THE TRANSCRIPTION FACTOR INTERFERON REGULATORY FACTOR-I IS ESSENTIAL FOR NATURAL-KILLER-CELL FUNCTION IN-VIVO

The activation of natural killer (NK) cells, cytotoxic lymphocytes cap able of major histocompatibility complex (MHC)-unrestricted killing an d early antiviral defense, is temporally related to the increased inte rferon (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 re sistance 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 f requency 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 vitr o, cytolytic activity in IRF-1-deficient NK cells remained defective a fter 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 do nor cells from the circulation. Thus, IRF-1 is essential for the induc tion of NK cell-mediated cytotoxicity and for the in vivo effector fun ctions that are mediated by this activity.