Absorption After Neural Tube Teratogenesis is Dependent on Maternal Immune Cell Function

Abstract

Abstract Introduction: Neural tube defects (NTDs), are severe malformations of the developing central nervous system. After having a pregnancy affected by NTD, the recurrence risk increases 20x. The predisposition to having children affected by NTDs has not been explained and may relate to surveillance by the maternal immune system as maternal immune cells such as NK and T cells have been shown to traffic in the fetal circulation. We hypothesized that maternal NK and T cells are necessary for selective fetal absorption after the development of an NTD. Methods: We challenged this hypothesis in an outbred murine model of valproic acid (VA)-induced fetal neural tube teratogenesis (NTT) performed of pregnant CD1 dams at E8. To evaluate protection from NTTs, maternal NK cells were selectively eliminated (mAb PK136) on E7. Maternal CD4+ and CD8+ T cells were selectively eliminated (GK1.5 and 2.43) on E6. All litters were harvested on E14 and prevalence of NTT compared between each treatment group and untreated controls. Results: The frequency of litters with VA-induced NTT was significantly higher when maternal NK cells or maternal T cells were selectively depleted compared to controls (100% and 88.2% vs 80.0%, p<0.05). Only 10% of NK depleted dams had greater than 3 late absorptions per litter and T cell depleted dams had 0% compared to controls that had 30%, p<0.05. This data shows that both cell types play a critical role in the late absorption process. Litter sizes were similar between the groups. Conclusion: These findings demonstrate that selective fetal absorption for NTT is dependent on intact maternal immune cell function. Further studies are needed to define the roles that maternal NK and T cells have in the absorption process during abnormal development.