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. 1985 Nov 1;162(5):1512–1530. doi: 10.1084/jem.162.5.1512

Natural killer (NK) cell-derived hematopoietic colony-inhibiting activity and NK cytotoxic factor. Relationship with tumor necrosis factor and synergism with immune interferon

PMCID: PMC2187923  PMID: 3932579

Abstract

We characterize the natural killer (NK) cell colony-inhibiting activity (CIA) produced in supernatants from cultures of human peripheral blood lymphocytes (PBL) with NK-sensitive target cell lines, and study its relationship with NK cell-derived cytotoxic factor (NKCF). Using monoclonal antibodies (mAb) specific for NK cells or other lymphocyte populations, we unambiguously identify NK cells as the only PBL subset able to produce both NKCF and NK-CIA. We present functional and biochemical data suggesting that NKCF and NK-CIA represent the same molecule: (a) a highly significant positive correlation exists between the quantity of NKCF and NK-CIA in supernatants independently produced by different PBL subsets; (b) both NK-CIA and NKCF are induced by culture of PBL with NK-sensitive, but not with NK-insensitive cell lines, and with HLA-DR+ bone marrow cells; (c) both NKCF and NK-CIA are absorbed on the same cell lines or bone marrow cell types; (d) the two activities coelute in the same gel filtration fractions; (e) D-mannose- 6-phosphate blocks both NKCF and NK-CIA activity, and prevents their absorption by K562 cells; and (f) both NKCF and NK-CIA activity are lost after 2 d at 37 degrees C. The NK-CIA-containing preparations are devoid of antiviral activity, and antiinterferon (anti-IFN) antibodies do not block the inhibitor activity of NK-CIA. The effect of NK-CIA on day 14 (early) colony-forming units of granulocytes and macrophages (CFU-GM) is synergistic with that of IFN-gamma, and this synergy is also evident on day 7 (late) CFU-GM growth. A combination of NK-CIA and IFN-gamma suppresses late CFU-GM, at concentrations of the two lymphokines that are completely ineffective when used independently. No synergy between NK-CIA and IFN-alpha or -beta was observed, due to a direct inhibitory effect of these two IFN types on late CFU-GM. Antibodies specific for tumor necrosis factor (TNF), but not those specific for lymphotoxins, inhibit both NK-CIA and NKCF activity in the NK cell-derived supernatant. Recombinant TNF, in the range of concentrations corresponding to that of the cytotoxic activity on L-929 cells present in supernatants, mediated both NKCF and NK-CIA activity.(ABSTRACT TRUNCATED AT 400 WORDS)

