Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1992 Mar 1;175(3):779–788. doi: 10.1084/jem.175.3.779

Response of human natural killer (NK) cells to NK cell stimulatory factor (NKSF): cytolytic activity and proliferation of NK cells are differentially regulated by NKSF

PMCID: PMC2119162  PMID: 1346796

Abstract

Natural killer cell stimulatory factor (NKSF) is a 70-kD heterodimeric cytokine that was initially isolated from conditioned medium of human B lymphoblastoid cell lines. The effects of recombinant NKSF on the function of human peripheral blood NK cells were examined. NKSF directly augmented the cytolytic activity of freshly isolated NK cells. Both CD56dim and CD56bright NK cells demonstrated enhanced cytotoxicity after brief exposure to NKSF. In contrast, highly purified T lymphocytes did not exhibit major histocompatibility complex- unrestricted cytotoxicity after short-term culture with NKSF. Like interleukin 2 (IL-2), NKSF augmented the lysis of NK-sensitive, NK- resistant, and antibody-coated targets. Both NKSF and IL-2 induced marked upregulation of several NK cell adhesion molecules known to participate in cytolysis, including CD2, CD11a, and CD54. However, NKSF activates NK cells through a pathway distinct from that of IL-2, since the presence of anti-IL-2 receptor (anti-IL-2R) antibodies or IL-4 did not inhibit the effects of NKSF. NKSF by itself induced very little proliferation of resting NK cells. NK cells preactivated in vitro with IL-2 demonstrated enhanced proliferation to NKSF, but the degree of proliferation was always inferior to that induced by IL-2 alone. Moreover, NKSF strongly inhibited IL-2-induced proliferation of either resting or preactivated NK cells. This inhibition was not the result of decreased IL-2R expression, because NKSF-activated NK cells expressed higher levels of both IL-2Rs p75 and p55. Furthermore, NKSF did not inhibit the proliferation of mitogen-activated T cells, indicating a selective effect on NK cell proliferation. Human NK cells expanded in vivo by prolonged continuous infusions of IL-2 remained fully responsive to NKSF. Picomolar concentrations of NKSF were as effective as nanomolar concentrations of IL-2 in augmenting the cytolytic activity of NK cells expanded in vivo by IL-2. NKSF may play an important role in the regulation of human NK cell function, and its possible use as a therapeutic cytokine deserves further investigation.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allison M. A., Jones S. E., McGuffey P. Phase II trial of outpatient interleukin-2 in malignant lymphoma, chronic lymphocytic leukemia, and selected solid tumors. J Clin Oncol. 1989 Jan;7(1):75–80. doi: 10.1200/JCO.1989.7.1.75. [DOI] [PubMed] [Google Scholar]
  2. Caligiuri M. A., Murray C., Soiffer R. J., Klumpp T. R., Seiden M., Cochran K., Cameron C., Ish C., Buchanan L., Perillo D. Extended continuous infusion low-dose recombinant interleukin-2 in advanced cancer: prolonged immunomodulation without significant toxicity. J Clin Oncol. 1991 Dec;9(12):2110–2119. doi: 10.1200/JCO.1991.9.12.2110. [DOI] [PubMed] [Google Scholar]
  3. Caligiuri M. A., Zmuidzinas A., Manley T. J., Levine H., Smith K. A., Ritz J. Functional consequences of interleukin 2 receptor expression on resting human lymphocytes. Identification of a novel natural killer cell subset with high affinity receptors. J Exp Med. 1990 May 1;171(5):1509–1526. doi: 10.1084/jem.171.5.1509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chan S. H., Perussia B., Gupta J. W., Kobayashi M., Pospísil M., Young H. A., Wolf S. F., Young D., Clark S. C., Trinchieri G. Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J Exp Med. 1991 Apr 1;173(4):869–879. doi: 10.1084/jem.173.4.869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Creekmore S. P., Harris J. E., Ellis T. M., Braun D. P., Cohen I. I., Bhoopalam N., Jassak P. F., Cahill M. A., Canzoneri C. L., Fisher R. I. A phase I clinical trial of recombinant interleukin-2 by periodic 24-hour intravenous infusions. J Clin Oncol. 1989 Feb;7(2):276–284. doi: 10.1200/JCO.1989.7.2.276. [DOI] [PubMed] [Google Scholar]
