Mechanism of T-Cell-Mediated Cytolysis: The Lethal Hit Stage

  • Pierre Golstein
  • Evan T. Smith
Part of the Contemporary Topics in Immunobiology book series (CTI, volume 7)


The existence of cell-mediated cell-destruction systems in higher organisms (extensively reviewed by Perlmann and Holm, 1969, and Cerottini and Brunner, 1974) raises two basic questions, namely: (1) Why; i.e., what is the selective advantage for the reproductive multicellular individual of possessing cytotoxic devices? (2) How; i.e., by which mechanism(s) is a cell able to destroy another cell? This chapter deals exclusively with the latter question, delineated as follows:

First, only model cytotoxicity experiments done in vitro will be described or discussed, irrespective of whether similar cytotoxic phenomena occur or do not occur in vivo. Cell-mediated cytotoxicity will thus be considered here, not from a utilitarian immunologic point of view, but as a problem of cell physiology studied under test-tube conditions.


Target Cell Effector Cell Specific Adsorption Recognition Stage Metabolic Complexity 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Amos, D.B., 1962, The use of simplified systems as an aid to the interpretation of mechanisms of graft rejection, Prog. Allergy 6:468.PubMedGoogle Scholar
  2. Andersson, L.C., Nordling, S., and Häyry, P., 1973, Allograft immunity in vitro. VI. Autonomy of T lymphocytes in target cell destruction, Scand. J. Immunol. 2:107.PubMedCrossRefGoogle Scholar
  3. Asherson, G.L., Ferluga, J., and Janossy, G., 1973, Non-specific cytotoxicity by T cells activated with plant mitogens in vitro and the requirement for plant agents during the killing reaction, Clin. Exp. Immunol. 15:573.PubMedGoogle Scholar
  4. Ax, W., Malchow, H., Zeiss, I., and Fischer, H., 1968, The behavior of lymphocytes in the process of target cell destruction in vitro, Exp. Cell Res. 53:108.PubMedCrossRefGoogle Scholar
  5. Becker, E.L., and Henson, P.M., 1973, In vitro studies of immunologically induced secretion of mediators from cells and related phenomena, Adv. Immunol. 17:93.PubMedCrossRefGoogle Scholar
  6. Benacerraf, B., Unanue, E.R., Dorff, M.E., and Kennedy, L.J., 1975, Binding of the terpolymer of L-glutamic acid, L-alanine, L-tyrosine by mouse thymic lymphocytes: Inhibition by anti-H-2 alloantisera, in: Membrane Receptors of Lymphocytes, pp. 127–130 (M. Seligmann, J.L. Preud’homme, and F. M. Kourilsky, eds.), North-Holland Publishing Co., Amsterdam.Google Scholar
  7. Berke, G., and Gabison, D., 1975, Energy requirements of the binding and lytic steps of T lymphocyte mediated cytolysis of leukaemic cells in vitro. Eur. J. Immunol. 5:671.PubMedCrossRefGoogle Scholar
  8. Berke, G., and Levey, R.H., 1972, Cellular immunoadsorbents in transplantation immunity. Specific in vitro deletion and recovery of mouse lymphoid cells sensitized against allogeneic tumours, J. Exp. Med. 135:972.PubMedCrossRefGoogle Scholar
  9. Berke, G., Sullivan, K.A., and Amos, D.B., 1972, Tumor immunity in vitro: Destruction of a mouse ascites tumor through a cycling pathway, Science 177:433.PubMedCrossRefGoogle Scholar
  10. Berke, G., Gabison, D., and Feldman, M., 1975, The frequency of effector cells in populations containing cytotoxic T lymphocytes, Eur. J. Immunol. 5:813.CrossRefGoogle Scholar
  11. Brondz, B.D., 1968, Complex specificity of immune lymphocytes in allogeneic cell cultures, Folia Biol. 14:115.Google Scholar
  12. Bubbers, J.E., and Henney, C.J., 1975, Studies on the synthetic capacity and antigenic expression of glutaraldehyde-fîxed target cells, J. Immunol. 114:1126.PubMedGoogle Scholar
  13. Cerottini, J.-C., and Brunner, K.T., 1972, Reversible inhibition of lymphocyte-mediated cytotoxicity by Cytochalasin B, Nature (London) New Biol. 237:272.Google Scholar
  14. Cerottini, J.-C., and Brunner, K.T., 1974, Cell mediated cytotoxicity, allograft rejection and tumour immunity, Adv. Immunol. 18:67.PubMedCrossRefGoogle Scholar
