Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Nov 1;184(5):2043–2048. doi: 10.1084/jem.184.5.2043

The transcription factor interferon regulatory factor-1 is essential for natural killer cell function in vivo

PMCID: PMC2192896  PMID: 8920893

Abstract

The activation of natural killer (NK) cells, cytotoxic lymphocytes capable of major histocompatibility complex (MHC)-unrestricted killing and early antiviral defense, is temporally related to the increased interferon (IFN)-alpha/beta production that is seen in the viral infection of mice. Type I IFN (IFN-alpha/beta) are expressed in many cell types early after primary viral infection and have been shown to mediate resistance against a variety of viruses. In this study, the role of the transcriptional activator IFN regulatory factor-1 (IRF-1) in murine NK cell activity was assessed. IRF-1-deficient mice displayed a normal frequency of NK marker-positive cells, but exhibited greatly reduced NK cell-mediated cytotoxicity after both virus infection and stimulation with the IFN inducer polyinosinic:polycytidilic acid in vivo. In vitro, cytolytic activity in IRF-1-deficient NK cells remained defective after stimulation with IFN-beta, IL-2, and IL-12. IRF-1- deficient mice were unable to eliminate syngeneic MHC class I-negative tumor cells in vivo, and had a reduced ability to reject parental semi- allogeneic donor cells from the circulation. Thus, IRF-1 is essential for the induction of NK cell-mediated cytotoxicity and for the in vivo effector functions that are mediated by this activity.

Full Text

The Full Text of this article is available as a PDF (498.3 KB).

Selected References

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

  1. Biron C. A. Cytokines in the generation of immune responses to, and resolution of, virus infection. Curr Opin Immunol. 1994 Aug;6(4):530–538. doi: 10.1016/0952-7915(94)90137-6. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Dalton D. K., Pitts-Meek S., Keshav S., Figari I. S., Bradley A., Stewart T. A. Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science. 1993 Mar 19;259(5102):1739–1742. doi: 10.1126/science.8456300. [DOI] [PubMed] [Google Scholar]
  4. Harada H., Fujita T., Miyamoto M., Kimura Y., Maruyama M., Furia A., Miyata T., Taniguchi T. Structurally similar but functionally distinct factors, IRF-1 and IRF-2, bind to the same regulatory elements of IFN and IFN-inducible genes. Cell. 1989 Aug 25;58(4):729–739. doi: 10.1016/0092-8674(89)90107-4. [DOI] [PubMed] [Google Scholar]
  5. Harada H., Willison K., Sakakibara J., Miyamoto M., Fujita T., Taniguchi T. Absence of the type I IFN system in EC cells: transcriptional activator (IRF-1) and repressor (IRF-2) genes are developmentally regulated. Cell. 1990 Oct 19;63(2):303–312. doi: 10.1016/0092-8674(90)90163-9. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Kamijo R., Harada H., Matsuyama T., Bosland M., Gerecitano J., Shapiro D., Le J., Koh S. I., Kimura T., Green S. J. Requirement for transcription factor IRF-1 in NO synthase induction in macrophages. Science. 1994 Mar 18;263(5153):1612–1615. doi: 10.1126/science.7510419. [DOI] [PubMed] [Google Scholar]
  8. Kawakami T., Matsumoto M., Sato M., Harada H., Taniguchi T., Kitagawa M. Possible involvement of the transcription factor ISGF3 gamma in virus-induced expression of the IFN-beta gene. FEBS Lett. 1995 Jan 30;358(3):225–229. doi: 10.1016/0014-5793(94)01426-2. [DOI] [PubMed] [Google Scholar]
  9. Kimura T., Nakayama K., Penninger J., Kitagawa M., Harada H., Matsuyama T., Tanaka N., Kamijo R., Vilcek J., Mak T. W. Involvement of the IRF-1 transcription factor in antiviral responses to interferons. Science. 1994 Jun 24;264(5167):1921–1924. doi: 10.1126/science.8009222. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Kägi D., Ledermann B., Bürki K., Seiler P., Odermatt B., Olsen K. J., Podack E. R., Zinkernagel R. M., Hengartner H. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature. 1994 May 5;369(6475):31–37. doi: 10.1038/369031a0. [DOI] [PubMed] [Google Scholar]
  12. Lowin B., Hahne M., Mattmann C., Tschopp J. Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature. 1994 Aug 25;370(6491):650–652. doi: 10.1038/370650a0. [DOI] [PubMed] [Google Scholar]
  13. Magram J., Connaughton S. E., Warrier R. R., Carvajal D. M., Wu C. Y., Ferrante J., Stewart C., Sarmiento U., Faherty D. A., Gately M. K. IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses. Immunity. 1996 May;4(5):471–481. doi: 10.1016/s1074-7613(00)80413-6. [DOI] [PubMed] [Google Scholar]
  14. Matsuyama T., Kimura T., Kitagawa M., Pfeffer K., Kawakami T., Watanabe N., Kündig T. M., Amakawa R., Kishihara K., Wakeham A. Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development. Cell. 1993 Oct 8;75(1):83–97. [PubMed] [Google Scholar]
  15. Miyamoto M., Fujita T., Kimura Y., Maruyama M., Harada H., Sudo Y., Miyata T., Taniguchi T. Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-beta gene regulatory elements. Cell. 1988 Sep 9;54(6):903–913. doi: 10.1016/s0092-8674(88)91307-4. [DOI] [PubMed] [Google Scholar]
  16. Reis L. F., Ruffner H., Stark G., Aguet M., Weissmann C. Mice devoid of interferon regulatory factor 1 (IRF-1) show normal expression of type I interferon genes. EMBO J. 1994 Oct 17;13(20):4798–4806. doi: 10.1002/j.1460-2075.1994.tb06805.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Salcedo T. W., Azzoni L., Wolf S. F., Perussia B. Modulation of perforin and granzyme messenger RNA expression in human natural killer cells. J Immunol. 1993 Sep 1;151(5):2511–2520. [PubMed] [Google Scholar]
  18. 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]
  19. Williamson E., Garside P., Bradley J. A., Mowat A. M. IL-12 is a central mediator of acute graft-versus-host disease in mice. J Immunol. 1996 Jul 15;157(2):689–699. [PubMed] [Google Scholar]
  20. Xiao L., Eneroth P. H., Qureshi G. A. Nitric oxide synthase pathway may mediate human natural killer cell cytotoxicity. Scand J Immunol. 1995 Nov;42(5):505–511. doi: 10.1111/j.1365-3083.1995.tb03687.x. [DOI] [PubMed] [Google Scholar]
  21. Yokoyama W. M. Hybrid resistance and the Ly-49 family of natural killer cell receptors. J Exp Med. 1995 Aug 1;182(2):273–277. doi: 10.1084/jem.182.2.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. van den Broek M. F., Kägi D., Zinkernagel R. M., Hengartner H. Perforin dependence of natural killer cell-mediated tumor control in vivo. Eur J Immunol. 1995 Dec;25(12):3514–3516. doi: 10.1002/eji.1830251246. [DOI] [PubMed] [Google Scholar]

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

RESOURCES