Regulatory T cells promote decidual vascular remodeling by modulating uterine natural killer cells to support pregnancy in mice

Regulatory T (Treg) cells are essential for maternal immune tolerance of the fetus and placenta. In preeclampsia, aberrant Treg cell tolerance is implicated, but whether and how Treg cells affect the uterine vascular dysfunction thought to precede placental impairment and maternal vasculopathy is unclear. We utilized Foxp3 DTR 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 and altered uterine artery function, resulting in late gestation fetal loss and fetal growth restriction. Treg cell depletion impaired acquisition of the activation receptor NKp46 on uterine natural killer (uNK cells) and was associated with reduced decidual synthesis of Treg cell-derived cytokines Il35, Il10 and Tgfb implicated in modulating uNK cell phenotype. When Treg cells were replaced, the adverse impact on uNK cell abundance and phenotype, decidual spiral artery remodeling, uterine artery function, and fetal loss was mitigated. These data implicate Treg cells as essential upstream drivers of uterine vascular adaptation to pregnancy through regulation of uNK cell recruitment and activation. The findings provide a mechanism linking impaired adaptive immune tolerance and altered spiral artery remodeling, two hallmark features of preeclampsia.