 2000; 191: 613–623. Apoptosis, cross-presentation, and the fate of the antigen specific immune response

    PubMed  Google Scholar 

  17. Russo V, Tanzarella S, Dalerba P, et al. Dendritic cells acquire the MAGE-3 human tumor antigen from apoptotic cells and induce a class I-restricted T cell response. Proc Natl Acad Sci USA 2000; 97: 2185–2190.

    PubMed  Google Scholar 

  18. Steinman RM, Turley S, Mellman I, Inaba K. The induction of tolerance by dendritic cells that have captured apototic cells. J Exp Med 2000; 191: 411–416.

    PubMed  Google Scholar 

  19. Germain RN, Margulies DH. The biochemistry and cell biology of antigen processing and presentation. Annu Rev Immunol 1999; 11: 403–450.

    Google Scholar 

  20. Germain RN, Castellino F, Ricai H, et al. Processing and presentation of endocytically acquired protein antigens by MHC class II and I molecules. Immunol Rev 1996; 151: 5–30.

    PubMed  Google Scholar 

  21. Jondal M, Schirmbeck R, Reimann J. MHC class I-restricted CTL responses to exogenous antigens. Immunity 1996; 5: 295–302.

    PubMed  Google Scholar 

  22. Bevan M. Cross-priming for secondary cytotoxic response to minor H antigens with H-2 congenic cells which do not crossreact in cytotoxicity assay. J Exp Med 1976; 143: 1283–1288.

    PubMed  Google Scholar 

  23. Bevan M. Minor H antigens introduced on H-2 different stimulating cells cross-react at the cytotoxicity T cell level during in vivo priming. J Immunol 1976; 117: 2233–2238.

    PubMed  Google Scholar 

  24. Bevan M. Antigen presentation to cytotoxic T lymphocytes in vivo. J Exp Med 1995; 182: 639–641.

    PubMed  Google Scholar 

  25. Heath WR, Kurts C, Miller JFAP, Carbone FR. Crosstolerance: Apathway for inducing tolerance to peripheral tissue antigens. J Exp Med 1998; 10: 1549–1553.

    Google Scholar 

  26. Heath WR, Carbone FR. Cytotoxic T lymphocyte activation by cross-priming. Curr Opin Immunol 1999; 11: 314–318.

    PubMed  Google Scholar 

  27. Rosen A, Casciola-Rosen L. Autoantigens as substrates for apoptotic proteases: Implications for the phatogenesis of systemic autoimmune disease. Cell Death Diff 1998; 6: 6–12.

    Google Scholar 

  28. Ohsako S, Elkon KB. Apoptosis in the effector phase of autoimmune diabetes, multiple scelrosis and thyroiditis. Cell Death Diff 1998; 6: 13–21.

    Google Scholar 

  29. Bellone M. Autoimmune disease: Pathogenesis. Encyclopedia of Life Science. London: Macmillan Reference Ltd., Stockton Press, in press.

  30. Vaishnaw AK, McNally JD, Elkon KB. Apoptosis in the rheumatic diseases. Arthr Rheum 1997; 40: 1917–1927.

    Google Scholar 

  31. Pistiner M, Wallace DJ, Nessim S, Metzger AL, Klinenberg JR. Lupus erythematosus in the 1980s: A survey of 570 patients. Semin Arthritis Rheum 1991; 21: 55–64.

    PubMed  Google Scholar 

  32. Utz PJ, Anderson P. Posttranslational protein modifications, apoptosis, and the bypass of tolerance to autoantigens. Arth Rheum 1998; 41: 1152–1160.

    Google Scholar 

  33. Mevorach D, Zhou JL, Song X, Elkon KB. Systemic exposure to irradiated apoptotic cells induces autoantibody production. J Exp Med 1998; 188: 387–392.

    PubMed  Google Scholar 

  34. Botto M, Dell'Agnola C, Bygrave AE, et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 1998; 19: 56–59.

    PubMed  Google Scholar 

  35. Witte T, Dumoulin FL, Gessner JE, et al. Defect of a complement receptor 3 epitope in a patient with systemic lupus erythematosus. J Clin Invest 1993; 92: 1181–1187.