  6. Gately M. K., Desai B. B., Wolitzky A. G., Quinn P. M., Dwyer C. M., Podlaski F. J., Familletti P. C., Sinigaglia F., Chizonnite R., Gubler U. Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor). J Immunol. 1991 Aug 1;147(3):874–882. [PubMed] [Google Scholar]
  7. Gearing D. P., Cosman D. Homology of the p40 subunit of natural killer cell stimulatory factor (NKSF) with the extracellular domain of the interleukin-6 receptor. Cell. 1991 Jul 12;66(1):9–10. doi: 10.1016/0092-8674(91)90131-h. [DOI] [PubMed] [Google Scholar]
  8. Gubler U., Chua A. O., Schoenhaut D. S., Dwyer C. M., McComas W., Motyka R., Nabavi N., Wolitzky A. G., Quinn P. M., Familletti P. C. Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4143–4147. doi: 10.1073/pnas.88.10.4143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Itoh K., Tilden A. B., Kumagai K., Balch C. M. Leu-11+ lymphocytes with natural killer (NK) activity are precursors of recombinant interleukin 2 (rIL 2)-induced activated killer (AK) cells. J Immunol. 1985 Feb;134(2):802–807. [PubMed] [Google Scholar]
  10. Kamio M., Uchiyama T., Hori T., Kodaka T., Ishikawa T., Onishi R., Uchino H., Yoneda N., Tatsumi E., Yamaguchi N. Selective expression of the p70 subunit of the interleukin-2 receptor on lymphocytes from patients with infectious mononucleosis. Blood. 1990 Jan 15;75(2):415–420. [PubMed] [Google Scholar]
  11. Kehrl J. H., Dukovich M., Whalen G., Katz P., Fauci A. S., Greene W. C. Novel interleukin 2 (IL-2) receptor appears to mediate IL-2-induced activation of natural killer cells. J Clin Invest. 1988 Jan;81(1):200–205. doi: 10.1172/JCI113295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kobayashi M., Fitz L., Ryan M., Hewick R. M., Clark S. C., Chan S., Loudon R., Sherman F., Perussia B., Trinchieri G. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989 Sep 1;170(3):827–845. doi: 10.1084/jem.170.3.827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lafreniere R., Rosenberg S. A. Successful immunotherapy of murine experimental hepatic metastases with lymphokine-activated killer cells and recombinant interleukin 2. Cancer Res. 1985 Aug;45(8):3735–3741. [PubMed] [Google Scholar]
  14. Lanier L. L., Benike C. J., Phillips J. H., Engleman E. G. Recombinant interleukin 2 enhanced natural killer cell-mediated cytotoxicity in human lymphocyte subpopulations expressing the Leu 7 and Leu 11 antigens. J Immunol. 1985 Feb;134(2):794–801. [PubMed] [Google Scholar]
  15. London L., Perussia B., Trinchieri G. Induction of proliferation in vitro of resting human natural killer cells: IL 2 induces into cell cycle most peripheral blood NK cells, but only a minor subset of low density T cells. J Immunol. 1986 Dec 15;137(12):3845–3854. [PubMed] [Google Scholar]
  16. Margolin K. A., Rayner A. A., Hawkins M. J., Atkins M. B., Dutcher J. P., Fisher R. I., Weiss G. R., Doroshow J. H., Jaffe H. S., Roper M. Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines. J Clin Oncol. 1989 Apr;7(4):486–498. doi: 10.1200/JCO.1989.7.4.486. [DOI] [PubMed] [Google Scholar]
  17. Mulé J. J., Shu S., Schwarz S. L., Rosenberg S. A. Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2. Science. 1984 Sep 28;225(4669):1487–1489. doi: 10.1126/science.6332379. [DOI] [PubMed] [Google Scholar]
  18. Nagler A., Lanier L. L., Cwirla S., Phillips J. H. Comparative studies of human FcRIII-positive and negative natural killer cells. J Immunol. 1989 Nov 15;143(10):3183–3191. [PubMed] [Google Scholar]
  19. Ozer H., Strelkauskas A. J., Callery R. T., Schlossman S. F. The functional dissection of human peripheral null cells with respect to antibody-dependent cellular cytotoxicity and natural killing. Eur J Immunol. 1979 Feb;9(2):112–118. doi: 10.1002/eji.1830090204. [DOI] [PubMed] [Google Scholar]
  20. Pestka S., Langer J. A., Zoon K. C., Samuel C. E. Interferons and their actions. Annu Rev Biochem. 1987;56:727–777. doi: 10.1146/annurev.bi.56.070187.003455. [DOI] [PubMed] [Google Scholar]
  21. Phillips J. H., Gemlo B. T., Myers W. W., Rayner A. A., Lanier L. L. In vivo and in vitro activation of natural killer cells in advanced cancer patients undergoing combined recombinant interleukin-2 and LAK cell therapy. J Clin Oncol. 1987 Dec;5(12):1933–1941. doi: 10.1200/JCO.1987.5.12.1933. [DOI] [PubMed] [Google Scholar]
