Oral Presentation ESA-SRB-APEG-NZSE 2022

Regulatory T cells modulate uterine natural killer cell activation to promote spiral artery remodelling in mice (#221)

Shanna L Hosking 1 , Holly M Groome 1 , Hon Yeung (Dexter) Chan 1 , Ella S Green 1 , Lachlan M Moldenhauer 1 , Claire T Roberts 2 , Sandra T Davidge 3 , Sarah A Robertson 1 , Alison S Care 1
  1. Robinson Research Institute, School of Biomedicine, University of Adelaide, Adelaide, SA, Australia
  2. Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA, Australia
  3. Women and Children’s Health Research Institute, Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, AB, Canada

Early-onset preeclampsia is preceded by impaired remodelling of the decidual spiral arteries during early placentation and results in fetal growth restriction in 20-25% of cases. A specialised subset of anti-inflammatory T cells called regulatory T (Treg) cells are deficient in many women with preeclampsia. Using Foxp3-DTR mice that enable transient Treg depletion, we have shown that Treg cells are required for robust spiral artery remodelling. Uterine natural killer (uNK) cells are key drivers of spiral artery remodelling, but whether Treg cells interact with uNK cells is unknown. Here, we hypothesised that depletion of Treg cells would reduce anti-inflammatory cytokines within decidual tissue and uNK cell numbers or function would be altered. Foxp3-DTR mice were mated and given diphtheria toxin (DT) on gestational day (gd) 3.5 and 5.5 to deplete Treg cells, with vehicle-treated mice as controls. On gd 10.5, decidua were collected for cytokine gene expression analysis by qPCR and immuno-staining with Dolichos Biflorus Agglutinin (DBA) lectin to detect uNK cells. Whole uterus was analysed by flow cytometry to quantify three distinct subsets of uNK cells – tissue-resident (trNKs), conventional (cNKs), and group 1 innate lymphoid cells (ILC1s) – each of which have unique roles in angiogenesis and tissue remodelling. qPCR showed that Treg cell depletion decreased Il10 by 47% (P<0.05), Tgfb by 60% (P<0.001), and Il35 by 58% (P<0.01). DBA staining showed Treg cell depletion led to a 20% reduction in total uNK cells (P<0.001). Flow cytometry showed Treg cell depletion reduced all three uNK cell subsets, with trNKs(NK1.1+Nkp46+EOMES+CD49a+) reduced by 62%, cNKs(NK1.1+Nkp46+EOMES+CD49a-) by 43%, and ILC1s(NK1.1+Nkp46+EOMES-CD49a+) by 57% (all P<0.05). Together, these data show that Treg cell deficiency alters decidual cytokines and impairs uNK maturation, constraining uNK cell ability to facilitate spiral artery remodelling. It is therefore important to investigate Treg-uNK cell interactions in women with preeclampsia.