Upon viral infection interferons (IFN), including IFN-α/β and IFN-γ, constitute the first line of defense. Although IFN-γ is mostly known to play an important role during bacterial infection, it also is a key player during anti-viral responses. However, it is still largely unknown to which extent different cell types contribute to the production of protective IFN-γ in virus infections. To address the cellular origin of protective IFN-γ in vaccinia virus (VACV) infection, we created IFN-γST/ST mice, in which the IFN-γ function can be reconstituted in a Cre-dependent manner. To generate mice in which only NK cells can produce IFN-γ we intercrossed IFN-γST/ST mice with Ncr1-Cre-/+ mice. The specificity of NK cell-derived IFN-γ reconstitution was verified by ex vivo stimulation of Ncr1-Cre-/+IFN-γST/ST derived splenocytes and subsequent intracellular IFN-γ staining by FACS as well as qPCR analysis of FACS-sorted cell types. Of note, during homeostasis no detrimental effect was detected in such mice. To analyze the importance of NK cell-derived IFN-γ in vivo, C57BL/6, IFN-γST/ST, and Ncr1-Cre-/+IFN-γST/ST mice were intravenously VACV infected and survival was monitored. Interestingly, upon VACV infection NK cell-derived IFN-γ responses sufficed to promote survival and to control the virus load in infected organs. Furthermore, in VACV infected Ncr1-Cre-/+IFN-γST/ST mice two waves of IFN-γ responses were detected, which both were reduced when compared with WT mice. This NK cell-derived IFN-γ response controlled the overall cytokine milieu and modulated myeloid cell function upon VACV infection.
Taken together, our results indicate that NK cell-derived IFN-γ responses are sufficient to regulate innate and adaptive immune responses upon VACV infection und to mediate survival.