  15. Cerottini, J.-C., Nordin, A.A., and Brunner, K.T., 1970, Specific in vitro cytotoxicity of thymus-derived lymphocytes sensitised to alloantigens, Nature (London) 228:1308.CrossRefGoogle Scholar
  16. Dickmeiss, E., 1974, Comparative study of antibody-dependent and direct lymphocyte-mediated cytotoxicity in vitro after alloimmunisation in the human. II. Chemical inhibitors, Scand. J. Immunol. 3:817.PubMedCrossRefGoogle Scholar
  17. Ferluga, J., and Allison, A.C., 1974, Observations on the mechanism by which T lymphocytes exert cytotoxic effects, Nature (London) 250:673.CrossRefGoogle Scholar
  18. Ferluga, J., and Allison, A.C., 1975, Cytotoxicity of isolated plasma membranes from lymph node cells, Nature (London) 255:708.CrossRefGoogle Scholar
  19. Ferluga, J., Asherson, G.L., and Becker, E.L., 1972, The effect of organophosphorus inhibitors, p-nitrophenol and cytochalasin B on cytotoxic killing of tumor cells by immune spleen cells, and the effect of shaking, Immunology 23:577.PubMedGoogle Scholar
  20. Foreman, J.C., Mongar J. L., and Gomperts, B.D., 1973, Calcium ionophores and movement of calcium ions following the physiological stimulus to a secretory process, Nature (London) 245:249.CrossRefGoogle Scholar
  21. Frye, L.D., and Friou, G.J., 1975, Inhibition of mammalian cytotoxic cells by phosphatidylcholine and its analogue, Nature (London) 258:333.CrossRefGoogle Scholar
  22. Golstein, P., 1974, Sensitivity of cytotoxic T cells to T cell mediated cytotoxicity, Nature (London) 252:81.CrossRefGoogle Scholar
  23. Golstein, P., 1975, Cell mediated cytolysis. Foetal liver cells as non-T effector cells, in vitro educated spleen cells as T effector cells, Proceedings of the XIth International Cancer Congress, Excerpta Med. Int. Congr. Ser. pp. 280–284.Google Scholar
  24. Golstein, P., and Blomgren, H., 1973, Further evidence for autonomy of T cells mediating specific in vitro cytotoxicity: Efficiency of very small amounts of highly purified T cells, Cell. Immunol. 9:127.PubMedCrossRefGoogle Scholar
  25. Golstein, P., and Fewtrell, C., 1975, Functional fractionation of human cytotoxic cells using differences in their cation requirements, Nature (London) 255:491.CrossRefGoogle Scholar
  26. Golstein, P., and Gomperts, B.D., 1975, Non-T cell mediated cytolysis of antibody-coated sheep red blood cells requires Mg++ but not Ca++: An argument against a conventional “stimulus secretion” mechanism for cytolysis, J. Immunol. 114:1264.PubMedGoogle Scholar
  27. Golstein, P., and Smith, E.T., 1976, The lethal hit stage of mouse T and non-T cell mediated cytolysis: Differences in cation requirements and characterisation of an analytical “cation pulse” method, Eur. J. Immunol. 6:31.PubMedCrossRefGoogle Scholar
  28. Golstein, P., Svedmyr, E.A.J., and Wigzell, H., 1971, Cells mediating specific in vitro cytotoxicity. I. Detection of receptor-bearing lymphocytes, J. Exp. Med. 134:1385.PubMedCrossRefGoogle Scholar
  29. Golstein, P., Svedmyr, E.A.J., and Blomgren, H., 1972a, Specific adsorption of cytotoxic thymus-processed lymphocytes (T cells) on glutaraldehyde-flxed fibroblast monolayers, Eur. J. Immunol. 2:380.PubMedCrossRefGoogle Scholar
  30. Golstein, P., Wigzell, H., Blomgren, H., and Svedmyr, E.A.J., 1972b, Cells mediating specific in vitro cytotoxicity. II. Probable autonomy of thymus-processed lymphocytes (T cells) for the killing of allogeneic target cells, J. Exp. Med. 135:890.PubMedCrossRefGoogle Scholar
  31. Hämmerling, G.J., Lonai, P., and McDevitt, H.O., 1975, Specificity and temperature requirements for T cell interaction with an antigen, in: Membrane Receptors of Lymphocytes, pp. 121–126 (M. Seligmann, J.L. Preud’homme, and F.M. Kourilsky, eds.), North-Holland Publishing Co., Amsterdam.Google Scholar
  32. Häyry, P., Andersson, L.C., Nordling, S., and Virolainen, M., 1972, Allograft response in vitro, Transplant. Rev. 12:91.PubMedGoogle Scholar
  33. Henney, C.S., 1973, Studies on the mechanism of lymphocyte-mediated cytolysis. II. The use of various target cell markers to study cytolytic events, J. Immunol. 110:73.PubMedGoogle Scholar
