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The Granule Exocytosis Model for Lymphocyte Cytotoxicity and Its Relevance to Target Cell DNA Breakdown

  • Pierre A. Henkart
  • Mark P. Hayes
  • John W. Shiver

Abstract

The granule exocytosis model for lymphocyte cytotoxicity was proposed some years ago (Henkart and Henkart, 1982, Henkart, 1985) and has become generally accepted as one pathway which cytotoxic lymphocytes use to kill target cells (Krahenbuhl and Tschapp, 1991). The model is appealing because it can account for most of the classically known properties of lymphocyte cytotoxicity, and it utilizes a basic process well known to cell biology: the regulated pathway of protein secretion (Henkart et al., 1987b). Indeed, it remains the only well-defined model which accounts for the rapid, lymphocyte-mediated death of target cells in vitro. However, there remain questions as to whether it is the major pathway of cytotoxicity, as it seems likely that cytotoxic T lymphocytes (CTL) can sometimes kill when this pathway is inoperative (Ostergaard et al., 1987; Trenn et al., 1987).

Keywords

Lymphocyte Cytotoxicity Granule Exocytosis Granule Component Immune Gamma Globulin Granule Extract 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Bashford CL, Menestrina G, Henkart PA, Pasternak CA (1988): Cell damage by cytolysin: Spontaneous recovery and reversible inhibition by divalent cations. J Immunol 141: 3965–3974Google Scholar
  2. Blakely A, Gorman K, Ostergaard H, Svoboda K, Liu CC, Young JD, Clark WR (1987): Resistance of cloned cytotoxic T lymphocytes to cell-mediated cytotoxicity. J Exp Med 166: 1070–1083CrossRefGoogle Scholar
  3. Blumenthal R, Millard PJ, Henkart MP, Reynolds CW, Henkart PA (1984): Liposomes as targets for granule cytolysin from cytotoxic LGL tumors. Proc Natl Acad Sci USA 81: 5551–5555CrossRefGoogle Scholar
  4. Carney DF, Koski CL, Shin ML (1985): Elimination of terminal complement intermediates from the plasma membrane of nucleated cells: The rate of disappearance differs for cells carrying C5b-7 or C5b-8 or a mixture of C5b-8 with a limited number of C5b-9. J Immunol 134: 1804–1809Google Scholar
  5. Chambers WH, Vujanovic NL, Deleo AB, Olszowy MW, Herberman RB, Hiserodt JC (1989): Monoclonal antibody to a triggering structure expressed on rat natural killer cells and adherent lymphokine-activated killer cells. J Exp Med 169: 1374–1389CrossRefGoogle Scholar
  6. Coffman FD, Green LM, Godwin A, Ware CF (1989): Cytotoxicity mediated by tumor necrosis factor in variant subclones of the ME-180 cervical carcinoma line: Modulation by specific inhibitors of DNA topoisomerase II. J Cell Biochem 39: 95–105CrossRefGoogle Scholar
  7. David A, Bernard J, Thiernesse N, Nicolas G, Cerottini JC, Zagury D (1979): Le processus d’exocytose lysomale localisee: Est-il responsable de l’action cytolytique des lymphocytes T tuers? CR Acad Sci Paris Ser D 288: 441–444Google Scholar
  8. Dennert G, Podack ER (1983): Cytolysis by H-2 specific T killer cells. Assembly of tubular complexes on target membranes. J Exp Med 157: 1483–1495CrossRefGoogle Scholar
  9. Dourmashkin RR, Deteix P, Simone CB, Henkart PA (1980): Electron microscopic demonstration of lesions on target cell membranes associated with antibody-dependent cytotoxicity. Clin Exp Immunol 43: 554–560Google Scholar
  10. Duke RC, Persechini PM, Chang S, Liu CC, Cohen JJ, Young JD (1989): Purified perforin induces target cell lysis but not DNA fragmentation. J Exp Med 170: 1451–1456CrossRefGoogle Scholar
  11. Fewtrell C, Metzger H (1981): Stimulus-secretion coupling in rat basophilic leukemia cells. KROC Found Ser 14: 295–314Google Scholar
  12. Fussle R, Bhakdi S, Sziegoleit A, Tranum-Jensen J, Kranz T, Wellensiek H-J, (1981): On the mechanism of membrane damage by S. aureus alpha-toxin. J Cell Biol 91: 83–90CrossRefGoogle Scholar
