Abstract
The mechanism of lymphocyte-mediated cytolysis is controversial (see recent reviews Bleackley et al. 1988; Brunet et al. 1988; Clark et al. 1988; Mueller et al. 1988; Müller-Eberhard 1988; Munger et al. 1988; Nagler-Anderson et al. 1988; Sitkovsky 1988; Young et al. 1988; Podack et al. 1988; Jenne and Tschopp 1988a, b; Bleackley 1988; Hershberger et al. 1988; Stevens et al. 1988; Tschopp and Nabholz 1990; Podack et al. 1991). The main contentions concern the question whether secretory functions of the killer cell, as proposed by the vectorial granule secretion model of cytotoxicity (Podack 1985; Henkart 1985), are required for target cell lysis and whether secretory models of cytotoxicity account for most of the cytotoxic activity. Other open questions are related to the role of DNA degradation (apoptosis, programmed cell death) in target cell lysis (Russel et al. 1982; Russel 1983; Duke et al. 1983; Lovell and Martz 1987) and how this process is mediated molecularly. No molecular tools are available at the present time to assess the importance, or even existence, of the putative secretion-independent pathway of lymphocyte-mediated cytolysis. Similarly, since the mechanism of DNA degradation is not understood, it is difficult to quantitate its role in cytolysis.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Allbritton NL, Verret CR, Wolley RC, Eisen HN (1988) Calcium ion concentrations and DNA fragmentation in target cell destruction by murine cloned cytotoxic T lymphocytes. J Exp Med 167: 514
Bleackley RC (1988) The isolation and characterization of two cytolytic lymphocyte specific serine protease genes. In: Podack ER (ed) Cytotoxic effector mechanisms. Springer, Berlin Heidelberg New York, p 67 (Current topics in microbiology and immunology, vol 140)
Bleackley RC, Lobe CG, Duggan B, Ehrman N, Fregeau C, Meier M, Letellier M, Caliopi H, Shaw J, Paetkau V (1988) The isolation and characterization of a family of serine protease genes expressed in activated cytotoxic lymphocytes. Immunol Rev 103: 5
Blumenthal RP, Millard PJ, Henkart MP, Reynolds CW, Henkart PA (1984) Liposomes as targets for granule cytolysin from cytotoxic large granular lymphocyte tumors. Proc Natl Acad Sci USA 81: 5551
Brunet J-F, Denizot F, Goldstein P (1988) A differential molecular biology search for genes preferentially expressed in functional T-lymphocytes: the CTLA genes. Immunol Rev 103: 21
Chakravarti DN, Chakravarti B, Parra CA, Muller-Eberhard HJ (1989) Structural homology of complement protein C6 with other channel-forming proteins of complement. Proc Natl Acad Sci USA 86: 2799
Clark W. Ostergaard H, Gormann K, Torbett B (1988) Molecular mechanism of CTL-mediated lysis: a cellular perspective. Immunol Rev 103: 37
Criado M, Lindstrom JM, Anderson CG, Dennert G (1985) Cytotoxic granules from killer cells: specificity of granules and insertion of channels of defined sizes into target membranes. J Immunol 135: 4245
Davies A, Simmons D, Hale G, Harrison RA, Tighe H, Lachmann PJ, Waldmann H (1989) CD59, and Ly-6 like protein expressed in human lymphoid cells, regulated the action of the complement membrane attack complex on homologous cells. J Exp Med 170: 637
Dennert G, Podack ER (1983) Cytolysis by H2-specific killer cells. J Exp Med 157: 1483
DiScipio RG, Gehring MR, Podack ER, Kan CC, Hugli TE, Fey GH (1984) Nucleotide sequence of cDNA and derived amino acid sequence of human complement component C9. Proc Natl Acad Sci USA 81: 7289
DiScipio RG, Chakravarti DN, Muller-Eberhard HJ, Fey GH (1988) Structure of human C7 and the C5b-7 complex. J Biol Chem 263: 549
Duke RC, Chervenak R, Cohen JJ (1983) Endogenous endonuclease-induced DNA fragmentation: An early event in cell-mediated cytolysis. Proc Natl Acad Sci USA 80: 6361
Groscurth P, Qiao BY, Podack ER, Hengartner H (1987) Cellular localization of perforin 1 in murine cloned cytotoxic lymphocytes. J Immunol 138: 2749
Groscurth P, Qiao B-Y, Podack ER, Hengarnter H (1987) Cellular localization of perforin 1 in murine cloned cytotoxic T lymphocytes. J Immunol 138: 2749–2752
