Improperly constrained inflammation at the placental-uterine interface is strongly implicated as a causal factor in preeclampsia. Inflammatory mediators and leukocytes in the decidua are key features of the underlying pathophysiology, with potential to cause uterine vascular anomalies that give rise to compromised placental function, particularly in the severe, early onet form of the disease. While uterine natural killer (uNK) cells are clearly involved, a critical question has been whether and how T cells might also contribute. Regulatory T (Treg) cells, immune-regulatory T cells that counteract inflammation and promote robust placentation, are commonly perturbed in preeclampsia, and systemic Treg cell insufficiency often precedes symptom onset. This review summarizes recent evidence from preclinical studies that collectively point to Treg cells as critical regulators of decidual spiral artery adaptation in early pregnancy, in part through modulating uNK cells. Transient depletion of Treg cells during early placental morphogenesis in mice causes fetal growth restriction and fetal loss associated with impaired remodeling of decidual spiral arteries, compromised uterine artery function, and uNK cell defects. Together with RNA sequencing data to evaluate the effects of Treg cell depletion on decidual biology, the findings provide compelling evidence to implicate Treg cells as essential upstream drivers of uterine vascular adaptation to pregnancy, through a mechanism involving regulation of uNK cells and trophoblast invasion. This new insight provides an important link between adaptive immune tolerance and spiral artery remodeling to better understand the origins of preeclampsia.
Robertson et al. (Fri,) studied this question.