Kai Wang,Shufen Zhang,Yunxia Wang,Xiaomei Wu,Lijuan Wen,Tingting Meng,Xiangyu Jin,Sufen Li,Yiling Hong,Jia Ke,Yichong Xu,Hong Yuan,Fuqiang Hu
Background and purpose Neurodevelopmental disorders (NDDs) are characterized by abnormalities in brain development and neurobehaviors, including autism. The maternal–fetal interface (MFI) is a highly specialized tissue through which maternal factors affect fetal brain development. However, limited research exists on restoring and maintaining MFI homeostasis and its potential impact on NDDs. This study explores the role of placental indoleamine 2,3-dioxygenase (IDO-1) in MFI homeostasis and fetal brain development. Experimental Approach The maternal-fetal barrier was disrupted by sodium valproate (VPA) in pregnant mice, whose offspring show typical autism-like behaviors. Ultrastructural analysis and flow cytometric analysis were conducted to observe the morphological and immune system changes. Behavioral tests and immunofluorescence staining was used to investigate the ability and mechanism of taprenepag to alleviate the abnormal behaviors of VPA-exposed offspring and normalize the development of serotonergic neurons. Key results In VPA-exposed pregnant mice, the downregulation of IDO-1 led to maternal immune overactivation and disruption of maternal-fetal barrier, resulting in excessive 5-HT synthesis in the placenta. This process disrupted the development of the serotonergic neuronal system in the offspring, resulting in impaired development of serotonergic neurons, thalamocortical axons, and NDDs in the progeny. However, a single injection of taprenepag at E13.5 ultimately upregulated placental IDO-1 through amplifying the positive feedback loop COX-2/PGE 2 /PTGER-2/IDO-1 and abolished these alterations. Conclusion Taprenepag improved autism-like behaviors in the offspring of VPA-exposed mice by addressing placental IDO-1 downregulation. This study highlights the potential of targeting IDO-1 to mitigate MFI disruption and NDD development. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-024-03300-7.
Decidual CD8 + T (dCD8 + T) cells are pivotal in the maintenance of the delicate balance between immune tolerance towards the fetus and immune resistance against pathogens. The endometrium and decidua represent uterine environments before and during pregnancy, respectively, and the composition and phenotypic alterations of uterine CD8 + T cells in these tissues remain unclear. Using flow cytometry and analysis of transcriptome profiles, we demonstrated that human dCD8 + T and endometrial CD8 + T (eCD8 + T) cells exhibited similar T cell differentiation statuses and phenotypes of tissue infiltrating or residency, compared to peripheral CD8 + T (pCD8 + T) cells. However, dCD8 + T cells showed decreased expression of coinhibitory (PD-1), chemotaxis (CXCR3), and tissue-resident (CD69 and CD103) markers and increased granzyme B and granulysin expression compared to eCD8 + T cells. In vitro, cytotoxicity assays demonstrated greater effector functions in dCD8 + T cells than in eCD8 + T cells. Further in vitro and in vivo chemotaxis assays confirmed the recruitment of non-resident effector memory T cell subsets to the pregnant decidua, contributing to the dCD8 + T cell-mediated anti-infection mechanism at the maternal-fetal interface. This work demonstrated dCD8 + T cells replenished from the circulation retained their cytotoxic capacity, which may serve as an enhanced defense mechanism against infection during pregnancy.
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