A Unified Theory for the Mechanism of the Lethal Hit by Cytotoxic T Lymphocytes (CTL) and Natural Killer (NK) Cells as Defined by Antisera Capable of Blocking the Lethal Hit Stage of Cytotoxicity

  • John C. Hiserodt
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 187)


Understanding the mechanisms in which cytotoxic lymphocytes (particularly cytotoxic T lymphocytes (CTL) and natural killer (NK) cells) mediate the lysis of target cells has been a fundamental problem in molecular immunology. While these reactions involve complex biochemical and physiological processes the mechanism of cytotoxicity has been resolved into several operationally identifiable stages (1–4). In the most simplistic scheme, the effector lymphocyte must recognize and bind to the appropriate target. Subsequent to binding, the killer cell undergoes of series of physiological responses collectively termed activation. It is during this activation phase that the killer cell initiates infliction of the lethal hit on the target. Once the lethal hit has been completed the killer cell can detach and recycle to other targets. Target cells having received the lethal hit are “programmed to lyse” and will rapidly do so during the final stage of the lytic reaction known as the killer cell independent stage.


Natural Killer Spleen Cell Murine Natural Killer Cell P815 Mastocytoma Target Cell Binding 
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. 1.
    Mechanisms of Cell-Mediated Cytotoxicity, in Adv. Expt. Medicine and Biology, Vol. 146 (Ed. W. R. Clark and P. Gostein), Plenum Press, New York, 1982.Google Scholar
  2. 2.
    Martz, E. Mechanism of specific tumor cell lysis by alloimmune T lymphocytes: Resolution and characterization of discrete steps in the cellular interaction. In: Contemporary Topics in Immunobiology. (ed. O. Stutman) Plenum Press, N.Y. 7:301, 1977.CrossRefGoogle Scholar
  3. 3.
    Golstein, P., and Smith, E.T. The lethal hit stage of mouse T and non T cell mediated cytolysis. Differences in cation requirements and characterization of an analytical “cation pulse” method. Eur. J. Immunol. 6:31, 1976.PubMedCrossRefGoogle Scholar
  4. 4.
    Berke, G. Cytotoxic T-lymphocytes: Ho do they function. Immunological Rev. 72:5, 1983.CrossRefGoogle Scholar
  5. 5.
    Gately, M.K., Wechter, W.J., and E. Martz. Early steps in specific tumor cell lysis by sensitized mouse T lymphocytes. IV. Inhibition of Programming for lysis by pharmacologic agents. J. Immunol. 125:783, 1980.PubMedGoogle Scholar
  6. 6.
    Hiserodt, J.C., Britvan, L.J., and S.R. Targan. Characterization of the cytolytic reaction mechanism of the human natural killer (NK) lymphocyte: Resolution into binding, programming and killer cell-independent steps. J. Immunol. 129:1782, 1982.PubMedGoogle Scholar
  7. 7.
    Fan, J., Ahmed, A., and Bonavida, B. Studies on the induction and expression of T cell mediated immunity. X. Inhibition by Lyt 2,3 antisera of cytotoxic T lymphocyte-mediated antigen-specific and nonspecific cytotoxicity: Evidence for the blocking of the binding between T lymphocytes and target cells and not the post-binding cytolytic steps. J. Immunol. 125:2444, 1980.PubMedGoogle Scholar
  8. 8.
    Davignon, E., Martz, E., Reynolds, T., Kurzinger, K., and Springer, T.A. Lymphocyte function associated antigens one (LFA-1): a surface antigen distinct from Lyt 2,3 that participates in T lymphocyte-mediated killing. Proc. Natl. Acad. Sci. USA 78:4535, 1981.PubMedCrossRefGoogle Scholar
  9. 9.
    Pierres, M., Goridis, C., and Golstein, P. Inhibition of murine T cell cytolysis and T cell proliferation by a rat monoclonal antibody immunoprecipitation two polypeptides of 94,000 and 180,000 molecular weight. Eur. J. Immunology 12:60, 1982.CrossRefGoogle Scholar
  10. 10.
    Pasternak, M.S., Sitkowski, M.V., and H.N. Eisen. The site of action of TLCK on cloned cytotoxic T lymphocytes. J. Immunol. 131:2477, 1983.Google Scholar
  11. 11.