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Selected References

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  1. Broxmeyer H. E., Bognacki J., Dorner M. H., de Sousa M. Identification of leukemia-associated inhibitory activity as acidic isoferritins. A regulatory role for acidic isoferritins in the production of granulocytes and macrophages. J Exp Med. 1981 Jun 1;153(6):1426–1444. doi: 10.1084/jem.153.6.1426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Broxmeyer H. E., Lu L., Platzer E., Feit C., Juliano L., Rubin B. Y. Comparative analysis of the influences of human gamma, alpha and beta interferons on human multipotential (CFU-GEMM), erythroid (BFU-E) and granulocyte-macrophage (CFU-GM) progenitor cells. J Immunol. 1983 Sep;131(3):1300–1305. [PubMed] [Google Scholar]
  3. Broxmeyer H. E., Platzer E. Lactoferrin acts on I-A and I-E/C antigen+ subpopulations of mouse peritoneal macrophages in the absence of T lymphocytes and other cell types to inhibit production of granulocyte-macrophage colony stimulatory factors in vitro. J Immunol. 1984 Jul;133(1):306–314. [PubMed] [Google Scholar]
  4. Cudkowicz G., Hochman P. S. Do natural killer cells engage in regulated reactions against self to ensure homeostasis? Immunol Rev. 1979;44:13–41. doi: 10.1111/j.1600-065x.1979.tb00266.x. [DOI] [PubMed] [Google Scholar]
  5. Degliantoni G., Perussia B., Mangoni L., Trinchieri G. Inhibition of bone marrow colony formation by human natural killer cells and by natural killer cell-derived colony-inhibiting activity. J Exp Med. 1985 May 1;161(5):1152–1168. doi: 10.1084/jem.161.5.1152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Granger G. A., Yamamoto R. S., Fair D. S., Hiserodt J. C. The human LT system. I. Physical-chemical heterogeneity of LT molecules released by mitogen activated human lymphocytes in vitro. Cell Immunol. 1978 Jul;38(2):388–402. doi: 10.1016/0008-8749(78)90069-2. [DOI] [PubMed] [Google Scholar]
  7. Gray P. W., Aggarwal B. B., Benton C. V., Bringman T. S., Henzel W. J., Jarrett J. A., Leung D. W., Moffat B., Ng P., Svedersky L. P. Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumour necrosis activity. Nature. 1984 Dec 20;312(5996):721–724. doi: 10.1038/312721a0. [DOI] [PubMed] [Google Scholar]
  8. Griffin J. D., Hercend T., Beveridge R., Schlossman S. F. Characterization of an antigen expressed by human natural killer cells. J Immunol. 1983 Jun;130(6):2947–2951. [PubMed] [Google Scholar]
  9. Hansson M., Kiessling R., Andersson B., Kärre K., Roder J. NK cell-sensitive T-cell subpopulation in thymus: inverse correlation to host NK activity. Nature. 1979 Mar 8;278(5700):174–176. doi: 10.1038/278174a0. [DOI] [PubMed] [Google Scholar]
  10. Inoue S., Ottenbreit M. J. Heterogeneity of human colony-forming cells. Blood. 1978 Feb;51(2):195–206. [PubMed] [Google Scholar]
  11. Klimpel G. R., Fleischmann W. R., Jr, Klimpel K. D. Gamma interferon (IFN gamma) and IFN alpha/beta suppress murine myeloid colony formation (CFU-C)N: magnitude of suppression is dependent upon level of colony-stimulating factor (CSF). J Immunol. 1982 Jul;129(1):76–80. [PubMed] [Google Scholar]
  12. Kurland J. I., Broxmeyer H. E., Pelus L. M., Bockman R. S., Moore M. A. Role for monocyte-macrophage-derived colony-stimulating factor and prostaglandin E in the positive and negative feedback control of myeloid stem cell proliferation. Blood. 1978 Aug;52(2):388–407. [PubMed] [Google Scholar]
  13. Lee S. H., Aggarwal B. B., Rinderknecht E., Assisi F., Chiu H. The synergistic anti-proliferative effect of gamma-interferon and human lymphotoxin. J Immunol. 1984 Sep;133(3):1083–1086. [PubMed] [Google Scholar]
  14. Leibson H. J., Gefter M., Zlotnik A., Marrack P., Kappler J. W. Role of gamma-interferon in antibody-producing responses. 1984 Jun 28-Jul 4Nature. 309(5971):799–801. doi: 10.1038/309799a0. [DOI] [PubMed] [Google Scholar]
  15. Mangan K. F., Hartnett M. E., Matis S. A., Winkelstein A., Abo T. Natural killer cells suppress human erythroid stem cell proliferation in vitro. Blood. 1984 Feb;63(2):260–269. [PubMed] [Google Scholar]