  34. Henney, C.S., 1974, Estimation of the size of a T cell-induced lytic lesion, Nature (London) 249:456.CrossRefGoogle Scholar
  35. Henney, C.S., and Bubbers, J.E., 1973a, Studies on the mechanism of lymphocyte-mediated cytolysis. I. The role of divalent cations in cytolysis by T lymphocytes, J. Immunol. 110:63.PubMedGoogle Scholar
  36. Henney, C.S., and Bubbers, J.E., 1973b, Antigen-T lymphocyte interactions: Inhibition by cy tochalasin B, J. Immunol. 111:85.PubMedGoogle Scholar
  37. Henney, C.S., Bourne, H.R., and Lichtenstein, L.M., 1972, The role of cyclic 3′,5′-adenosine monophosphate in the specific cytolytic activity of lymphocytes, J. Immunol. 108: 1526.PubMedGoogle Scholar
  38. Kedar, E., Ortiz de Landazuri, M., Bonavida, B., and Fahey, J.L., 1974, Cellular immuno-adsorbents. An improved technique for specific depletions of cytotoxic (T) lymphoid cells, J. Immunol. Methods 5:97.PubMedCrossRefGoogle Scholar
  39. Kemp, A.S., and Berke, G., 1973, Inhibition of lymphocyte-mediated cytolysis by the local anaesthetics benzyl and salicyl alcohol, Eur. J. Immunol. 3:674.PubMedCrossRefGoogle Scholar
  40. Koprowski, H., and Fernandes, M.V., 1962, Autosensitization reaction in vitro. Contactual agglutination of sensitized lymph node cells in brain tissue culture accompanied by destruction of glial elements, J. Exp. Med. 116:467.PubMedCrossRefGoogle Scholar
  41. Koren, H.S., Ax, W., and Freund-Moelbert, E., 1973, Morphological observations on the contact-induced lysis of target cells, Eur. J. Immunol. 3:32.PubMedCrossRefGoogle Scholar
  42. Lohmann-Matthes, M.-L., and Fischer, H., 1972, Specific cytotoxicity of a mouse thymocyte population sensitised in vitro against H-2 alloantigens, Eur. J. Immunol. 2:290.PubMedCrossRefGoogle Scholar
  43. MacDonald, H.R., 1975, Early detection of potentially lethal events in T cell-mediated cytolysis, Eur. J. Immunol. 5:251.PubMedCrossRefGoogle Scholar
  44. Martz, E., 1975, Early steps in specific tumor cell lysis by sensitized mouse T lymphocytes. I. Resolution and characterization, J. Immunol. 115:261.PubMedGoogle Scholar
  45. Martz, E., and Benacerraf, B., 1976, Multiple target cell killing by the cytolytic T lymphocyte and the mechanism of cytotoxicity, Transplantation 21:5.PubMedCrossRefGoogle Scholar
  46. Martz, E., and Benacerraf, B., 1973, An effector cell-independent step in target cell lysis by sensitized mouse lymphocytes, J. Immunol. 111:1538.PubMedGoogle Scholar
  47. Martz, E., Burakoff, S.J., and Benacerraf, B., 1974, Interruption of the sequential release of small and large molecules from tumor cells by low temperature during cytolysis mediated by immune T cells or complement, Proc. Natl. Acad. Sci. U.S.A. 71:177.PubMedCrossRefGoogle Scholar
  48. Mauel, J., Rudolf, H., Chapuis, B., and Brunner, K.T., 1970, Studies of allograft immunity in mice. II. Mechanism of target cell inactivation in vitro by sensitized lymphocytes, Immunology 18:517.PubMedGoogle Scholar
  49. Miller, R.G., and Dunkley, M., 1974, Quantitative analysis of the 51Cr release cytotoxicity assay for cytotoxic lymphocytes, Cell. Immunol. 14:284.PubMedCrossRefGoogle Scholar
  50. Orange, R.P., Kaliner, M.A., and Austen, K.F., 1971, The immunological release of histamine and slow-reacting substance of anaphylaxis from human lung. III. Biochemical control mechanisms involved in the immunologic release of the chemical mediators, in: Biochemistry of the Acute Allergic Reactions, pp. 189–204 (K.F. Austen and E.L. Becker, eds.), Blackwell Scientific Publications, Oxford.Google Scholar
  51. Perlmann, P., and Holm, G., 1969, Cytotoxic effects of lymphoid cells in vitro, Adv. Immunol. 11:117.PubMedCrossRefGoogle Scholar
  52. Plaut, M., Lichtenstein, L.M., and Henney, C.S., 1973, Studies on the mechanism of lymphocyte-mediated cytolysis. III. The role of microfilaments and microtubules, J. Immunol. 110:771.PubMedGoogle Scholar
  53. Plaut, M., Bubbers, J.E., and Henney, C.S., 1976, Studies on the mechanism of lymphocyte-mediated cytolysis. VII. Two stages in the T cell mediated lytic cycle with distinct cation requirements, J. Immunol. 116:150.PubMedGoogle Scholar
