Maternal NKG2D-mediated immune activation shapes fetal neural development

Area of Science:

• Immunology
• Neuroscience
• Developmental Biology

Background:

• Maternal immune activation (MIA) disrupts immune homeostasis at the maternal-fetal interface, impacting fetal development and potentially causing conditions like autism spectrum disorder (ASD).
• Influenza A virus (IAV) infection in pregnant women is associated with specific natural killer (NK) cell changes in the decidua basalis, including CD56dimCD16+CD49a- NK cells with increased NKG2D expression.

Purpose of the Study:

• To investigate the role of NK cells and NKG2D in MIA-induced neurodevelopmental abnormalities.
• To explore the therapeutic potential of NKG2D blockade in mitigating MIA-associated developmental issues.

Main Methods:

• Utilized mouse models of MIA induced by IAV and poly I:C.
• Analyzed NK cell populations and NKG2D expression at the maternal-fetal interface.
• Administered NKG2D blocking antibodies in poly I:C and IAV models.
• Assessed prenatal cortical development, neuronal plasticity, progenitor cell proliferation, and behavioral outcomes in offspring.

Main Results:

• MIA increased NK cell accumulation at the maternal-fetal interface with elevated NKG2D expression, persisting until late gestation.
• Dual administration of NKG2D blockade in poly I:C mice ameliorated cortical dysplasia, enhanced neuronal development, and improved ASD-like behaviors.
• Single NKG2D blockade was insufficient, while dual blockade modulated neurodevelopment-related gene expression in excitatory neurons.
• Findings were consistent in the IAV model, supporting NK cell modulation as a therapeutic strategy.

Conclusions:

• NK cells and NKG2D signaling are critical mediators of MIA-induced neurodevelopmental deficits.
• Targeting NKG2D with repeated blockade shows promise as a therapeutic strategy for maternal infection-associated neurodevelopmental disorders.