IRF2 deficiency disrupts pyroptosis, NK cell interferon-γ production and resistance to Francisella

IRF2 plays an indirect role in inflammasome activation by regulating Caspase-4 and Gasdermin D (GSDMD) levels. However, the in vivo relevance of this regulatory circuit is unknown. We generate IRF2^KO mice and demonstrate that they are equally susceptible to Francisella novicida infection as GSDMD^KO mice. Interestingly, the phenotypes of IRF2^KO and GSDMD^KO mice diverge with respect to IFN-γ. Specifically, IRF2^KO mice exhibit a profound defect in IFN-γ production, which we attribute to an intrinsic role of IRF2 in regulating both the number and maturation of NK cells. IRF2^KO NK cells fail to express the antibacterial effectors IL-18R and Granzyme A, thereby impairing bacterial clearance. IFN-γ therapy partially restores immune responses in IRF2^KO mice and resistance to infection. These findings confirm IRF2 as a dual regulator of inflammasome activity and NK cell function, highlighting its pivotal role in innate immunity. Moreover, they underscore the potential of IFN-γ therapy as a promising treatment for severe infections in patients with primary immunodeficiencies affecting multiple immune pathways.