Activation of Natural Killer (NK) Cells and Mechanism of Their Cytotoxic Effects

  • Ronald B. Herberman
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 213)


Natural killer (NK) cells are lymphoid cells with spontaneous activity against a wide variety of tumor cell lines and against primary or metastatic tumor cells (1–3). It is now possible to isolate highly enriched populations of NK cells and demonstrate that this cytotoxic activity is mediated predominantly, if not solely, by a small subpopulation of lymphocytes, morphologically identified as large granular lymphocytes (LGL). In addition, a large proportion of LGL have NK activity (3,4). NK activity has been found to be positively regulated by a variety of agents, with the interferons and interleukin 2 (IL-2) being identified as the principal cytokines mediating this stimulation of reactivity (5).


Natural Killer Tumor Necrosis Factor Cytoplasmic Granule Human Peripheral Blood Lymphocyte Large Granular Lymphocyte 
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.
    R. B. Herberman, and J. R. Ortaldo. Natural Killer cells: Their role in defenses against disease. Science 214:24, (1981).ADSCrossRefGoogle Scholar
  2. 2.
    J. R. Ortaldo, and R. B. Herberman. Heterogeneity of natural killer cells. Annu. Ref. Immunol. 2:359. (1984).CrossRefGoogle Scholar
  3. 3.
    R. B. Herberman. Multiple functions of natural killer cells, including immunoregulation as well as resistance to tumor growth. Concepts Immunopathol. 1:96, (1985).Google Scholar
  4. 4.
    T. Timonen, J. R. Ortaldo, and R. B. Herberman. Characteristics of human large granular lymphocytes and relationship to natural killer and K cells. J. Exp. Med. 153:569, (1981).CrossRefGoogle Scholar
  5. 5.
    R. B. Herberman, and A. Santoin. Regulation of natural killer (NK) cell activity. In Mihich, E. (Ed.): Biological Responses in Cancer, Vol. 2. New York, Pleunum Pub. Corp. New York, Plenum Publ. Corp. pp. 121–144, (1984).Google Scholar
  6. 6.
    T. Timonen, J. R. Ortaldo, B. M. Stadler, G. D. Bonnard, S. O. Sharrow, and R. B. Herberman. Cultures of purified human natural killer cells: Growth in the presence of interleukin 2. Cell Immunol. 72:178, (1982).CrossRefGoogle Scholar
  7. 7.
    S. Yamada, F. W. Ruscetti, W. R. Overton, R. B. Herberman, and J. R. Ortaldo. Regulation of human large granular lymphocytes and T cell growth and function by recombinant interleukin 2. I. Induction of interleukin 2 receptor and promotion of growth of cells with enhance cytotoxicity. Manuscript submitted.Google Scholar
  8. 8.
    G. D. Bonnard, K. Yasaka, and D. Jacobson. Ligand-activated mitogenic factor-induced T-cell proliferation. Adsorption of mitogenic factor by activated T cells. J. Immunol. 123:2704–2708, (1979).Google Scholar
  9. 9.
    J. E. Talmadge, R. H. Wiltrout, D. F. Counts, R. B. Herberman, T. McDonald, and J. Ortaldo. Proliferation of human peripheral blood lymphocytes induced by recombinant human interleukin-2: Contribution of large granular lymphocytes and T lymphocytes. Manuscript submitted to Cell Immunology.Google Scholar
  10. 10.
    K. Itoh, A. B. Tilden, K. Kumagai, and C. M. Balch. Leu 11+ lymphocytes with natural killer (NK) activity are precursors of recombinant interleukin 2 (IL-2) included activated kill (AK) cells. J. Immunol. 134:802–807, (1985).Google Scholar
  11. 11.
    E. A. Grimm, R. J. Robb, J. A. Roth, L. M. Neckers, L. B. Lachman, D. J. Wilson, and S. A. Rosenberg. Lymphokine-activated killer cell phenomenon III. Evidence that IL-2 is sufficient for direct activation of peripheral blood lymphocytes into lymphokine activated killer cells. J. Exp. Med. 158:1356, (1983).CrossRefGoogle Scholar
  12. 12.
    J. E. Ortaldo, A. T. Mason, J. P. Gerard, L. E. Henderson, W. Farrar, R. F. Hopkins III, R. B. Herberman, and H. Rabin. Effects of natural and recombinant IL-2 on regulation of IFN production and natural killer activity: Lack of involvement of the Tac antigen for these immunoregulatory effects. J. Immunol. 133:779, (1984).Google Scholar
  13. 13.
