Maternal natural killer cells drive neuroimmune disorders in offspring through aberrant secretion of extracellular...

Prenatal viral infections can lead to neurodevelopmental disorders in offspring. However, how viral-induced maternal perturbations impact fetal brain macrophages remains insufficiently clear. Here, we demonstrated that inflammatory decidual natural killer (NK) cells, triggered by viral infection-induced maternal immune activation, drove macrophage activation, neurodevelopmental disorders, and behavioral deficits in offspring. Extracellular granzyme B (GzmB), predominantly released by the maternal CD49a⁺ tissue-resident NK subset under type I interferon stimulation, crossed the maternal-fetal barrier and promoted interferon-stimulated gene (ISG)-expressing fetal macrophage accumulation and microglial activation. Targeting extracellular GzmB through the systemic administration of the serine protease inhibitor Serpina3n or genetic ablation of Gzmb in maternal NK cells mitigated neuroimmune disorders in the fetal brain. These findings suggest that exposure to a perturbed maternal milieu reprograms decidual NK cell immunity, disrupting fetal neuroimmune homeostasis and increasing offspring susceptibility to neurodevelopmental disorders later in life.