    PubMed  Google Scholar 

  36. Mevorach D, Mascarenhas JO, Gershov D, Elkon KB. Complement-dependent clearance of apoptotic cells by human macrophages J Exp Med 1998; 188: 2313–2320.

    PubMed  Google Scholar 

  37. Bell DA, Morrison B. The spontaneous apoptotic cell death of normal human lymphocytes in vitro: The release of, and immunoproliferative response to, nucleosomes in vitro. Clin Immunol Immunopathol 1991; 60: 13–26.

    PubMed  Google Scholar 

  38. Takizawa F, Tsuji S, Nagasawa S. Enhancement of macrophage phagocytosis upon iC3b deposition on apoptotic cells. FEBS Lett 1996; 397: 269–272.

    PubMed  Google Scholar 

  39. Manfredi AA, Rovere P, Galati G, et al. Apoptotic cell clearance in systemic lupus erythematosus. I. Opsonization by antiphospholipid antibodies. Arth Rheum 1998; 41: 205–214.

    Google Scholar 

  40. Manfredi AA, Rovere P, Heltai S, et al. Apoptotic cell clearance in systemic lupus erythematosus. II. Role of ¯2 glycoprotein I. Arth Rheum 1998; 41: 215–223.

    Google Scholar 

  41. Rovere P, Sabbadini MG, Vallinoto C, et al. Dendritic cell presentation of antigens from apoptotic cells in a proinflammatory context: Role of opsonizing anti-¯2 glycoprotein I antibodies. Arth Rheum 1999; 42: 1412–1420.

    Google Scholar 

  42. Mamula MJ. The inability to process a self-peptide allows autoreactive T cells to escape tolerance. J Exp Med 1993; 177: 567–571.

    PubMed  Google Scholar 

  43. Watts C, Lanzavecchia A. Suppressive effect of antibody on processing of T cell epitopes. J Exp Med 1993; 178: 1459–1463.

    PubMed  Google Scholar 

  44. Bockenstedl LK, Gee RJ, Mamula MJ. Self-peptides in the initiation of lupus autoimmunity. J Immunol 1995; 154: 3516–3524.

    PubMed  Google Scholar 

  45. Lanzavecchia A. How cryptic epitopes trigger autoimmunity. J Exp Med 1995; 181: 1945–1948.

    PubMed  Google Scholar 

  46. Simitsek PD, Campbell DG, Lanzavecchia A, Fariweather N, Watts C. Modulation of antigen processing by bound antibody can boost or suppress class II MHC presentation of different T cell determinants. J Exp Med 1995; 181: 1957–1963.

    PubMed  Google Scholar 

  47. Salemi S, Caporossi AP, Boffa L, Longobardi MG, Barnaba V. HIV-gp120 activates autoreactive CD4-specificTcell responses by unveiling of hidden CD4 peptides during processing. J Exp Med 1995; 181: 2253–2257.

    PubMed  Google Scholar 

  48. Casciola-Rosen L, Andrade F, Ulanet D, Wong WB, Rosen A. Cleavage by granzyme B is strongle predictive of autoantigen status: Implications for initiation of autoimmunity. J Exp Med 1999; 190: 815–825.

    PubMed  Google Scholar 

  49. Casciola-Rosen LA, Anhalt G, Rosen A. Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med 1994; 179: 1317–1330.

    PubMed  Google Scholar 

  50. Karre K, Ljunggren H-G, Piontek G, Kiessling R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 1986; 319: 675–678.

    PubMed  Google Scholar 

  51. Bellone M, Iezzi G, Rovere P, et al. Processing of engulfed apoptotic bodies yields T cell epitopes. J Immunol 1997; 159: 5391–5399.

    PubMed  Google Scholar 

  52. Yewdell JW, Norbury CC, Bennink JR. Mechanisms of exogenous antigen presentation by MHC class I molecules in vitro and in vivo: Implications for generating CD8+ T cell responses to infectious agents, tumors, transplants and vaccines. Adv Immunol 1999; 73: 1–77.

    PubMed  Google Scholar 

  53. Huang AYC, Bruce AT, Pardoll DM, Levitsky HI. In vivo crosspriming of MHC class I-restricted antigens requires the TAP transporter. Immunity 1996; 4: 349–355.

