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. 1991 May;59(5):1709–1715. doi: 10.1128/iai.59.5.1709-1715.1991

Regulation of gamma interferon production by natural killer cells in scid mice: roles of tumor necrosis factor and bacterial stimuli.

J C Wherry 1, R D Schreiber 1, E R Unanue 1
PMCID: PMC257906  PMID: 1902195

Abstract

CB-17 scid mice exhibit a T-cell-independent but gamma interferon (IFN-gamma)-dependent immunity to Listeria monocytogenes. In this study, we analyzed the specific cellular interactions involved in this process. scid mouse-derived natural killer (NK) cells cultured with heat-killed (HK) L. monocytogenes and macrophages secreted IFN-gamma. No IFN-gamma was produced in cultures containing HK L. monocytogenes but lacking macrophages. However, medium derived from macrophages incubated with HK L. monocytogenes or other microorganisms stimulated IFN-gamma production by isolated NK cells. Treatment of macrophage-conditioned supernatants with neutralizing monoclonal anti-tumor necrosis factor (TNF) significantly reduced their capacity to stimulate NK cells to produce IFN-gamma. Yet, purified recombinant TNF-alpha by itself was unable to stimulate NK cells. Thus, TNF was necessary but not sufficient to induce maximal IFN-gamma production by NK cells. Sonicated L. monocytogenes stimulated production of IFN-gamma by NK cells that was resistant to anti-TNF. Stimulation was markedly enhanced by the addition of recombinant TNF-alpha. These studies demonstrated that activation of scid NK cells for secretion of IFN-gamma requires two signals: TNF-alpha and a second product which may be of bacterial origin and may require processing by mononuclear phagocytes. We suggest that the T-cell-independent production of IFN-gamma by NK cells provides the host with a rapid mechanism to temporarily heighten nonspecific resistance to infection until such time as T-cell-dependent sterilizing immune responses can be generated.