  22. Phillips J. H., Lanier L. L. Dissection of the lymphokine-activated killer phenomenon. Relative contribution of peripheral blood natural killer cells and T lymphocytes to cytolysis. J Exp Med. 1986 Sep 1;164(3):814–825. doi: 10.1084/jem.164.3.814. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ritz J., Campen T. J., Schmidt R. E., Royer H. D., Hercend T., Hussey R. E., Reinherz E. L. Analysis of T-cell receptor gene rearrangement and expression in human natural killer clones. Science. 1985 Jun 28;228(4707):1540–1543. doi: 10.1126/science.2409597. [DOI] [PubMed] [Google Scholar]
  24. Robertson M. J., Caligiuri M. A., Manley T. J., Levine H., Ritz J. Human natural killer cell adhesion molecules. Differential expression after activation and participation in cytolysis. J Immunol. 1990 Nov 15;145(10):3194–3201. [PubMed] [Google Scholar]
  25. Robertson M. J., Ritz J. Biology and clinical relevance of human natural killer cells. Blood. 1990 Dec 15;76(12):2421–2438. [PubMed] [Google Scholar]
  26. Rosenberg S. A., Lotze M. T., Muul L. M., Chang A. E., Avis F. P., Leitman S., Linehan W. M., Robertson C. N., Lee R. E., Rubin J. T. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med. 1987 Apr 9;316(15):889–897. doi: 10.1056/NEJM198704093161501. [DOI] [PubMed] [Google Scholar]
  27. Rosenberg S. A., Lotze M. T., Yang J. C., Aebersold P. M., Linehan W. M., Seipp C. A., White D. E. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg. 1989 Oct;210(4):474–485. doi: 10.1097/00000658-198910000-00008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Schmidt R. E., Michon J. M., Woronicz J., Schlossman S. F., Reinherz E. L., Ritz J. Enhancement of natural killer function through activation of the T11 E rosette receptor. J Clin Invest. 1987 Jan;79(1):305–308. doi: 10.1172/JCI112800. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sondel P. M., Kohler P. C., Hank J. A., Moore K. H., Rosenthal N. S., Sosman J. A., Bechhofer R., Storer B. Clinical and immunological effects of recombinant interleukin 2 given by repetitive weekly cycles to patients with cancer. Cancer Res. 1988 May 1;48(9):2561–2567. [PubMed] [Google Scholar]
  30. Stern A. S., Podlaski F. J., Hulmes J. D., Pan Y. C., Quinn P. M., Wolitzky A. G., Familletti P. C., Stremlo D. L., Truitt T., Chizzonite R. Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6808–6812. doi: 10.1073/pnas.87.17.6808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Timonen T., Gahmberg C. G., Patarroyo M. Participation of CD11a-c/CD18, CD2 and RGD-binding receptors in endogenous and interleukin-2-stimulated NK activity of CD3-negative large granular lymphocytes. Int J Cancer. 1990 Dec 15;46(6):1035–1040. doi: 10.1002/ijc.2910460615. [DOI] [PubMed] [Google Scholar]
  32. Timonen T., Patarroyo M., Gahmberg C. G. CD11a-c/CD18 and GP84 (LB-2) adhesion molecules on human large granular lymphocytes and their participation in natural killing. J Immunol. 1988 Aug 1;141(3):1041–1046. [PubMed] [Google Scholar]
  33. Trinchieri G. Biology of natural killer cells. Adv Immunol. 1989;47:187–376. doi: 10.1016/S0065-2776(08)60664-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Trinchieri G., Matsumoto-Kobayashi M., Clark S. C., Seehra J., London L., Perussia B. Response of resting human peripheral blood natural killer cells to interleukin 2. J Exp Med. 1984 Oct 1;160(4):1147–1169. doi: 10.1084/jem.160.4.1147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Tsudo M., Goldman C. K., Bongiovanni K. F., Chan W. C., Winton E. F., Yagita M., Grimm E. A., Waldmann T. A. The p75 peptide is the receptor for interleukin 2 expressed on large granular lymphocytes and is responsible for the interleukin 2 activation of these cells. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5394–5398. doi: 10.1073/pnas.84.15.5394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wolf S. F., Temple P. A., Kobayashi M., Young D., Dicig M., Lowe L., Dzialo R., Fitz L., Ferenz C., Hewick R. M. Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immunol. 1991 May 1;146(9):3074–3081. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES