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

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-α/β production that is seen in the viral infection of mice. Type 1 IFN (IFN-α/β) 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 polymosinic:polycytidilic acid in vivo. In vitro, cytolytic activity in IRF-1-deficient NK cells remained defective after stimulation with IFN-β, IL-2, and IL-12 IRF-1 deficient mice were unable to eliminate syngeneic MHC class 1-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.