Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1984 Oct 1;160(4):1147–1169. doi: 10.1084/jem.160.4.1147

Response of resting human peripheral blood natural killer cells to interleukin 2

PMCID: PMC2187474  PMID: 6434688

Abstract

The present study shows that recombinant interleukin 2 (IL-2) purified to homogeneity induces a rapid and potent enhancement of spontaneous cytotoxicity of human peripheral blood lymphocytes. The cells mediating cytotoxicity after 18-h treatment with IL-2 have surface markers of natural killer (NK) cells and are generated from the peripheral blood subset containing spontaneous cytotoxic cells. A parallel production of gamma interferon (IFN-gamma) is induced by recombinant IL-2 (rIL-2), and NK cells appear to be the major producer cells, whereas T cells are unable to produce IFN-gamma under these experimental conditions. However, the kinetics of the enhancement of cytotoxicity are faster than those of IFN-gamma production, and monoclonal anti-IFN-gamma antibodies do not suppress this effect, making it unlikely that the IFN- gamma produced is responsible for the enhancement. The enhancement of NK cell activity induced by rIL-2 precedes any proliferative response of the lymphocytes, which is instead observed in longer-term cultures of both NK and T cells.

Full Text

The Full Text of this article is available as a PDF (1.5 MB).

Selected References

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

  1. Abo T., Balch C. M. A differentiation antigen of human NK and K cells identified by a monoclonal antibody (HNK-1). J Immunol. 1981 Sep;127(3):1024–1029. [PubMed] [Google Scholar]
  2. Abo T., Cooper M. D., Balch C. M. Postnatal expansion of the natural killer and keller cell population in humans identified by the monoclonal HNK-1 antibody. J Exp Med. 1982 Jan 1;155(1):321–326. doi: 10.1084/jem.155.1.321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Abo T., Miller C. A., Balch C. M., Cooper M. D. Interleukin 2 receptor expression by activated HNK-1+ granular lymphocytes: a requirement for their proliferation. J Immunol. 1983 Oct;131(4):1822–1826. [PubMed] [Google Scholar]
  4. Baker P. E., Gillis S., Smith K. A. Monoclonal cytolytic T-cell lines. J Exp Med. 1979 Jan 1;149(1):273–278. doi: 10.1084/jem.149.1.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Blalock J. E., Baron S., Johnson H. M., Stanton G. J. Transmission of IFN-induced activities by cell to cell communication. Tex Rep Biol Med. 1981;41:344–349. [PubMed] [Google Scholar]
  6. Clark S. C., Arya S. K., Wong-Staal F., Matsumoto-Kobayashi M., Kay R. M., Kaufman R. J., Brown E. L., Shoemaker C., Copeland T., Oroszlan S. Human T-cell growth factor: partial amino acid sequence, cDNA cloning, and organization and expression in normal and leukemic cells. Proc Natl Acad Sci U S A. 1984 Apr;81(8):2543–2547. doi: 10.1073/pnas.81.8.2543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dennert G., Yogeeswaran G., Yamagata S. Cloned cell lines with natural killer activity. Specificity, function, and cell surface markers. J Exp Med. 1981 Mar 1;153(3):545–556. doi: 10.1084/jem.153.3.545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Djeu J. Y., Stocks N., Zoon K., Stanton G. J., Timonen T., Herberman R. B. Positive self regulation of cytotoxicity in human natural killer cells by production of interferon upon exposure to influenza and herpes viruses. J Exp Med. 1982 Oct 1;156(4):1222–1234. doi: 10.1084/jem.156.4.1222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Freundlich B., Trinchieri G., Perussia B., Zurier R. B. The cytotoxic effector cells in preparations of adherent mononuclear cells from human peripheral blood. J Immunol. 1984 Mar;132(3):1255–1260. [PubMed] [Google Scholar]
