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

## TL;DR

IRF2 is crucial for immune defense by regulating pyroptosis and NK cell function, and its deficiency can be partially reversed with IFN-γ therapy.

## Contribution

This study identifies IRF2 as a dual regulator of inflammasome activity and NK cell maturation in vivo.

## Key findings

- IRF2 deficiency leads to impaired IFN-γ production and defective NK cell responses.
- IFN-γ therapy partially restores immune function in IRF2-deficient mice.
- IRF2 regulates GSDMD levels and is essential for NK cell maturation and antibacterial effector expression.

## Abstract

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 IRF2KO mice and demonstrate that they are equally susceptible to Francisella novicida infection as GSDMDKO mice. Interestingly, the phenotypes of IRF2KO and GSDMDKO mice diverge with respect to IFN-γ. Specifically, IRF2KO 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. IRF2KO 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 IRF2KO 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.

IRF2 regulates inflammasome activity and is essential for NK cell function. Mice deficient for IRF2 show reduced IFN-γ levels and defective NK responses, impairing bacterial clearance. IFN-γ therapy partly restores immunity.

IRF2 regulates GSDMD in vivo in both naïve and infected mice, revealing control of inflammasome-related pathways.IRF2 is essential for NK cell maturation and function.IRF2 KO disrupts immune defense by reducing NK cells and impairing effector expression, weakening resistance to F. novicida.IFN-γ supplementation restores GSDMD and improves NK cell responses, even with predominantly immature NK cells.

IRF2 regulates GSDMD in vivo in both naïve and infected mice, revealing control of inflammasome-related pathways.

IRF2 is essential for NK cell maturation and function.

IRF2 KO disrupts immune defense by reducing NK cells and impairing effector expression, weakening resistance to F. novicida.

IFN-γ supplementation restores GSDMD and improves NK cell responses, even with predominantly immature NK cells.

IRF2 regulates inflammasome activity and is essential for NK cell function. Mice deficient for IRF2 show reduced IFN-γ levels and defective NK responses, impairing bacterial clearance. IFN-γ therapy partly restores immunity.