Hosking Shanna L, Moldenhauer Lachlan M, Tran Ha M, Chan Hon Y, Groome Holly M, Lovell Evangeline Ak, Green Ella S, O'Hara Stephanie E, Roberts Claire T, Foyle Kerrie L, Davidge Sandra T, Robertson Sarah A, Care Alison S
Robinson Research Institute and School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia.
Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia.
JCI Insight. 2024 Dec 10;10(2):e169836. doi: 10.1172/jci.insight.169836.
Regulatory T (Treg) cells are essential for maternal immune tolerance of the fetus and placenta. In preeclampsia, aberrant Treg cell tolerance is implicated, but how Treg cells affect the uterine vascular dysfunction thought to precede placental impairment and maternal vasculopathy is unclear. We used Foxp3-diphtheria toxin receptor mice to test the hypothesis that Treg cells are essential regulators of decidual spiral artery adaptation to pregnancy. Transient Treg cell depletion during early placental morphogenesis caused impaired remodeling of decidual spiral arteries, altered uterine artery function, and fewer Dolichos biflorus agglutinin+ uterine natural killer (uNK) cells, resulting in late-gestation fetal loss and fetal growth restriction. Replacing the Treg cells by transfer from wild-type donors mitigated the impact on uNK cells, vascular remodeling, and fetal loss. RNA sequencing of decidua revealed genes associated with NK cell function and placental extravillous trophoblasts were dysregulated after Treg cell depletion and normalized by Treg cell replacement. These data implicate Treg cells as essential upstream drivers of uterine vascular adaptation to pregnancy, through a mechanism likely involving phenotypic regulation of uNK cells and trophoblast invasion. The findings provide insight into mechanisms linking impaired adaptive immune tolerance and altered spiral artery remodeling, 2 hallmark features of preeclampsia.
调节性T（Treg）细胞对于母体对胎儿和胎盘的免疫耐受至关重要。在子痫前期，Treg细胞的耐受性异常，但Treg细胞如何影响被认为先于胎盘损伤和母体血管病变的子宫血管功能障碍尚不清楚。我们使用Foxp3-白喉毒素受体小鼠来检验Treg细胞是蜕膜螺旋动脉适应妊娠的关键调节因子这一假设。在早期胎盘形态发生过程中短暂耗尽Treg细胞会导致蜕膜螺旋动脉重塑受损、子宫动脉功能改变以及双花扁豆凝集素阳性子宫自然杀伤（uNK）细胞减少，从而导致妊娠晚期胎儿丢失和胎儿生长受限。通过从野生型供体转移来替换Treg细胞可减轻对uNK细胞、血管重塑和胎儿丢失的影响。对蜕膜进行RNA测序发现，Treg细胞耗尽后与NK细胞功能和胎盘绒毛外滋养层相关的基因失调，而通过Treg细胞替换可使其恢复正常。这些数据表明，Treg细胞是子宫血管适应妊娠的关键上游驱动因素，其机制可能涉及uNK细胞的表型调节和滋养层侵袭。这些发现为子痫前期的两个标志性特征——适应性免疫耐受受损和螺旋动脉重塑改变之间的联系机制提供了见解。