    R. B. Herberman. NK Cells and Other Natural Effector Cells. New York: Academic (1982).Google Scholar
  14. 14.
    R. B. Herberman, Calleweart, eds. Mechanisms of Cytotoxicity by NK Cells. Orlando, Fla: Academic (1985).Google Scholar
  15. 15.
    S. Targan, R. L. Deem, in R. B. Herberman and D. Calleweart, (eds). Mechanisms of Cytotoxicity by NK Cells. Orlando, Academic Press, Inc., p 155, (1985).Google Scholar
  16. 16.
    B. Perussia, O. Acuto, C. Terhorst, J. Faust, R. Lazaruz, V. Fanning, and G. Trinchieri. Human natural killer cells analyzed by B731.1, a monoclonal antibody blocking Fc receptor functions. J. Immunol. 130:2142, (1983).Google Scholar
  17. 17.
    C. W. Reynolds, S. O. Sharrow, J. R. Ortaldo, and R. B. Herberman. Natural killer (NK) activity in the rat. II. Analysis of surface antigens on LGL by flow cytometry. J. Immunol. 127:2204. (1981).Google Scholar
  18. 18.
    J. R. Ortaldo, S. O. Sharrow, T. Timonen, and R. B. Herberman. Determination of surface antigens on highly purified human NK cells by flow cytometry with monoclonal antibodies. J. Immunol. 127:2401. (1981).Google Scholar
  19. 19.
    R. Kiessling, E. Klein, H. Pross, and H. Wigzell. “Natural” killer cells in the mouse. II. Cutoptoxic cells with specificity for mouse Maloney leukemia cells. Characteristics of the killer cells. Eur. J. Immunol. 5:117, (1975).CrossRefGoogle Scholar
  20. 20.
    J. C. Hiserodt, K. A. Laybourn and J. Varani. Expression of a laminin-like substance on the surface of murine natural killer (NK) lymphocytes and its role in NK recognition of tumor target cells. J. Immunol. 135:1484, (1985).Google Scholar
  21. 21.
    Y. Yanagi, N. Caccia, M. Kronenberg, B. Chin, J. Ropder, D. Rohel, T. Kiyohara, R. Lauzon, B. Toyanaga, O. K. Rosenthal, G. Dennert, H. Acha-Orbea, H. Hengartner, L. Hood, and T. W. Mak. Gene rearrangement in cells with natural killer activity and expression of the -chain of the T cell antigen receptor. Nature 314:631, (1985).ADSCrossRefGoogle Scholar
  22. 22.
    J. Ritz, T. J. Campen, R. E. Schmidt, H. D. Royer, T. Hercend, R. E. Hussey, and E. L. Reinherz. Analysis of T-cell receptor gene rearrangement and expression in human natural killer cell clones. Science 228:1540, (1985).ADSCrossRefGoogle Scholar
  23. 23.
    T. Hercend, S. C. Meuer, A. Brennan, M. A. Edson, O. Acuto, E. L. Reinherz, S. F. Schlossman, and J. Ritz. Identification of a clonally restricted 90 KID heterodimer on two cloned natural killer cell lines: its role cytotoxic effector function. J. Exp. Med. 158:1547, (1983).CrossRefGoogle Scholar
  24. 24.
    C. W. Reynolds, M. Bonyhadi, R. B. Herberman, H. A. Young, and S. M. Hedrick. Lack of gene rearrangement and mRNA expression of the beta chain of the T cell receptor in spontaneous rat large granular lymphocyte leukemia lines. J. Exp. Med. 161:1249, (1985).CrossRefGoogle Scholar
  25. 25.
    H. A. Young, J. R. Ortaldo, R. B. Herberman, and C. W. Reynolds. Analysis of T cell receptors in highly purified rat and human large granular lymphocytes (LGL): Lack of functional 1.3 kb large granular lymphocytes (LGL): Lack of functional 1.3 kb β-chain mRNA. J. Immunol. 137:2701–2704, (1986).Google Scholar
  26. 26.
    H. Binz, M. Fenner, D. Frei, and H. Wigzell. Two independent receptors allow selective target lysis by T cell clones. J. Exp. Med. 157:1252, (1983).CrossRefGoogle Scholar
  27. 27.
