Understanding the NK Cytolytic Process by Studying Mechanisms of Activation

  • Stephen R. Targan
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 146)


It has become apparent from recent observations that the definition of the human NK effector cell is more complex then initially suspected. The effector cell which is a lymphocyte has been most accurately defined functionally by its ability to lyse particular “sensitive” target cells (1–4); however, the active NK cell appears to be Fc receptor positive and possibly of T-cell lineage (5), In addition, a large granular lymphocyte has been isolated which has many of these aforementioned characteristics and also possesses most of the NK and activated NK lytic activity (6). Recent observations have shown that NK activity can be augmented by various in vitro modalities. These stimuli appear to be divided into those that can augment NK activity within minutes to 24 hours of culture (Interferon (IF), Poly-IC, viruses) and those that require 48–72 hours of incubation before detectable augmentation (B-cell lines (MLC), pokeweed mitogen, and fetal calf serum) (2, 5, 7–10). The variable length of exposure required for each of these classes of agents to augment NK activity suggest that there may be multiple stages of differentiation and responsiveness of NK cells. Pre-NK cells have been defined as effector cells possessing NK receptors and therefore able to bind target cells, but needing further activation in order to express their lytic capabilities (11). In addition, agents such as interferon can also enhance the lytic abilities of the pre-NK and NK cells to become functionally more efficient killer cells (activated NK cells) (11).