Haefliger JA, Tschopp J, Nardelli D, Wahli W, Kocher HP, Tosi M, Stanley KK (1987) Complementary DNA cloning of complement C8 beta and its sequence homology to C9. Biochemistry 26: 3551
Haefliger J-A, Tschopp J, Vial N, Jenne DE (1989) Complete primary structure and functional characterization of the sixth component of the human complement system: identification of the C5b-binding domain in complement C6. J Biol Chem 264: 18041–18051
Hänsch GM (1988) The homologous species restriction of the complement attack: structure and function of the C8 binding protein. In: Podack ER (ed) Cytoxic effector mechanisms. Springer, Berlin Heidelberg New York, p 109 (Currennt topics in microbiology and immunology, vol 140)
Henkart PA (1985) Mechanism of lymphocyte mediated cytotoxicity. Annu Rev Immunol 3: 31
Hershberger RJ, Mueller C, Gershenfeld HK, Weissman IL (1988) A serine protease encoding gene that marks activated cytotoxic T-cells in vivo and in vitro. In: Podack ER (ed) Cytotoxic effector mechanisms. Springer, Berlin Heidelberg New York, pp 81–90 (Current topics in microbiology and immunology, vol 140)
Holguin MH, Fredrick LR, Bernshaw NJ, Wilcox LA, Parker CJ (1989) Isolation and characterization of a membrane protein from normal human erythrocytes that inhibits reactive lysis of the erythrocytes of paroxysmal nocturnal hemoglobinuria. J Clin Invest 84: 7
Hollander N, Shin M, Rosse WR, Springer TA (1989) Distinct restriction of complement and cell-mediated lysis. J Immunol 142: 3913
Howard OMZ, Rao AG, Sodetz JM (1987) Complementary DNA and derived amino acid sequence of the beta subunit of complement protein C8: identification of a close structural and ancestral relationship to the alpha subunit and C9. Biochemistry 26: 3565
Jenne D, Tschopp J (1988a) Granzymes, a family of serine protease released from granules of cytolytic T lymphocytes upon cell receptor stimulation. Immunol Rev 103: 53
Jenne DE, Tschopp J (1988b) Granzymes: a family of serine esterases in granules of cytolytic lymphocytes. In: Podack ER (ed) Cytotoxic effector mechanisms. Springer, Berlin Heidelberg New York, p 33 (Current topics in microbiology and immunology, vol 140)
Jiang S, Pereschini PM, Zychlinsky A, Liu C-C, Perussia B, Young JD-E (1988) Resistance of cytolytic lymphocytes to perforin-mediated killing. Lack of correlation with complement-associated homologous species restriction. J Exp Med 169: 2207
Krähenbühl OP, Peter HH, Tschopp J (1989) Absence of homologous restriction factor does not affect CTL-mediated cytolysis. Eur J Immunol 19: 217
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
Kwon BS, Wakulchik M, Liu CC, Pereschini PM, Trapani JA, Haq AK, Kim Y, Young JD-E (1989) The structure of the mouse lymphocyte pore-forming protein perforin. Biochem Biophys Res Commun 158: 1–10
Lichtenheld MG, Lu P, Olsen KJ, Lowrey DM, Hameed A, Hengartner H, Podack ER (1988) Structure and function of human perforin. Nature 335: 448
Lovell DM, Martz E (1987) The degree of CTL induced DNA solubilization is not determined by the human vs mouse origin of the target cell. J Immunol 138: 3695
Lowrey DM, Olsen KJ, Lichtenheld MG, Aebischer T, Rupp F, Hengartner H, Podack ER (1989) Cloning and analysis and expression of murine perforin 1 cDNA, a component of cytolytic T-cell granules with homology to complement component C9. Proc Natl Acad Sci USA 86: 247
Masson D, Tschopp J (1985) Isolation of a lytic, pore-forming protein (perforin) from cytolytic T-lymphocytes. J Biol Chem 260: 9069
Masson D, Corthesy P, Nabholz M, Tschopp J (1985) Appearance of cytolytic granules upon induction of cytolytic activity in CTL-hybrids. EMBO J 4: 2533
McDermott RP, Schmidt RE, Caulfield JP, Hein A, Bartley GT, Ritz J, Schlossman SF, Austen KF, Stevens RL (1985) Proteoglycans in cell mediated cytotoxicity. Identification, localization and exocytosis of a Chondroitinsulfate proteoglycan from human cloned natural killer cells during target cell lysis. J Exp Med 162: 1771
Medof EM (1988) Decay accelerating factor and the defect of paroxysmal nocturnal hemoglobinuria. In: Podack ER (ed) Cytolytic lymphocytes and complement: effectors of the immune system. CRC Press, Boca Raton, pp 57–88