  13. Gaido ML, Cidlowski JA (1991): Identification, purification and characterization of a calcium-dependent endonuclease (NUC18) from apoptotic rat thymocytes. NUC18 is not histone H, B. J Biol Chem 266: 18580–18585Google Scholar
  14. Gold AM, Fahrney D (1964): Sulfonyl fluorides as inhibitors of enzymes. II. Formation and reactions of phenylmethanesulfonyl alpha-chymotrypsin. Biochemistry 3: 783–791CrossRefGoogle Scholar
  15. Green H, Fleischer RA, Barrow P, Goldberg B (1959): The cytotoxic action of immune gamma globulin and complement on Krebs ascites tumor cells. II. Chemical studies. J Exp Med 109: 510–511CrossRefGoogle Scholar
  16. Gromkowski SH, Brown TC, Masson D, Tschopp J (1988): Lack of DNA degradation in target cells lysed by granules derived from cytolytic T lymphocytes. J Immunol 141: 77Google Scholar
  17. Hameed A, Olsen KJ, Lee MK, Lichtenheld MG, Podack ER (1989): Cytolysis by Ca-permeable transmembrane channels. J Exp Med 169: 765–777CrossRefGoogle Scholar
  18. Hayes MP, Berrebi GA, Henkart PA (1989): Induction of target cell DNA release by the cytotoxic T lymphocyte granule protease granzyme A. J Exp Med 170: 933–946CrossRefGoogle Scholar
  19. Henkart MP, Henkart PA (1982): Lymphocyte mediated cytolysis as a secretory phenomenon. Adv Exp Med Biol 146: 227–242Google Scholar
  20. Henkart PA (1985): Mechanism of lymphocyte-mediated cytotoxicity. Annu Rev Immunol 3: 31–58CrossRefGoogle Scholar
  21. Henkart P, Blumenthal R (1975): Interaction of lymphocytes with lipid bilayer membranes: A model for the lymphocyte-mediated lysis of target cells. Proc Natl Acad Sci USA 72: 2789–2793CrossRefGoogle Scholar
  22. Henkart P, Yue CC (1988): The role of cytoplasmic granules in lymphocyte cytotoxicity. Prog Allergy 40: 44–81Google Scholar
  23. Henkart PA, Berrebi GA, Takayama H, Munger WE, Sitkovsky MV (1987a): Biochemical and functional properties of serine esterases in acidic cytoplasmic granules of cytotoxic T lymphocytes. J Immunol 139: 2398–2405Google Scholar
  24. Henkart P, Henkart M, Hodes R, Taplits M (1987b): Secretory processes in lymphocyte function. Biosci Rep 7: 345–353CrossRefGoogle Scholar
  25. Henkart PA, Millard PJ, Reynolds CW, Henkart MP (1984): Cytolytic activity of purified cytoplasmic granules from cytotoxic rat LGL tumors. J Exp Med 160: 75–93CrossRefGoogle Scholar
  26. Henney CS (1977): T cell-mediated cytolysis: An overview of some current issues. Contemp Top Immunobiol 7: 245–272Google Scholar
  27. Ishikawa H, Shinkai YI, Yagita H, Yue CC, Henkart PA, Sawada S, Young HA, Reynolds CW, Okumura K ( 1989: Molecular cloning of rat cytolysin. J Immunol 143: 3069–3073Google Scholar
  28. Ishizaka T, Ishizaka K (1984): Activation of mast cells for mediator release through IgE receptors. Prog Allergy 34: 188–236Google Scholar
  29. Jiang S, Ojcius DM, Persechini PM, Young, JD (1990): Resistance of cytolytic lymphocytes to perforin-mediated killing. J Immunol 144: 998–1003Google Scholar
  30. Kane KP, Goldstein SAN, Mescher MF (1988): Class I alloantigen is sufficient for cytolytic T lymphocyte binding and transmembrane signaling. Eur J Immunol 18: 1925–1929CrossRefGoogle Scholar
  31. Kim SH, Carney DF, Papadimitriou JC, Shin ML (1989): Effect of osmotic protection or. nucleated cell killing by C5b-9. Cell death is not affected by the prevention of cell swelling Mol Immunol 26: 323–331CrossRefGoogle Scholar
  32. Krahenbuhl O, Tschopp J (1991): Debate: The mechanism of lymphocyte-mediated killing. Perforin-induced pore formation. Immunol Today 12: 399–401CrossRefGoogle Scholar
  33. Kranz DM, Eisen HN (1987): Resistance of cytotoxic T lymphocytes to lysis by a clone of cytotoxic T lymphocytes. Proc Natl Acad Sci USA 84: 3375–3379CrossRefGoogle Scholar
  34. Kupfer A, Singer SJ (1989): Cell biology of cytotoxic and helper T cell functions: Immunofluorescence microscopic studies of single cells and cell couples. Ann Rev Immunol 7: 309–337CrossRefGoogle Scholar