    Targan, S. and W. Newman. Definition of a “trigger” stage in the NK cytolytic reaction sequence by a monclonal antibody to the glycoprotein T-200. J. Immunol. 131:1149, 1983.PubMedGoogle Scholar
  12. 12.
    Hiserodt, J.C., and Bonavida, B. Studies on the induction and expression of T cell-mediated immunity. XI. Inhibition of the “lethal hit11 on T cell mediated cytotoxicity by heterologous rat antiserum made against alloimmune cytotoxic T lymphocytes. J. Immunol. 126:256, 1981.PubMedGoogle Scholar
  13. 13.
    Neville, M.E., and J.C. Hiserodt. Inhibition of human antibody dependent cellular cytotoxicity, T cell mediated cytotoxicity, and natural killing by heterologous rat antiserum made against alloimmune human cytotoxic lymphocytes. J. Immunol. 128:1246, 1982.PubMedGoogle Scholar
  14. 14.
    Ware, C.F., and Granger, G.A. Mechanisms of lymphocyte- mediated cytotoxicity I. The effect of anti-human lymphotoxin antisera on the cytolysis of allogeneic B cell lines by MLC-sensitized human lymphocytes in vitro. J. Immunol. 126:1919, 1981.PubMedGoogle Scholar
  15. 15.
    Lawlor, D.A., Saunders, P.H., and Ware, C.F. Rat antisera directed against alloimmune cytotoxic T “lymphocytes inhibit cytotoxic T lymphocyte and natural killer activity: Strain specificity of inhibition. Cellular Immunol. 62:128, 1982.CrossRefGoogle Scholar
  16. 16.
    Kahle, R., Hiserodt, J. and B. Bonavida. Characterization of antibody mediated inhibition of natural killer (NK) cytotoxicity: Evidence for blocking of both recognition and lethal hit stages of cytolysis. Cell. Immunol. 80:97, 1983.PubMedCrossRefGoogle Scholar
  17. 17.
    Hiserodt, J.C., Britvan, L.J. and S.R. Targan. Inhibition of human natural killing by heterologous and monoclonal antibodies. J. Immunol. 129:2248, 1982.PubMedGoogle Scholar
  18. 18.
    Bohmer, V., Hengartner, H., Nabholz, M., Lernhardt, W., Schrier, M.H., and Haas, W. Fine specificity of a continuously growing killer cell clone specific for H-Y antigen. Eur. J. Immunol. 9:592, 1979.CrossRefGoogle Scholar
  19. 19.
    Hiserodt, J.C., Britvan, L.J., and S.R. Targan. Studies on the mechanism of the human natural killer cell lethal hit: Evidence for transfer of protease-sensitive structures requisite for target cell lysis. J. Immunol. 131:2710, 1983.PubMedGoogle Scholar
  20. 20.
    Henkart, M., Blumenthal, R., Millard, P., Reynolds, C., and P. Henkart. Correlation of ring structures and activity of the calcium dependent cytolysin from LGL granules. Fed. Proc. 43:1756, 1984.Google Scholar
  21. 21.
    Schneider, E.M., G.P. Pawelec, S. Uangru, and P. Wernet. A novel type of human T cell clone with highly potent natural killer-like cytotoxicity divorced from large granular lymphocyte morphology. J. Immunol. 133:173, 1984.PubMedGoogle Scholar
  22. 22.
    Hiserodt, J.C. and G.A. Granger. The human lymphotoxin system. J. Reticuloendothelial Soc. 24:427, 1978.Google Scholar
  23. 23.
    Weirtzen, M. and G.A. Granger. The Human LT System. VIII. A target cell-dependent enzymatic activation step required for the expression of cytotoxic activity of human lymphotoxin. J. Immunol. 125:719, 1980.Google Scholar
  24. 24.
    Doumashkin, R.R., P. Deteix, C.B. Simone, and P. Henkart. Electron microscope demonstration of lesions on target cell membranes associated with antibody dependent cellular cytotoxicity. Clin. Exp. Immunol. 43:554, 1980.Google Scholar
  25. 25.
    Podack, E.R., and G. Dennert. Assembly of two types of tubules with putative cytolytic function in cloned natural killer cells. Nature (Lond.) 302:442, 1983.CrossRefGoogle Scholar
  26. 26.
    Dennert, G. and E.R. Podack. Cytolysis by H-2 specific T killer cells. Assembly of tubular complexes on target membranes. J. Exp. Med. 157:1483, 1983.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1985

Authors and Affiliations

  • John C. Hiserodt
    • 1
  1. 1.Department of PathologyUniversity of MichiganAnn ArborUSA

Personalised recommendations