Meri S, Morgan BP, Wing M, Jones J, Davies A, Podack ER, Lachmann PJ (1990) Human protectin (CD59), and 18–20-kD homologous complement restriction factor, does not restrict perforin-mediated lysis. J Exp Med 172: 367
Millard PJ, Reynolds CW, Henkart MP (1984) Cytolytic activity of purified cytoplasmic granules from cytotoxic rat large granular lymphocyte tumors. J Exp Med 160: 75
Mueller C, Gershenfeld HK, Weissman IL (1988) Activation of CTL-specific genes during cell-mediated cytolysis in vivo: expression of HF gene analyzed by in situ hybridization. Immunol Rev 103: 73
Müller-Eberhard HJ (1988) The molecular basis of target cell killing by human lymphocytes and of killer self protection. Immunol Rev 103: 87
Munger WE, Berrebi GA, Henkart PA (1988) Possible involvement of CTL granule protease in Target cell DNA breakdown. Immunol Rev 103: 99
Nagler-Anderson C, Allbritton NL, Verret CR, Eisen HN (1988) A comparison of the cytolytic properties of CD8+ cytotoxic T lymphocytes and cloned cytotoxic T cell lines. Immunol Rev 103: 111
Okada NR, Harada T, Fujita T, Okada H (1989) A novel membrane glycoprotein capable of inhibiting membrane attack by homologous complement. Int Immunol 1: 205
Peters PJ, Geuze HJ, Van der Donk HA, Slot JW, Griffith JM, Stam NJ, Clevers HC, Borst J (1989) Molecules relevant for T cell-target cell interaction are present in cytolytic granules of human T lymphocytes. Eur J Immunol 19: 1469–1475
Peters PJ, Geuze HJ, Van der Donk HA, Borst J (1990) A new model for lethal hit delivery by cytotoxic T lymphocytes. Immunol Today 11: 38–32
Podack ER (1984) Molecular composition of the tubular structure of the membrane attack complex of complement. J Biol Chem 259: 8641
Podack ER (1985) The molecular mechanism of lymphocyte mediated tumor lysis. Immunol Today 6: 12
Podack ER (1986) Molecular mechanism of cytolysis by complement and by cytolytic lymphocytes. J Cell Biochem 30: 133
Podack ER (1987) Perforins: a family of pore forming proteins in immune cytolysis. In: Collier, Bonavide (eds) Membrane mediated cytotoxicity. Liss, New York, pp 339–352
Podack ER, Dennert G (1983) Cell mediated cytolysis: assembly of two types of tubules with putative cytolytic function by cloned natural killer cells. Nature 302: 442
Podack ER, Konigsberg PJ (1984) Cytolytic T-cell granules: Isolation, structural, biochemical and functional characterization. J Exp Med 160: 695
Podack ER, Tschopp J (1982) Polymerization of the ninth component of complement (C9): formation of poly (C9) with a tubular ultrastructure resembling the membrane attack complex of complement. Proc Natl Acad Sci USA 79: 574
Podack ER, Tschopp J, Muller-Eberhard HJ (1982) Molecular organization of C9 within the membrane attack complex of complement. J Exp Med 156: 268
Podack ER, Young JDE, Cohn ZA (1985) Isolation and biochemical and functional characterization of perforin 1 from cytolytic T-cell granules. Proc Natl Acad Sci USA 82: 8629
Podack ER, Lowrey DM, Lichtenheld MG, Olsen KJ, Aebischer T, Binder D, Rupp F, Hengartner H (1988) Structure, function and expression of murine and human perforin 1 (P1). Immunol Rev 103: 203
Podack ER, Hengartner H, Lichtenheld MG (1991) A central role of perforin in cytolysis? Annu Rev Immunol 9: 129–157
Rao AG, Howard SC, Whitehead AS, Colten HR, Sodetz JM (1987) Complementary DNA and derived amino acid sequence of the alpha subunit of human complement protein C8: evidence for the existence of a separate alpha subunit mRNA. Biochemistry 26: 3556
Russel JH (1983) Internal disintegration model of cytotoxic lymphocyte induced target damage. Immunol Rev 72: 97
Russel JH, Masakowski V, Rucinsky T, Phillips G (1982) Mechanisms of immune lysis. III. Characterization of the nature and kinetics of the cytotoxic T lymphocyte-induced nuclear lesion in the target. J Immunol 128: 2087
Shinkai Y, Takio K, Okumura K (1988) Homology of perforin to the ninth component of complement. Nature 334: 525
Sitkovsky MV (1988) Mechanistic, functional, and immunopharmacological implications of biochemical studies of antigen receptor triggered cytolytic T-lymphocyte activation. Immunol Rev 103: 127
