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Shanna L. Hosking1, Hon Y. Chan1, Ha M. Tran1, Holly M. Groome1, Lachlan M. Moldenhauer1, Ella S. Green1, Stephanie E. O’Hara1, Claire T. Roberts2, Sandra T. Davidge3, Sarah A. Robertson1, Alison S. Care1*

1 The Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, SA 5000, Australia. 2 Flinders Health and Medical Research Institute, Flinders University, Adelaide, SA 5042, Australia. 3 Women and Children’s Health Research Institute, Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, AB, T6G 2S2, Canada

* Corresponding author: Dr Alison S. Care, Robinson Research Institute and School of Biomedicine, The University of Adelaide, South Australia, 5001, Australia.

E-mail:

Conflict of Interest Statement: The authors have declared that no conflict of interest exists

Abstract

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.