  10. Grimm E. A., Mazumder A., Zhang H. Z., Rosenberg S. A. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med. 1982 Jun 1;155(6):1823–1841. doi: 10.1084/jem.155.6.1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Grimm E. A., Ramsey K. M., Mazumder A., Wilson D. J., Djeu J. Y., Rosenberg S. A. Lymphokine-activated killer cell phenomenon. II. Precursor phenotype is serologically distinct from peripheral T lymphocytes, memory cytotoxic thymus-derived lymphocytes, and natural killer cells. J Exp Med. 1983 Mar 1;157(3):884–897. doi: 10.1084/jem.157.3.884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Handa K., Suzuki R., Matsui H., Shimizu Y., Kumagai K. Natural killer (NK) cells as a responder to interleukin 2 (IL 2). II. IL 2-induced interferon gamma production. J Immunol. 1983 Feb;130(2):988–992. [PubMed] [Google Scholar]
  13. Henney C. S., Kuribayashi K., Kern D. E., Gillis S. Interleukin-2 augments natural killer cell activity. Nature. 1981 May 28;291(5813):335–338. doi: 10.1038/291335a0. [DOI] [PubMed] [Google Scholar]
  14. Hercend T., Meuer S., Brennan A., Edson M. A., Acuto O., Reinherz E. L., Schlossman S. F., Ritz J. Identification of a clonally restricted 90 kD heterodimer on two human cloned natural killer cell lines. Its role in cytotoxic effector function. J Exp Med. 1983 Nov 1;158(5):1547–1560. doi: 10.1084/jem.158.5.1547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kawase I., Brooks C. G., Kuribayashi K., Olabuenaga S., Newman W., Gillis S., Henney C. S. Interleukin 2 induces gamma-interferon production: participation of macrophages and NK-like cells. J Immunol. 1983 Jul;131(1):288–292. [PubMed] [Google Scholar]
  16. Kawase I., Brooks C. G., Kuribayashi K., Olabuenaga S., Newman W., Gillis S., Henney C. S. Interleukin 2 induces gamma-interferon production: participation of macrophages and NK-like cells. J Immunol. 1983 Jul;131(1):288–292. [PubMed] [Google Scholar]
  17. Kornbluth J., Flomenberg N., Dupont B. Cell surface phenotype of a cloned line of human natural killer cells. J Immunol. 1982 Dec;129(6):2831–2837. [PubMed] [Google Scholar]
  18. Kuribayashi K., Gillis S., Kern D. E., Henney C. S. Murine NK cell cultures: effects of interleukin-2 and interferon on cell growth and cytotoxic reactivity. J Immunol. 1981 Jun;126(6):2321–2327. [PubMed] [Google Scholar]
  19. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  20. Lanier L. L., Le A. M., Phillips J. H., Warner N. L., Babcock G. F. Subpopulations of human natural killer cells defined by expression of the Leu-7 (HNK-1) and Leu-11 (NK-15) antigens. J Immunol. 1983 Oct;131(4):1789–1796. [PubMed] [Google Scholar]
  21. Larsson E. L. Mechanism of T cell activation. II. Antigen- and lectin-dependent acquisition of responsiveness to TCGF is a nonmitogenic, active response of resting T cells. J Immunol. 1981 Apr;126(4):1323–1326. [PubMed] [Google Scholar]
  22. Leonard W. J., Depper J. M., Robb R. J., Waldmann T. A., Greene W. C. Characterization of the human receptor for T-cell growth factor. Proc Natl Acad Sci U S A. 1983 Nov;80(22):6957–6961. doi: 10.1073/pnas.80.22.6957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Malek T. R., Robb R. J., Shevach E. M. Identification of a membrane antigen that is distinct from the interleukin 2 receptor and that may be required for interleukin 2-driven proliferative responses. J Immunol. 1983 Feb;130(2):747–755. [PubMed] [Google Scholar]