    PubMed  Google Scholar 

  54. Iezzi G, Rivolta L, Ronchetti A, et al. The immunogenicity of experimental tumors is strongly biased by the expression of dominant viral cytotoxic T-lymphocyte epitopes. Cancer Res 1997; 57: 2564–2568.

    PubMed  Google Scholar 

  55. Voll RE, Herrmann M, Roth EA, et al. Immunosuppressive effects of apoptotic cells. Nature 1997; 390: 350–351.

    PubMed  Google Scholar 

  56. Fadok V, Bratton DL, Konowal A, et al. Macrophages that have ingested apoptotic cells in vitro ihnibit proinflammatory cytokines production through autocrine/paracrine mecanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 1998; 101: 890–898.

    PubMed  Google Scholar 

  57. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998; 392: 245–252. M. Bellone

    Google Scholar 

  58. Gallucci S, Lolkema M, Matzinger P. Natural adjuvants: Endogenous activators of dendritic cells. Nat Med 1999; 5: 1249–1255.

    PubMed  Google Scholar 

  59. Sauter B, Albert ML, Francisco L, et al. Consequences of cell death: Exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J Exp Med 2000; 191: 423–433.

    PubMed  Google Scholar 

  60. Salio M, Cerundolo V, Lanzavecchia A. Dendritic cell maturation is induced by mycoplasma infection but not by necrotic cells. Eur J Immunol 2000; 30: 705–708.

    PubMed  Google Scholar 

  61. Mincheff MS, Getsov SI, Meryman HT. Mechanisms of alloimmunization and immunosuppression by blood transfusions in an inbred rodent model. Transplantation 1995; 60: 815–821.

    PubMed  Google Scholar 

  62. Ronchetti A, Rovere P, Iezzi G, et al. Immunogenicity of apoptotic cells in vivo: Role of antigen load, antigen presenting cells, and cytokines. J Immunol 1999; 163: 130–136.

    PubMed  Google Scholar 

  63. Ronchetti A, Iezzi G, Crosti MC, et al. Role of antigen presenting cells in cross-priming of cytotoxic T lymphocytes by apoptotic cells. J Leuk Biol 1999; 66: 247–251.

    Google Scholar 

  64. Kurts C, Miller JFAP, Subramaniam RM, Carbone FR, Heath W. Major histocompatibility complex class I-restricted crosspresentation is biased towards high dose antigens and those released during cellular destruction. J Exp Med 1998; 188: 409–414.

    PubMed  Google Scholar 

  65. Henry F, Boisteau O, Bretaudeau L, et al. Antigen-presentung cells that phagocytose apoptotic tumor-derived cells are potent tumor vaccines. Cancer Res 1999; 59: 3329–3332.

    PubMed  Google Scholar 

  66. Melcher A, Todryk S, Hardwick N, et al. Tumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression. Nat Med 1998; 4: 581–586.

    PubMed  Google Scholar 

  67. TamuraY, Peng P, Liu K, Daou M, Srivastava PK. Immunotherapy of tumors with autologous tumor-derived heath shock protein preparations. Science 1997; 278: 117–120.

    PubMed  Google Scholar 

  68. Martin SJ, Green DR. Apoptosis as a goal of cancer therapy. Curr Opin Oncol 1994; 6: 616–621.

    PubMed  Google Scholar 

  69. Griffith TS, Yu X, Herndon JM, Green DR, Ferguson TA. CD95-induced apoptosis of lymphocytes in an immune privileged site induces immunological tolerance. Immunity 1996; 5: 7–16.

    PubMed  Google Scholar 

  70. Li Y, Li XC, Zheng XX, et al. 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.

    PubMed  Google Scholar 

  71. Wells AD, Li XC, Li Y, et al. Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance. Nat Med 1999; 5: 1303–1307.

    PubMed  Google Scholar 

  72. Sallusto F, Lanzavecchia A. Mobilizing dendritic cells for tolerance, priming, and chronic inflammation. J Exp Med 1999; 189: 611–614.

    PubMed  Google Scholar 

  73. Inaba K, Inaba M, Naito M, Steinman RM. Dendritic cells progenitors phagocytose particulates, including Bacillus Calmette-Guerin organisms, and sensitize mice to mycobacterial antigens in vivo. J Exp Med 1993; 178: 479–488.