  16. Nathan C. F., Murray H. W., Wiebe M. E., Rubin B. Y. Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J Exp Med. 1983 Sep 1;158(3):670–689. doi: 10.1084/jem.158.3.670. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Pennica D., Nedwin G. E., Hayflick J. S., Seeburg P. H., Derynck R., Palladino M. A., Kohr W. J., Aggarwal B. B., Goeddel D. V. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984 Dec 20;312(5996):724–729. doi: 10.1038/312724a0. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Perussia B., Dayton E. T., Fanning V., Thiagarajan P., Hoxie J., Trinchieri G. Immune interferon and leukocyte-conditioned medium induce normal and leukemic myeloid cells to differentiate along the monocytic pathway. J Exp Med. 1983 Dec 1;158(6):2058–2080. doi: 10.1084/jem.158.6.2058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Perussia B., Dayton E. T., Lazarus R., Fanning V., Trinchieri G. Immune interferon induces the receptor for monomeric IgG1 on human monocytic and myeloid cells. J Exp Med. 1983 Oct 1;158(4):1092–1113. doi: 10.1084/jem.158.4.1092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Perussia B., Fanning V., Trinchieri G. A leukocyte subset bearing HLA-DR antigens is responsible for in vitro alpha interferon production in response to viruses. Nat Immun Cell Growth Regul. 1985;4(3):120–137. [PubMed] [Google Scholar]
  22. 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]
  23. 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]
  24. Perussia B., Trinchieri G., Lebman D., Jankiewicz J., Lange B., Rovera G. Monoclonal antibodies that detect differentiation surface antigens on human myelomonocytic cells. Blood. 1982 Feb;59(2):382–392. [PubMed] [Google Scholar]
  25. Ruff M. R., Gifford G. E. Purification and physico-chemical characterization of rabbit tumor necrosis factor. J Immunol. 1980 Oct;125(4):1671–1677. [PubMed] [Google Scholar]
  26. Stone-Wolff D. S., Yip Y. K., Kelker H. C., Le J., Henriksen-Destefano D., Rubin B. Y., Rinderknecht E., Aggarwal B. B., Vilcek J. Interrelationships of human interferon-gamma with lymphotoxin and monocyte cytotoxin. J Exp Med. 1984 Mar 1;159(3):828–843. doi: 10.1084/jem.159.3.828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Trinchieri G., Granato D., Perussia B. Interferon-induced resistance of fibroblasts to cytolysis mediated by natural killer cells: specificity and mechanism. J Immunol. 1981 Jan;126(1):335–340. [PubMed] [Google Scholar]
  29. 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]
  30. Trinchieri G., Santoli D. Anti-viral activity induced by culturing lymphocytes with tumor-derived or virus-transformed cells. Enhancement of human natural killer cell activity by interferon and antagonistic inhibition of susceptibility of target cells to lysis. J Exp Med. 1978 May 1;147(5):1314–1333. doi: 10.1084/jem.147.5.1314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Trucco M., Rovera G., Ferrero D. A novel human lymphokine that inhibits haematopoietic progenitor cell proliferation. Nature. 1984 May 10;309(5964):166–168. doi: 10.1038/309166a0. [DOI] [PubMed] [Google Scholar]
  32. Trucco M., Shaw S., Korngold R. Inhibitory effect of a human T cell hybrid factor on both cell growth and mixed lymphocyte reactivity. Correlation with class II molecule expression. J Clin Invest. 1985 Sep;76(3):1032–1041. doi: 10.1172/JCI112056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wang A. M., Creasey A. A., Ladner M. B., Lin L. S., Strickler J., Van Arsdell J. N., Yamamoto R., Mark D. F. Molecular cloning of the complementary DNA for human tumor necrosis factor. Science. 1985 Apr 12;228(4696):149–154. doi: 10.1126/science.3856324. [DOI] [PubMed] [Google Scholar]
  34. Williams T. W., Bellanti J. A. In vitro synergism between interferons and human lymphotoxin: enhancement of lymphotoxin-induced target cell killing. J Immunol. 1983 Feb;130(2):518–520. [PubMed] [Google Scholar]
  35. Williamson B. D., Carswell E. A., Rubin B. Y., Prendergast J. S., Old L. J. Human tumor necrosis factor produced by human B-cell lines: synergistic cytotoxic interaction with human interferon. Proc Natl Acad Sci U S A. 1983 Sep;80(17):5397–5401. doi: 10.1073/pnas.80.17.5397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wright S. C., Bonavida B. 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. 1982 Jul;129(1):433–439. [PubMed] [Google Scholar]
  37. Wright S. C., Bonavida B. Studies on the mechanism of natural killer cell-mediated cytotoxicity. IV. Interferon-induced inhibition of NK target cell susceptibility to lysis is due to a defect in their ability to stimulate release of natural killer cytotoxic factors (NKCF). J Immunol. 1983 Jun;130(6):2965–2968. [PubMed] [Google Scholar]
  38. Wright S. C., Weitzen M. L., Kahle R., Granger G. A., Bonavida B. Studies on the mechanism of natural killer cytotoxicity. II. coculture of human PBL with NK-sensitive or resistant cell lines stimulates release of natural killer cytotoxic factors (NKCF) selectively cytotoxic to NK-sensitive target cells. J Immunol. 1983 May;130(5):2479–2483. [PubMed] [Google Scholar]
  39. Zoumbos N. C., Djeu J. Y., Young N. S. Interferon is the suppressor of hematopoiesis generated by stimulated lymphocytes in vitro. J Immunol. 1984 Aug;133(2):769–774. [PubMed] [Google Scholar]

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