  35. Kupfer A, Dennert G, Singer SJ (1985): The reorientation of the Golgi apparatus and the microtubule-organizing center in the cytotoxic effector cell is a prerequisite in the lysis of bound target cells. J Mol Cell Immunol 2: 37–49Google Scholar
  36. Kuppers RC, Henney CS (1977): Studies on the mechanism of lymphocyte-mediated cytolysis. IX. Relationships between antigen recognition and lytic expression in killer T cells. J Immunol 118: 71–76Google Scholar
  37. Lichtenheld MG, Olsen KJ, Lu P, Lowrey DM, Hameed A, Hengartner, Podack ER (1988): Structure and function of human perforin. Nature 335: 448–451CrossRefGoogle Scholar
  38. MacLennan ICM, Gotch FM, Golstein P (1980): Limited specific T-cell mediated cytolysis in the absence of extracellular Ca’. Immunology 39: 109–117Google Scholar
  39. Millard PJ, Henkart MP, Reynolds CW, Henkart PA (1984): Purification and properties of cytoplasmic granules from cytotoxic rat LGL tumors. J Immunol 132: 3197–3204Google Scholar
  40. Munger WE, Berrebi GA, Henkart PA (1988): Possible involvement of CTL granule proteases in target cell DNA breakdown. Immunol Rev 103: 99–109CrossRefGoogle Scholar
  41. Nagler-Anderson C, Verret CR, Firmenich AA, Berne M, Eisen HJ (1988): Resistance of primary CD8+ cytotoxic T lymphocytes to lysis by cytotoxic granules from cloned T cell lines. J Immunol 141: 3299–3305Google Scholar
  42. Ojcius DM, Jiang S, Persechini PM, Detmers PA, Young JD-E (1991): Cytoplasts from cytotoxic T lymphocytes are resistant to perforin-mediated lysis. Mol Immunol 28: 1011–1018CrossRefGoogle Scholar
  43. Orci L, Ravazzola M, Anderson RG (1987): The condensing vacuole of exocrine cells is more acidic than the mature secretory vesicle. Nature 326: 77–79CrossRefGoogle Scholar
  44. Ostergaard HL, Kane KP, Mescher MF, Clark WR (1987): Cytotoxic T lymphocyte mediated lysis without release of serine esterase. Nature 330: 71–72CrossRefGoogle Scholar
  45. Pasternack MS, Blier KJ, McInerney TN (1991): Granzyme A binding to target cell proteins. Granzyme A binds to and cleaves nucleolin in vitro. J Biol Chem 266: 14703–14708Google Scholar
  46. Pasternack MS, Verret CR, Liu MA, Eisen HN (1986): Serine esterase in cytolytic T lymphocytes. Nature 322: 740–743CrossRefGoogle Scholar
  47. Podack ER, Hengartner H, Lichtenheld MG (1991): A central role of perforin in cytolysis? Ann Rev Immunol 9: 129–157CrossRefGoogle Scholar
  48. Podack ER, Young JD, Cohn ZA (1985): Isolation and biochemical and functional characterization of perforin 1 from cytolytic T-cell granules. Proc Natl Acad Sci USA 82: 8629–8633CrossRefGoogle Scholar
  49. Ruddle NH, Schmid DS (198): The role of lymphotoxin in T-cell-mediated cytotoxicity. Ann Inst Pasteur Immunol 138: 314–320Google Scholar
  50. Russell JH (1983): Internal disintegration model of cytotoxic lymphocyte-induced target damage. Immunol Rev 72: 97–118CrossRefGoogle Scholar
  51. Schmidt RE, MacDermott RP, Bartley G, Bertovich M Amato DA, Austen KF, Schlossman SF, Stevens RL, Ritz J (1985): Specific release of proteoglycans from human natural killer cells during target lysis. Nature 318: 289–291CrossRefGoogle Scholar
  52. Sellins KS, Cohen JJ (1991): Cytotoxic T lymphocytes induce different types of DNA damage in target cells of different origins J Immunol 147: 795–803Google Scholar
  53. Selmaj K, Raine CS, Farooq M, Norton WT, Brosnan CF (1991): Cytokine cytotoxicity against oligodendrocytes: Apoptosis induced by lymphotoxin. J Immunol 147: 1522–1529Google Scholar
  54. Serafin WE, Reynolds DS (1990): Neutral proteases of mouse mast cells. Monogr Allergy 27: 31–50Google Scholar
  55. Shi L, Kraut RP, Aebersold R, Greenberg AH (1992): A natural killer cell granule protein that induces DNA fragmentation and apoptosis. J Exp Med 175: 553–566CrossRefGoogle Scholar
  56. Shinkai Y, Ishikawa H, Hattori M, Okumura K (1988): Resistance of mouse cytolytic cells to pore-forming protein-mediated cytolysis. Eur J Immunol 18: 29–33CrossRefGoogle Scholar
  57. Shinkai Y, Takio K, Okumura K (1988b): Homology of perforin to the ninth component of complement (C9). Nature 334: 525–527CrossRefGoogle Scholar