  24. Merluzzi V. J., Savage D. M., Mertelsmann R., Welte K. Generation of nonspecific murine cytotoxic T cells in vitro by purified human interleukin 2. Cell Immunol. 1984 Mar;84(1):74–84. doi: 10.1016/0008-8749(84)90078-9. [DOI] [PubMed] [Google Scholar]
  25. Miyasaka N., Darnell B., Baron S., Talal N. Interleukin 2 enhances natural killing of normal lymphocytes. Cell Immunol. 1984 Mar;84(1):154–162. doi: 10.1016/0008-8749(84)90086-8. [DOI] [PubMed] [Google Scholar]
  26. Moretta A., Pantaleo G., Mingari M. C., Melioli G., Moretta L., Cerottini J. C. Assignment of human natural killer (NK)-like cells to the T cell lineage. Single allospecific T cell clones lyse specific or NK-sensitive target cells via distinct recognition structures. Eur J Immunol. 1984 Feb;14(2):121–125. doi: 10.1002/eji.1830140204. [DOI] [PubMed] [Google Scholar]
  27. Morgan D. A., Ruscetti F. W., Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science. 1976 Sep 10;193(4257):1007–1008. doi: 10.1126/science.181845. [DOI] [PubMed] [Google Scholar]
  28. Olabuenaga S. E., Brooks C. G., Gillis S., Henney C. S. Interleukin 2 is not sufficient for the continuous growth of cloned NK-like cytotoxic cell lines. J Immunol. 1983 Nov;131(5):2386–2391. [PubMed] [Google Scholar]
  29. Pearlstein K. T., Palladino M. A., Welte K., Vilcek J. Purified human interleukin-2 enhances induction of immune interferon. Cell Immunol. 1983 Aug;80(1):1–9. doi: 10.1016/0008-8749(83)90088-6. [DOI] [PubMed] [Google Scholar]
  30. Perussia B., Acuto O., Terhorst C., Faust J., Lazarus R., Fanning V., Trinchieri G. Human natural killer cells analyzed by B73.1, a monoclonal antibody blocking Fc receptor functions. II. Studies of B73.1 antibody-antigen interaction on the lymphocyte membrane. J Immunol. 1983 May;130(5):2142–2148. [PubMed] [Google Scholar]
  31. Perussia B., Lebman D., Ip S. H., Rovera G., Trinchieri G. Terminal differentiation surface antigens of myelomonocytic cells are expressed in human promyelocytic leukemia cells (HL60) treated with chemical inducers. Blood. 1981 Oct;58(4):836–843. [PubMed] [Google Scholar]
  32. Perussia B., Starr S., Abraham S., Fanning V., Trinchieri G. Human natural killer cells analyzed by B73.1, a monoclonal antibody blocking Fc receptor functions. I. Characterization of the lymphocyte subset reactive with B73.1. J Immunol. 1983 May;130(5):2133–2141. [PubMed] [Google Scholar]
  33. Perussia B., Trinchieri G. Antibody 3G8, specific for the human neutrophil Fc receptor, reacts with natural killer cells. J Immunol. 1984 Mar;132(3):1410–1415. [PubMed] [Google Scholar]
  34. Perussia B., Trinchieri G., Cerottini J. C. Functional studies of Fc receptor-bearing human lymphocytes: effect of treatment with proteolytic enzymes. J Immunol. 1979 Aug;123(2):681–687. [PubMed] [Google Scholar]
  35. Perussia B., Trinchieri G. Inactivation of natural killer cell cytotoxic activity after interaction with target cells. J Immunol. 1981 Feb;126(2):754–758. [PubMed] [Google Scholar]
  36. Perussia B., Trinchieri G., Jackson A., Warner N. L., Faust J., Rumpold H., Kraft D., Lanier L. L. The Fc receptor for IgG on human natural killer cells: phenotypic, functional, and comparative studies with monoclonal antibodies. J Immunol. 1984 Jul;133(1):180–189. [PubMed] [Google Scholar]
  37. Pross H. F., Baines M. G., Rubin P., Shragge P., Patterson M. S. Spontaneous human lymphocyte-mediated cytotoxicity against tumor target cells. IX. The quantitation of natural killer cell activity. J Clin Immunol. 1981 Jan;1(1):51–63. doi: 10.1007/BF00915477. [DOI] [PubMed] [Google Scholar]
