Abstract
During early viral infection, activation of natural killer (NK) cells elicits the effector functions of target cell lysis and cytokine production. However, the cellular and molecular mechanisms leading to NK cell activation during viral infections are incompletely understood. In this study, using a model of acute viral infection, we investigated the mechanisms controlling cytotoxic activity and cytokine production in response to influenza (flu) virus. Analysis of cytokine receptor deficient mice demonstrated that type I interferons (IFNs), but not IL-12 or IL-18, were critical for the NK cell expression of both IFN-γ and granzyme B in response to flu infection. Further, adoptive transfer experiments revealed that NK cell activation was mediated by type I IFNs acting directly on NK cells. Analysis of signal transduction molecules showed that during flu infection, STAT1 activation in NK cells was completely dependent on direct type I IFN signaling, whereas STAT4 activation was only partially dependent. In addition, granzyme B induction in NK cells was mediated by signaling primarily through STAT1, but not STAT4, while IFN-γ production was mediated by signaling through STAT4, but not STAT1. Therefore, our findings demonstrate the importance of direct action of type I IFNs on NK cells to mount effective NK cell responses in the context of flu infection and delineate NK cell signaling pathways responsible for controlling cytotoxic activity and cytokine production.
Highlights
natural killer (NK) cells are innate lymphocytes that have potent activity for controlling viral infections through the production of cytokines and the direct killing of infected target cells [1,2,3]
Following acute i.v. flu infection, we found that both IFN-c and granzyme B expression levels in NK cells from infected wild type (WT) mice were increased compared to uninfected animals similar to the in vitro infection data at 8–12 hpi (Figures 1A and S2)
We measured the expression of the activation marker CD69 and found NK cells from flu-infected WT, IL-12R2/2 and IL-18R2/2 mice displayed increased levels of CD69, whereas CD69 levels on NK cells from infected IFNAR2/2 mice were similar to those observed for uninfected controls (Figure 1B)
Summary
NK cells are innate lymphocytes that have potent activity for controlling viral infections through the production of cytokines and the direct killing of infected target cells [1,2,3]. The importance of NK cell antiviral activity was first appreciated when an individual with high susceptibility to recurring herpesvirus infection was found to be deficient for NK cells [4]. Since this discovery, numerous studies have demonstrated strong association between NK cell activity and the control of herpesviruses, including human cytomegalovirus (CMV) in particular [1,5,6]. Much less is known about how NK cells respond to other viruses, including influenza virus, an important human pathogen that causes substantial morbidity and mortality worldwide [23]
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