  54. Rosenau, W., 1963, Interaction of lymphoid cells with target cells in tissue culture, in: Cell-Bound Antibodies, p. 75 (B. Amos and H. Koprowski, eds.), The Wistar Institute Press, Philadelphia.Google Scholar
  55. Rubin, R.P., 1970, The role of calcium in the release of neurotransmitter substances and hormones, Pharmacol. Rev. 22:389.PubMedGoogle Scholar
  56. Scornik, J.C., and Cosenza, H., 1974, Antibody-dependent cell-mediated cytotoxicity. III. Two functionally different effector cells, J. Immunol. 113:1527.PubMedGoogle Scholar
  57. Strom, T.B., Deisseroth, A., Morganroth, J., Carpenter, C.B., and Merrill, J.P., 1972, Alteration of the cytotoxic action of sensitized lymphocytes by cholinergic agents and activators of adenylate cyclase, Proc. Natl. Acad. Sci. U.S.A. 69:2995.PubMedCrossRefGoogle Scholar
  58. Stulting, R.D., and Berke, G., 1973, Nature of lymphocyte—tumor interaction. A general method for cellular immunoadsorption, J. Exp. Med. 137:932.PubMedCrossRefGoogle Scholar
  59. Stulting, R.D., Berke, G., and Hiemstra, K., 1973, Evaluation of the effects of cytochalasin B on lymphocyte-mediated cytolysis, Transplantation 16:684.PubMedCrossRefGoogle Scholar
  60. Stulting, R.D., Todd, R.F., III., and Amos, D.B., 1975, Lymphocyte-mediated cytolysis of allogeneic tumour cells in vitro. II. Binding of cytotoxic lymphocytes to formaldehyde-fixed target cells, Cell. Immunol. 20:54.PubMedCrossRefGoogle Scholar
  61. Taylor, R.B., Duffus, W.P.H., Raff, M.C., and de Petris, S., 1971, Redistribution and pinocytosis of lymphocyte surface immunoglobulin molecules induced by anti-immunoglobulin antibody, Nature (London) New Biol. 233:225. Todd, R.F., 1975, Inhibition of binding between cytotoxic (T) lymphocytes and tumor target cells by inhibitors of energy metabolism, Transplantation 20:350.Google Scholar
  62. Wagner, H., 1971, Cell-mediated immune response in vitro: Independent differentiation of thymocytes into cytotoxic lymphocytes, Eur. J. Immunol. 1:498.CrossRefGoogle Scholar
  63. Wagner, H., and Röllinghoff, M., 1974, T cell-mediated cytotoxicity: Discrimination between antigen recognition, lethal hit and cytolysis phase, Eur. J. Immunol. 4:745.PubMedCrossRefGoogle Scholar
  64. Wagner, H., Trostmann, H., Pfizenmaier, K., and Röllinghoff, M., 1975, The cytotoxic activity of mouse T lymphocytes against allogeneic cytotoxic T cells, Z. Immunitaets-forsch. 150:81.Google Scholar
  65. Walker W.S., and Demus, A., 1975, Antibody-dependent cytolysis of chicken erythrocytes by an in vitro-established line of mouse peritoneal macrophages, J. Immunol. 114:765.PubMedGoogle Scholar
  66. Wekerle, H., Lonai, P., and Feldman, M., 1972, Fractionation of antigen reactive cells on a cellular immunoadsorbent: Factors determining recognition of antigens by T lymphocytes, Proc. Natl. Acad. Sci. U.S.A. 69:1620.PubMedCrossRefGoogle Scholar
  67. Wekerle, H., Kölsch, E., and Feldman, M., 1974, T cell recognition of cell-surface antigens. II. Antigen recognition is necessary yet not sufficient for triggering T cell-mediated immunity, Eur. J. Immunol. 4:246.PubMedCrossRefGoogle Scholar
  68. Wigzell, H., 1970, Specific fractionation of immunocompetent cells, Transplant. Rev. 5:76.PubMedGoogle Scholar
  69. Wilson, D.B., 1965, Quantitative studies on the behavior of sensitized lymphocytes in vitro. I. Relationship of the degree of destruction of homologous target cells to the number of lymphocytes and to the time of contact in culture and consideration of the effects of isoimmune serum, J. Exp. Med. 122:143.PubMedCrossRefGoogle Scholar
  70. Wolberg, G., Hiemstra, K., Burge, J.J., and Singler, R.C., 1973, Reversible inhibition of lymphocyte-mediated cytolysis by dimethyl sulfoxide (DMSO), J. Immunol. 111: 1435.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1977

Authors and Affiliations

  • Pierre Golstein
    • 1
  • Evan T. Smith
    • 1
  1. 1.Department of ZoologyUniversity College LondonLondonEngland

Personalised recommendations