Maternal NKG2D-mediated immune activation shapes fetal neural development

Maternal immune activation (MIA) shapes fetal growth and neurodevelopment, in part by disrupting immune homeostasis at the maternal-fetal interface, thereby contributing to developmental abnormalities such as autism spectrum disorder (ASD). In women with a history of influenza A virus (IAV) infection, we found an enrichment off CD56^dimCD16⁺CD49a^- natural killer (NK) cells displaying enhanced NKG2D expression in the decidua basalis, as assessed at delivery. Using IAV- and poly I:C-induced MIA mouse models, we demonstrated that MIA significantly increases the proportion of NK cells at the maternal-fetal interface, characterized by elevated expression of NKG2D, with this local accumulation persisting until late gestation. Importantly, in the poly I:C model, blocking maternal NKG2D through two administrations alleviated prenatal cortical dysplasia, as well as enhancing dendritic plasticity, neural progenitor cells proliferation, and the morphological and transcriptomic changes in cortical excitatory neurons, accompanied by improved ASD-like behaviors in the offspring. However, a single peripheral NKG2D blockade failed to rescue neurodevelopment retardation. In addition, NKG2D blockade through two administrations altered neurodevelopment-related gene signatures, particularly in L2-4 Itpr1-expressing excitatory neurons. Key findings were further corroborated in the IAV model, highlighting NK cell modulation as a potential therapeutic strategy for maternal infection-associated neurodevelopmental disorders.