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Selected References

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  1. Bancroft G. J., Bosma M. J., Bosma G. C., Unanue E. R. Regulation of macrophage Ia expression in mice with severe combined immunodeficiency: induction of Ia expression by a T cell-independent mechanism. J Immunol. 1986 Jul 1;137(1):4–9. [PubMed] [Google Scholar]
  2. Bancroft G. J., Schreiber R. D., Bosma G. C., Bosma M. J., Unanue E. R. A T cell-independent mechanism of macrophage activation by interferon-gamma. J Immunol. 1987 Aug 15;139(4):1104–1107. [PubMed] [Google Scholar]
  3. Bancroft G. J., Sheehan K. C., Schreiber R. D., Unanue E. R. Tumor necrosis factor is involved in the T cell-independent pathway of macrophage activation in scid mice. J Immunol. 1989 Jul 1;143(1):127–130. [PubMed] [Google Scholar]
  4. Blanchard D. K., Friedman H., Stewart W. E., 2nd, Klein T. W., Djeu J. Y. Role of gamma interferon in induction of natural killer activity by Legionella pneumophila in vitro and in an experimental murine infection model. Infect Immun. 1988 May;56(5):1187–1193. doi: 10.1128/iai.56.5.1187-1193.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Buchmeier N. A., Schreiber R. D. Requirement of endogenous interferon-gamma production for resolution of Listeria monocytogenes infection. Proc Natl Acad Sci U S A. 1985 Nov;82(21):7404–7408. doi: 10.1073/pnas.82.21.7404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Djeu J. Y., Huang K. Y., Herberman R. B. Augmentation of mouse natural killer activity and induction of interferon by tumor cells in vivo. J Exp Med. 1980 Apr 1;151(4):781–789. doi: 10.1084/jem.151.4.781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dorshkind K., Pollack S. B., Bosma M. J., Phillips R. A. Natural killer (NK) cells are present in mice with severe combined immunodeficiency (scid). J Immunol. 1985 Jun;134(6):3798–3801. [PubMed] [Google Scholar]
  8. Fuhlbrigge R. C., Sheehan K. C., Schreiber R. D., Chaplin D. D., Unanue E. R. Monoclonal antibodies to murine IL-1 alpha. Production, characterization, and inhibition of membrane-associated IL-1 activity. J Immunol. 1988 Oct 15;141(8):2643–2650. [PubMed] [Google Scholar]
  9. Gidlund M., Orn A., Wigzell H., Senik A., Gresser I. Enhanced NK cell activity in mice injected with interferon and interferon inducers. Nature. 1978 Jun 29;273(5665):759–761. doi: 10.1038/273759a0. [DOI] [PubMed] [Google Scholar]
  10. Hackett J., Jr, Bosma G. C., Bosma M. J., Bennett M., Kumar V. Transplantable progenitors of natural killer cells are distinct from those of T and B lymphocytes. Proc Natl Acad Sci U S A. 1986 May;83(10):3427–3431. doi: 10.1073/pnas.83.10.3427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Herberman R. B., Nunn M. E., Holden H. T., Staal S., Djeu J. Y. Augmentation of natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic target cells. Int J Cancer. 1977 Apr 15;19(4):555–564. doi: 10.1002/ijc.2910190417. [DOI] [PubMed] [Google Scholar]
  13. Holmberg L. A., Springer T. A., Ault K. A. Natural killer activity in the peritoneal exudates of mice infected with Listeria monocytogenes: characterization of the natural killer cells by using a monoclonal rat anti-murine macrophage antibody (M1/70). J Immunol. 1981 Nov;127(5):1792–1799. [PubMed] [Google Scholar]
  14. Kasahara T., Hooks J. J., Dougherty S. F., Oppenheim J. J. Interleukin 2-mediated immune interferon (IFN-gamma) production by human T cells and T cell subsets. J Immunol. 1983 Apr;130(4):1784–1789. [PubMed] [Google Scholar]
  15. Lauzon R. J., Siminovitch K. A., Fulop G. M., Phillips R. A., Roder J. C. An expanded population of natural killer cells in mice with severe combined immunodeficiency (SCID) lack rearrangement and expression of T cell receptor genes. J Exp Med. 1986 Nov 1;164(5):1797–1802. doi: 10.1084/jem.164.5.1797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ojo E., Haller O., Wigzell H. Corynebacterium parvum-induced peritoneal exudate cells with rapid cytolytic activity against tumour cells are non-phagocytic cells with characteristics of natural killer cells. Scand J Immunol. 1978;8(3):215–222. doi: 10.1111/j.1365-3083.1978.tb00513.x. [DOI] [PubMed] [Google Scholar]
  17. Ortaldo J. R., Mason A. T., Gerard J. P., Henderson L. E., Farrar W., Hopkins R. F., 3rd, Herberman R. B., Rabin H. Effects of natural and recombinant IL 2 on regulation of IFN gamma production and natural killer activity: lack of involvement of the Tac antigen for these immunoregulatory effects. J Immunol. 1984 Aug;133(2):779–783. [PubMed] [Google Scholar]
  18. Reem G. H., Yeh N. H. Interleukin 2 regulates expression of its receptor and synthesis of gamma interferon by human T lymphocytes. Science. 1984 Jul 27;225(4660):429–430. doi: 10.1126/science.6429853. [DOI] [PubMed] [Google Scholar]
  19. Sheehan K. C., Ruddle N. H., Schreiber R. D. Generation and characterization of hamster monoclonal antibodies that neutralize murine tumor necrosis factors. J Immunol. 1989 Jun 1;142(11):3884–3893. [PubMed] [Google Scholar]
  20. Shellam G. R., Winterbourn V., Dawkins H. J. Augmentation of cell-mediated cytotoxicity to a rat lymphoma. III. In vitro stimulation of natural killer cells by a soluble factor. Int J Cancer. 1980 Mar 15;25(3):331–339. doi: 10.1002/ijc.2910250305. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Tartof D., Check I. J., Matutis A., Hunter R. L., Fitch F. W. Studies on stimulation of cell-mediated cytotoxicity by skin test antigens. I. Candida antigen stimulation of cell-mediated cytotoxicity in vitro correlated with the skin test response to candida antigen in vivo. J Immunol. 1980 Dec;125(6):2790–2796. [PubMed] [Google Scholar]
  23. 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]
  24. Trinchieri G., Santoli D., Dee R. R., Knowles B. B. Anti-viral activity induced by culturing lymphocytes with tumor-derived or virus-transformed cells. Identification of the anti-viral activity as interferon and characterization of the human effector lymphocyte subpopulation. J Exp Med. 1978 May 1;147(5):1299–1313. doi: 10.1084/jem.147.5.1299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Vilcek J., Henriksen-Destefano D., Siegel D., Klion A., Robb R. J., Le J. Regulation of IFN-gamma induction in human peripheral blood cells by exogenous and endogenously produced interleukin 2. J Immunol. 1985 Sep;135(3):1851–1856. [PubMed] [Google Scholar]
  26. Welsh R. M., Jr Cytotoxic cells induced during lymphocytic choriomeningitis virus infection of mice. I. Characterization of natural killer cell induction. J Exp Med. 1978 Jul 1;148(1):163–181. doi: 10.1084/jem.148.1.163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Wolfe S. A., Tracey D. E., Henney C. S. BCG-induced murine effector cells. II. Characterization of natural killer cells in peritoneal exudates. J Immunol. 1977 Sep;119(3):1152–1158. [PubMed] [Google Scholar]
  28. Ythier A., Delmon L., Reinherz E., Nowill A., Moingeon P., Mishal Z., Bohuon C., Hercend T. Proliferative responses of circulating human NK cells: delineation of a unique pathway involving both direct and helper signals. Eur J Immunol. 1985 Dec;15(12):1209–1215. doi: 10.1002/eji.1830151213. [DOI] [PubMed] [Google Scholar]

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