The transcription factor interferon regulatory factor-1 is essential for natural killer cell function in vivo.
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.
Duncan
G S
GS
Amgen Institute, Toronto, Ontario, Canada.
Mittrücker
H W
HW
Kägi
D
D
Matsuyama
T
T
Mak
T W
TW
D000818:Animals; D000941:Antigens / Q000032:analysis; D000954:Antigens, Surface; D017690:Cell Transplantation; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006183:H-2 Antigens / Q000276:immunology; D050856:Interferon Regulatory Factor-1; D016899:Interferon-beta / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D055651:NK Cell Lectin-Like Receptor Subfamily B; D009374:Neoplasms, Experimental / Q000276:immunology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000032:analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D000941:Antigens; D000954:Antigens, Surface; D004268:DNA-Binding Proteins; D006183:H-2 Antigens; D050856:Interferon Regulatory Factor-1; D007376:Interleukin-2; C494258:Irf1 protein, mouse; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D010750:Phosphoproteins; D011506:Proteins; D014157:Transcription Factors; D018664:Interleukin-12; D016899:Interferon-beta