Stanley KK (1988) The molecular mechanism of complement component C9 insertion and polymerization in biological membranes. In: Podack ER (ed) Cytotoxic effector mechanisms. Springer, Berlin Heidelberg New York, p 49 (Current topics in microbiology and immunology, vol 140)
Stanley KK, Kocher HP, Luzio JP, Jackson P, Tschopp J (1985) The sequence and topology of human complement component C9. EMBO J 4: 375–382
Stevens RL, Kamada MN, Serafin WE (1988) Structure and function of the family of proteoglycans that reside in the secretory granules of natural killer cells and other effector cell of the immune response. In: Podack ER (ed) Cytotoxic effector mechanisms. Springer, Berlin Heidelberg New York, p 93 (Current topics in microbiology and immunology, vol 140)
Sugita Y, Nakano Y, Tomita M (1988) Isolation from human erythrocytes of a new membrane protein which inhibits the formation of complement transmembrane channels. J Biochem (Tokyo) 104: 633
Thielens NM, Lohner K, Esser A (1988) Human complement protein C9 is a Calcium binding protein. J Biol Chem 263: 6665
Tschopp J, Nabholz M (1990) Perforin-mediated target cell lysis by cytolytic T lymphocytes. Annu Rev Immunol 8: 279–302
Tschopp J, Muller-Eberhard HJ, Podack ER (1982) Formation of transmembrane tubules by spontaneous polymerization of the hydrophilic complement protein C9. Nature 298: 534
Tschopp J, Podack ER, Muller-Eberhard HJ (1985) The membrane attack complex of complement: C5b-8 complex as accelerator of C9 polymerization. Proc Natl Acad Sci USA 134: 495
Tschopp J, Schafer S, Masson D, Peitsch MC, Heusser C (1989) Phosphorylcholine acts as Ca2+- dependent receptor molecule for lymphocyte perforin. Nature 337: 272
Young JDE, Cohn ZA, Podack ER (1986a) The ninth component of complement and the pore-forming protein (perforin 1) from cytotoxic T-cells: Structural and functional homologies. Science 233: 184–190
Young JDE, Hengartner H, Podack ER, Cohn ZA (1986b) Purification and characterization of a cytolytic pore-forming protein from granules of cloned lymphocytes with natural killer cell activity. Cell 44: 849
Young JDE, Damiano A, DiNome MA, Leong LG, Cohn ZA (1987) Dissociation of membrane binding and lytic activities of the lymphocyte pore-forming protein (perforin). J Exp Med 165: 1371
Young JD-E, Liu C-C, Persechini PM, Cohn ZA (1988) Perforin-dependent and -independent pathways of cytotoxicity mediated by lymphocytes. Immunol Rev 103: 161
Yue CC, Reynolds CW, Henkart PA (1987) Inhibition of cytolysin activity in large granular lymphocyte granules by lipids: evidence for a membrane insertion mechanism of lysis. Mol Immunol 24: 647
Zalman LS, Brothers MA, Müller-Eberhard HJ (1985) A C9 related channel forming protein in the cytoplasmic granules of human larger granular lymphocytes. Biosci Rep 5: 1093
Zalman LS, Brothers MA, Chiu FJ, Müller-Eberhard HJ (1986) Mechanism of cytotoxicity of human large granular lymphocytes: relationship of cytotoxic lymphocyte protein to C8 and C9 of human complement. Proc Natl Acad Sci USA 83: 562
Zalman LS, Wood LM, Müller-Eberhard HJ (1987) Inhibition of antibody dependent lymphocyte cytotoxicity by homologous restriction factor incorporated into target cell membranes. J Exp Med 166: 947
Zalman LS, Brothers MA, Müller-Eberhard HJ (1988) Self protection of cytotoxic lymphocytes: a soluble form of homologous restriction factor in cytoplasmic granules. Proc Natl Acad Sci USA 83: 5262–5266
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1992 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Podack, E.R. (1992). Perforin: Structure, Function, and Regulation. In: Parker, C.J. (eds) Membrane Defenses Against Attack by Complement and Perforins. Current Topics in Microbiology and Immunology, vol 178. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-77014-2_11
Download citation
DOI: https://doi.org/10.1007/978-3-642-77014-2_11
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-77016-6
Online ISBN: 978-3-642-77014-2
eBook Packages: Springer Book Archive