  58. Shiver JW, Henkart PA (1991a): A noncytotoxic mast cell tumor line exhibits potent IgE-dependent cytotoxicity after transfection with the cytolysin/perforin gene. Cell 62: 1174–1181Google Scholar
  59. Shiver JW, Henkart PA (1991b): Cytolytic activity of RBL cells transfected with the cytolysin/perforin gene. In: NK Cell-mediated Cytotoxicity: Receptors, Signalling and Mechanisms, Herberman RB, Lotzova E, eds. Miami: CRC Press. pp 341–348Google Scholar
  60. Simone CB, Henkart P (1980): Permeability changes induced in erythrocyte ghost targets by antibody-dependent cytotoxic effector cells: Evidence for membrane pores. J Immunol 124: 954–963Google Scholar
  61. Skinner M, Marbrook J (1987): The most efficient cytotoxic T lymphocytes are the least susceptible to lysis. J Immunol 139: 985–987Google Scholar
  62. Stanley KK, Herz J (1987): Topological mapping of complement component C9 by recombinant DNA techniques suggests a novel mechanism for its insertion into target membranes. EMBO J 6: 1951–1957Google Scholar
  63. Tian Q, Streuli M, Saito H, Schlossman SF, Anderson P (1991): A polyadenylate binding protein localized to the granules of cytolytic lymphocytes induces DNA fragmentation in target cells. Cell 67: 629–639CrossRefGoogle Scholar
  64. Tirosh R, Berke G (1985): T-lymphocyte-mediated cytolysis as an excitatory process of the target. I. Evidence that the target cell may be the site of CA2+ action. Cell Immunol 95: 113–123CrossRefGoogle Scholar
  65. Trenn G, Takayama H, Sitkovsky MV (1987): Exocytosis of cytolytic granules may not be required for target cell lysis by cytotoxic T lymphocytes. Nature 330: 72–74CrossRefGoogle Scholar
  66. Tschopp JP, Schfer S, Masson D, Peitsch MC, Heusser C (1989): Phosphorylcholine acts as a Ca’+-dependent receptor molecule for lymphocyte perforin. Nature 337: 272–274CrossRefGoogle Scholar
  67. Williams JM, Deloria D, Hansen JA, Dinarello CA, Loertscher R, Shapiro HM, Strom TB (1985): The events of primary T cell activation can be staged by use of Sepharose-bound anti-T3 (64:1) monoclonal antibody and purified interleukin 1. J Immunol 135: 2249–2255Google Scholar
  68. Wyllie AH, Kerr JFR, Currie AR (1980): Cell death: The significance of apoptosis. Int Rev Cytol 68: 251–306CrossRefGoogle Scholar
  69. Yannelli JR, Sullivan JA, Mandell GL, Engelhard VH (1986): Reorientation and fusion of cytotoxic T lymphocyte granules after interaction with target cells as determined by high resolution cinemicrography. J Immunol 136: 377–382Google Scholar
  70. Young JD, Cohn ZA, Podack ER (1986a): The ninth component of complement and the pore-forming protein (perforin 1) from cytotoxic T cells: Structural immunological, and functional similarities. Science 233: 184–190CrossRefGoogle Scholar
  71. Young JD, Hengartner H, Podack ER, Cohn ZA (1986b): Purification and characterization of a cytolytic pore-forming protein from granules of cloned lymphocytes with natural killer activity. Cell 44: 849–859CrossRefGoogle Scholar
  72. Yue C-C, Reynolds CW, Henkart PA (1987): Inhibition of cytolysin activity in granules for a membrane insertion mechanism of lysis. Mol Immunol 24: 647–653CrossRefGoogle Scholar
  73. Zagury D (1982): Direct analysis of individual killer T cells: Susceptibility of target cells to lysis and secretion of hydrolytic enzymes by CTL. Adv Exp Med Biol 146: 149–163Google Scholar
  74. Zunino SJ, Bleackley RC, Martinez J, Hudig D (1990): RNKP-1, a novel natural killer associated serine protease gene cloned from RNK-16 cytotoxic lymphocytes. J Immunol 144: 2001–2009Google Scholar

Copyright information

© Birkhäuser Boston 1993

Authors and Affiliations

  • Pierre A. Henkart
  • Mark P. Hayes
    • 1
  • John W. Shiver
    • 2
  1. 1.Division of Cytokine BiologyCBER, FDABethesdaUSA
  2. 2.Merck, Sharp and Dohme Research LaboratoriesWest PointUSA

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