Natural Killer Cell Human Natural Killer Cell Lytic Process Interferon Activation Lytic Mechanism 
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.
    Pross, H.F., and M.G. Baines. Spontaneous human lymphocyte-mediated cytotoxicity against tumor targetcells. VI. A brief review. Cancer Immunol. Immunother. 3:74 (1978).Google Scholar
  2. 2.
    Santoli, D., and H. Kaprowskl. Mechanisms of activation of htanan killer cells against tumor and virus Infected cells, Immunol. Rev. 44:125. (1979).PubMedCrossRefGoogle Scholar
  3. 3.
    Jondal, M. Spina C., and S. Targan. Human Spontaneous killer cells: selective for tumor-derved target cells. Nature 272:62 (1978).PubMedCrossRefGoogle Scholar
  4. 4.
    Bonnard, G.D., and H.W. West. Cell mediated cytotoxicity in humans. A critidal review of experimental models and clinically oriented studies. In: Immunodiagnosis of Cancer. Edited by R.B. Herberman and K.R. Mclntire. Marcel Dekker Publishers, New York. (1978).Google Scholar
  5. 5.
    Herberman, R., Djeu, H., Kay, D., Ortaldo, J.R., Ricardi, C., Bonnard, G.D., Holden, H.T., Fagnani, R., Santoni, A., and P. Puccetti. Natural killer cells: characteristics and regulation of activity. Immunol. Rev. 44:43 (1979).PubMedCrossRefGoogle Scholar
  6. 6.
    Timonen, T., Ortaldo, J.R., and R.B. Herberman. Characteristics of human large granular lymphoctyes and relationship to natural killer and K cells. J.Exp. Med. 153:569. (1981).PubMedCrossRefGoogle Scholar
  7. 7.
    Jondal, M. and S.R. Targan. In vitro induction of cytotoxic effector cells with spontaneous killer (SK) cell specificity. J. Exp. Med. 147: 1621 (1978).PubMedCrossRefGoogle Scholar
  8. 8.
    Zarling, J.M., Eskra, L., Borden, E.C., Horoszcwicz, J., and W.A. Cantar. Activation of human natural killer cells cytotoxic for human leukemia cells by purified interferon. J. Immunol. 123:63 (1979).PubMedGoogle Scholar
  9. 9.
    Kasai, M., Leclerc, J.C., McVay-Boudreau, L., Sheni, F.W., and H. Cantor. Direct evidence that natural killer cells in nonimmune spleen cell populations prevent tumor growth in vivo. J. Exp. Med. 149:1260 (1979).PubMedCrossRefGoogle Scholar
  10. 10.
    Seeley, J.K., and S.H. Golub. Studies on cytotoxicity generated in human mixed lymphocyte cultures. I. Time course and target spectrum of several distinct concomitant cytotoxic activities. J. Immunol. 120:1415 (1978).PubMedGoogle Scholar
  11. 11.
    Targan, S. and F. Dorey. Interferon activation of “prespontan- eous killer” (pre-SK) cells and alteration kinetics of lysis of both “pre-SK” and active SK cells. J. Immunol 124:2157 (1980).PubMedGoogle Scholar
  12. 12.
    Welsh, R.M. Jr. Mouse natural killer cells: induction, specificity, and function. J. Immunol. 122:1631 (1978).Google Scholar
  13. 13.
    Hansson, M., Kiessling, R., Anderson, B., Karre, K., and J. Roder. NK cell-sensitive T-cell subpopulation in thymus: inverse correlation to host NK activity. Nature 278:174. (1979).PubMedCrossRefGoogle Scholar
  14. 14.
    Ono, A., Amos, D.B., and H.S. Koren. Selective cellular natural killing against human leukaemic T cells and thymus. Nature 266:546 (1977).PubMedCrossRefGoogle Scholar
  15. 15.
    Kiessling R., Hochman, P.S., Haller, O., Shearer, G.M., and O. Cudkowicz. Evidence for a similar or common mechanism for natural killer cell activity and resistance to hemopoietic grafts. Eur. J. Immunol. 79:655 (1977).CrossRefGoogle Scholar
  16. 16.
    Masucci, M.G., Masucci, G., Klein, E., and W. Berthold. Target selectivity of interferon-induced human killer lymphocytes related to theri Fc receptor expression. (1980).Google Scholar
  17. 17.
    Hansson M., Kiessling, R., and R. Welsh. Interaction between NK cells and normal tissue: definition of a NK-sensitive thjmiocyte population. In: Natural Cell-Mediated Immunity Against Tumors. Edited by R.B. Herberman. Academic Press, New York, p 855 (1980).Google Scholar
  18. 18.
    Ortaldo, J.R., Oldham, R.K., Cannon, G.C., and R.B. Herberman. Specificity of natural cytotoxic reactivity or normal human lymphocytes against a myeloid leukemia cell line. J. Natl. Cancer Inst. 59:77 (1977).PubMedGoogle Scholar
  19. 19.
    Callewaert, D.J., Lightbody, J.J., Kaplan, J., Jaroszewski, J., Peterson, W.D., and J.C. Rosenberg. Spontaneous cytotoxicity of cultured human cell lines by normal PBL. II. Specificity for target antigens. Cell Immunol. 42:103 (1979).PubMedCrossRefGoogle Scholar
  20. 20.
    Takasugi, M., Akira, D., Takasugi, J., and M. Mickey. Specificities of human cell-mediated cytotoxicity. J. Natl. Cancer Inst. 59:69 (1977).PubMedGoogle Scholar
  21. 21.
    Phillips, W.H., Ortaldo, J.R., and R.B. Herberman. Selective depletion of human natural killer cells on monolayers of target cells. J. Immunol. 125:2322 (1980).PubMedGoogle Scholar
  22. 22.
    Durdik, J.M., Beck, B.N., Clark, W.A., and C.S. Henney. Characterization of a lymphoma cell variant selectively resistant to natural killer cells. J. Immunol 125:683 (1980).PubMedGoogle Scholar
  23. 23.
    Roder, J.C., Rosen, A., Fenyo, E.M., and F.A. Troy. Target- effector interaction in the natural killer cell system: Isolation of target structures. Proc. Natl. Acad. Sci. USA 76:1405 (1979).PubMedCrossRefGoogle Scholar
  24. 24.
    Roder, J.C., and R. Kiessling. A model of target cell recognition and lysis by natural killer cells. Adv. Exp. Med. Biol. 114:745 (1979).PubMedCrossRefGoogle Scholar
  25. 25.
    Roder, J.C., and T. Haliotis. A comparative analysis of the NK cytolytic mechanism and regulatory genes. In “Natural Cell-Mediated Immunity Against Tumors.” Edited by R.B. Herberman. Academic Press, New York, P379. (1980).Google Scholar
  26. 26.
    Roder, J.C., and M. Klein. Target-effector interaction in the natural killer cell system. IV. Modulation by cyclic nucleotides. J. Immunol. 123:2785. (1979).PubMedGoogle Scholar
  27. 27.
    Kiuchi, M., and M. Takasugi. The nonselective cytotoxic cell (N cell). J. Natl. Cancer Inst. 56:575. (1976).PubMedGoogle Scholar
  28. 28.
    Perussia, B., Trinchieri, G., and J.C. Cerottini. Functional studies of Fc receptor-bearing human l3nmphocytes: effect of treatment with proteolytic enzymes. J. Immunol 123:681 (1979).PubMedGoogle Scholar
  29. 29.
    Lilve, A., Bonavida, B., and S. Targan. Mode of action of interferon-mediated modulation of natural killer cytotoxic activity: Recruitment of pre-NK cells and enhanced kinetics of lysis. J. Immunol. 125:479. (1980).Google Scholar
  30. 30.
    Ullberg, M., and M. Jondal. Recycling and target-binding capacity of human natural killer cells. J. Exp. Med. 153:615. (1981).PubMedCrossRefGoogle Scholar
  31. 31.
    Targan, S., Britvan, L, and F. Dorey, Activation of human NKCC by moderate exercise: increased frequency of NK cells with enhanced capability of effector-target lytic interactions. J. Clin. Exp. Immunol. 45:352 (1981).Google Scholar
  32. 32.
    Chany, Rousset, C.S. Bourgeade, M.F., Mathieu, D., and A. Gregoire. In “Regulatory Functions on Interferons.” Edited by J. Vilcek, Gresser I., and T.C. Merigan. New York Academy of Sciences, New York, p 254. (1980).Google Scholar
  33. 33.
    Fridman, W.H., Gresser, I., Bandu, M.T., Aguet, M., and C. Neauport-Sautes. Interferon enhances the expression of Fc receptors. J. Immunol. 124:2436. (1980).PubMedGoogle Scholar
  34. 34.
    Itoh, K., Inoue, M., Kataoka, S., and K. Kumagi. Differential effect of interferon expression of IgG- and IgM-Fc receptors on human Ijnnpohocytes. J. Immunol. 124:2589. (1980).PubMedGoogle Scholar
  35. 35.
    Ortaldo, J.R., Herberman, R.B., and J.Y. Djeu. Characteristics of augmentation of interferon of cell-mediated cytotoxicity. In “Natural Cell-Mediated Immunity Against Tumors.” Edited by R.B. Herberman. Academic Press, New York, P 593. (1980).Google Scholar
  36. 36.
    Hiserodt, J., Britvan, L., and S. Targan. Blockage of natural killer cytotoxicity by heterologous and monoclonal antibodies (In Submission). (1981).Google Scholar
  37. 37.
    Targan S., Grimm, E., and B. Bonavida. A single cell marker of active NK cytotoxicity: Only a fraction of target binding lymphocytes are killer cells. J. Clin. Lab. Immunol. 4:165. (1980).PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1982

Authors and Affiliations

  • Stephen R. Targan
    • 1
    • 2
  1. 1.Geriatric Research and Education Center Medical and Research ServicesWadsworth VA Medical CenterUSA
  2. 2.Department of MedicineUCLA Center for the Health SciencesLos AngelesUSA

Personalised recommendations