    P. Allavena, A. Rambaldi, P. G. Palliocci, R. Della-Favera, and A. Mantovani. Immunolgical and genotype analysis of human large granular lymphocytes expansions. J. Leukocyte Biol. 38:59, (1985).Google Scholar
  28. 28.
    C. G. Brooks. Reversible induction of natural killer cell activity in clonal murine cytotoxic T lymphocytes. Nature 305:155, (1983).ADSCrossRefGoogle Scholar
  29. 29.
    P. A. Henkart, P. J. Willard, C. W. Reynolds, and M.P. Henkart. Cytolytic activity of purified cytoplasmic granules from cytotoxic rat LGL tumors. J. Exp. Med. 160:75, (1984).CrossRefGoogle Scholar
  30. 30.
    C. W. Reynolds, E. W. Bere, and J. M. Ward. Natural killer activity in the rat. III. Characterization of transplantable large granular lymphocyte (LGL) leukemias in the F344 rat. J. Immunol. 132:534, (1984).Google Scholar
  31. 31.
    C. W. Reynolds, D. Reichardt, M. Henkart, P. Millard, and P. Henkart. Inhibition of NK and ADCC activity by antibodies against purified cytoplasmic granules from rat LGL tumors. J. Exp. Med. in press.Google Scholar
  32. 32.
    S. C. Wright, and B. Bonavida. Studies on the mechanism of natural killer (NK) cell-mediated cytotoxicity (CMC). I. Release of cytotoxic factors specific for NK-sensitive target cells (NKCF) during co-culture of NK effector cells with NK target cells. J. Immunol. 129:433, (1982).Google Scholar
  33. 33.
    J. R. Ortaldo, I. Bianca, and R. B. Herberman. Studies of human natural killer cytotoxic factor (NKCF); Characterization and analysis of its mode of action. In P. Henkart, E. Martz, eds. Mechanisms of Cell-Mediated Cytotoxicity. New York: Plenum. 203 pp (1985).CrossRefGoogle Scholar
  34. 34.
    I. Bianca, R. B. Herberman, and J. R. Ortaldo. Human natural killer cytotoxic factor. Natural Immunity Cell Growth Resul. 4:48, (1985).Google Scholar
  35. 35.
    J. E. Blalock, J. A. Georgiades, N. F. Langford, and H. M. Johnson. Purified human immune interferon has more potent anticellular activity than fibroblast or leukocyte interferon. Cell Immunol. 49:390, (1980).CrossRefGoogle Scholar
  36. 36.
    B. B. Aggarwal, W. J. Henzel, B. Moffat, W. J. Kohn, and R. N. Harkins. Primary structure of human lymphotoxin derived from 1788 lymphoblastoid cell line. J. Biol. Chem. 260:2334. (1985).Google Scholar
  37. 37.
    E. A. Carswell, L. J. Old, R. L. Kassel, S. Green, N. Fiore, and N. Williamson. An endotoxin-induced serum factor that causes necrosis of tumors. Proc. Natl. Acad. Sci. USA 72:P3666. (1975).ADSCrossRefGoogle Scholar
  38. 38.
    D. Pennica, G. W. Nedwin, J. S. Hayflick, P. H. Seeburg, R. Derynck, M. A. Paladino, W. J. Kohr, B. B. Aggarwal, and D. V. Goeddel. Human tumor necrosis factor: Precursor structure, expression and homology to lymphotoxin. Nature 312:724, (1984).ADSCrossRefGoogle Scholar
  39. 39.
    J. H. Ransom, C. H. Evans, R. P. McCabe, N. Pomato, J. A. Heinbaugh, M. Chin, and M. G. Hanna Jr. Leukoregulin, a direct-acting anticancer immunological hormone that is distinct from lymphotoxin and interferon. Cancer Res. 45:851, (1985).Google Scholar
  40. 40.
    O. Stutman, C. J. Paige, and E. F. Figarella. Natural cytotoxic cells against solid tumors in mice. I. Strain and age distribution and target cell susceptibility. J. Immunol. 121:1819, (1978).Google Scholar
  41. 41.
    J. R. Ortaldo, L. H. Mason, B. J. Mathieson, S. M. Liang, D. A. flick, and R. B. Herberman. Mediation of mouse natural cytotoxic (NC) activity by tumor necrosis factor (TNF). Nature in press.Google Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • Ronald B. Herberman
    • 1
  1. 1.Pittsburgh Cancer Institute and Departments of Medicine and PathologyUniversity of PittsburghPittsburghUSA

Personalised recommendations