  38. Robb R. J., Munck A., Smith K. A. T cell growth factor receptors. Quantitation, specificity, and biological relevance. J Exp Med. 1981 Nov 1;154(5):1455–1474. doi: 10.1084/jem.154.5.1455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Rosenberg S. A., Grimm E. A., McGrogan M., Doyle M., Kawasaki E., Koths K., Mark D. F. Biological activity of recombinant human interleukin-2 produced in Escherichia coli. Science. 1984 Mar 30;223(4643):1412–1414. doi: 10.1126/science.6367046. [DOI] [PubMed] [Google Scholar]
  40. Sanchez-Madrid F., Nagy J. A., Robbins E., Simon P., Springer T. A. A human leukocyte differentiation antigen family with distinct alpha-subunits and a common beta-subunit: the lymphocyte function-associated antigen (LFA-1), the C3bi complement receptor (OKM1/Mac-1), and the p150,95 molecule. J Exp Med. 1983 Dec 1;158(6):1785–1803. doi: 10.1084/jem.158.6.1785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Smith K. A. T-cell growth factor. Immunol Rev. 1980;51:337–357. doi: 10.1111/j.1600-065x.1980.tb00327.x. [DOI] [PubMed] [Google Scholar]
  42. Suzuki R., Handa K., Itoh K., Kumagai K. Natural killer (NK) cells as a responder to interleukin 2 (IL 2). I. Proliferative response and establishment of cloned cells. J Immunol. 1983 Feb;130(2):981–987. [PubMed] [Google Scholar]
  43. Teh H. S., Yu M. Activation of nonspecific killer cells by interleukin 2-containing supernatants. J Immunol. 1983 Oct;131(4):1827–1833. [PubMed] [Google Scholar]
  44. Torten M., Sidell N., Golub S. H. Interleukin 2 and stimulator lymphoblastoid cells will induce human thymocytes to bind and kill K562 targets. J Exp Med. 1982 Nov 1;156(5):1545–1550. doi: 10.1084/jem.156.5.1545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Trinchieri G., De Marchi M., Mayr W., Savi M., Ceppellini R. Lymphocyte antibody lymphocytolytic interaction (LALI) with special emphasis on HL-A. Transplant Proc. 1973 Dec;5(4):1631–1649. [PubMed] [Google Scholar]
  46. Uchiyama T., Broder S., Waldmann T. A. A monoclonal antibody (anti-Tac) reactive with activated and functionally mature human T cells. I. Production of anti-Tac monoclonal antibody and distribution of Tac (+) cells. J Immunol. 1981 Apr;126(4):1393–1397. [PubMed] [Google Scholar]
  47. Ullberg M., Jondal M. Recycling and target binding capacity of human natural killer cells. J Exp Med. 1981 Mar 1;153(3):615–628. doi: 10.1084/jem.153.3.615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Vose B. M., Riccardi C., Bonnard G. D., Herberman R. B. Limiting dilution analysis of the frequency of human T cells and large granular lymphocytes proliferating in response to interleukin 2. II. Regulatory role of interferon on proliferative and cytotoxic precursors. J Immunol. 1983 Feb;130(2):768–772. [PubMed] [Google Scholar]
  49. Weigent D. A., Stanton G. J., Johnson H. M. Interleukin 2 enhances natural killer cell activity through induction of gamma interferon. Infect Immun. 1983 Sep;41(3):992–997. doi: 10.1128/iai.41.3.992-997.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Welte K., Wang C. Y., Mertelsmann R., Venuta S., Feldman S. P., Moore M. A. Purification of human interleukin 2 to apparent homogeneity and its molecular heterogeneity. J Exp Med. 1982 Aug 1;156(2):454–464. doi: 10.1084/jem.156.2.454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. van de Griend R. J., van Krimpen B. A., Ronteltap C. P., Bolhuis R. L. Rapidly expanded activated human killer cell clones have strong antitumor cell activity and have the surface phenotype of either T gamma, T-non-gamma, or null cells. J Immunol. 1984 Jun;132(6):3185–3191. [PubMed] [Google Scholar]

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

RESOURCES