    PubMed  Google Scholar 

  74. Rodriguez A, Regnault A, Kleijmeer M, Ricciardi-Castagnoli P, Amigorena S. Selective transport of internalised antigens to the cytosol for MHC class I presentation in dendritic cells. Nat Cell Biol 1999; 1: 362–368.

    PubMed  Google Scholar 

  75. Watts C. Dendritic cells spill the beans. Nat Cell Biol 1999; 1: E152–154.

    PubMed  Google Scholar 

  76. Inaba K, Turley S, Iyoda T, et al. The formation of immunogenic major histocompatibility complex class II-peptide ligands in lysosomal compartments of dendritic cells is regulated by in-flammatory stimuli. J Exp Med 2000; 191: 927–936.

    PubMed  Google Scholar 

  77. Cella M, Engering A, Pinet V, Pieters J, Lanzavecchia A. In-flammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature 1997; 388: 782–787.

    PubMed  Google Scholar 

  78. Pierre P, Turley SJ, Gatti E, et al. Developmental regulation of MHC class II trafficking in mouse dendritic cells. Nature 1997; 388: 787–792.

    PubMed  Google Scholar 

  79. Morel S, Levy F, Burlet-Schiltz O, et al. Processing of some antigens by the standard proteasome but not by the immuneproteasome results in poor presentation by dendritic cells. Immmunity 2000; 12: 107–117.

    Google Scholar 

  80. Sijts AJAM, Ruppert T, Rehermann B, et al. Efficient generation of a hepatitis B virus cytotoxic T lymphocyte epitope requires the structural features of immunoproteasomes. J Exp Med 2000; 191: 503–513.

    PubMed  Google Scholar 

  81. Randolph G, Inaba K, Robbiani DF, Steinman RM, Muller WA. Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo. Immunity 1999; 11: 753–761.

    PubMed  Google Scholar 

  82. Matzinger P. Tolerance, danger and the extended family. Annu Rev Imunol 1994; 12: 991–1045.

    Google Scholar 

  83. Matzinger P, Guerder S. Does T-cell tolerance require a dedicated antigen-presenting cell? Nature 1989; 338: 74–76.

    PubMed  Google Scholar 

  84. Zal T, Volkmann A, Stockinger B. Mechanisms of tolerance induction in major histocompatibility complex class II-restricted T cells specific for a blood-borne self-antigen. J Exp Med 1994; 180: 2089–2099.

    PubMed  Google Scholar 

  85. Adler AJ, Marsh DW, Yochum JL, et al. CD4+ T cell tolerance to parenchymal self-antigens requires presentation by bone marrow-derived antigen presenting cells. J Exp Med 1998; 187: 1555–1564.

    PubMed  Google Scholar 

  86. Kurts C, Kosaka H, Carbone FR, Miller JFAP, Heath WR. Class I-restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8+ T cells. J Exp Med 1997; 186: 239–245.

    PubMed  Google Scholar 

  87. Huang F-P, Platt N, Wykes M, et al. A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J Exp Med 2000; 191: 435–443.

    PubMed  Google Scholar 

  88. Bonnotte B, Favre N, Moutet M, et al. Role of tumor cell apoptosis in tumor antigen migration to draining lymph nodes. J Immunol 2000; 164: 1995–2000.

    PubMed  Google Scholar 

  89. Ardavin C, Wu L, Li C-L, Shortman K. Thymic dendritic cells and T cells develop simultaneously in the thymus from a common precursor population. Nature 1993; 362: 761–763.

    PubMed  Google Scholar 

  90. Kronin V, Winkel K, Suss G. A subclass of dendritic cells regulates the response of naive CD8 T cells by limiting their IL-2 production. J Immunol 1996; 157: 3819–3827.

    PubMed  Google Scholar 

  91. Cyster JG. Chemokines and the homing of dendritic cells to the T cell areas of lymphoid organs. J Exp Med 1999; 189: 447–450.

    PubMed  Google Scholar 

  92. Orlowski RZ. The role of the ubiquitin-proteasome pathway in apoptosis. Cell Death Diff 1999; 6: 303–313.

    PubMed  Google Scholar 

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Bellone, M. Apoptosis, cross-presentation, and the fate of the antigen specific immune response. Apoptosis 5, 307–314 (2000). https://doi.org/10.1023/A:1009671105696

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