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.