Oral Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Maternal regulatory T cell deficiency impairs adult offspring cardiometabolic health. (#224)

Evangeline A. Lovell 1 , Shanna L. Hosking 1 , Amy L. Wooldridge 2 , Rianna J. De Poi 1 , Lisa M. Nicholas 1 , Matthew Chapman 3 , Sven Y. Surikow 3 , Laura J. Parry 2 , Lachlan M. Moldenhauer 1 , Sarah A. Robertson 1 , Alison S. Care 1
  1. Robinson Research Institute and School of Biomedicine, University of Adelaide, Adelaide, SA, Australia
  2. Robinson Research Institute and School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia
  3. Cardiology Unit, Lyell McEwin Hospital, Northern Adelaide Local Health Network, Adelaide, SA, Australia

Preeclampsia and fetal growth restriction are major causes of maternal and offspring morbidity and mortality. Deficiency in immune cells called regulatory T (Treg) cells has been implicated in these conditions. Treg cells suppress maternal inflammation and immune activation and support vascular adaptations to pregnancy. Whether there is an impact of gestational deficiency in Treg cells on fetal programming of adult offspring cardiometabolic health is unknown. We evaluated in mice whether maternal Treg cell deficiency in early pregnancy impairs offspring cardiometabolic parameters, and tested whether adoptive transfer of Treg cells could mitigate these changes. Transgenic Foxp3DTR mice have FOXP3 promoter-driven expression of the human diphtheria toxin (DT) receptor, which allows depletion of FOXP3+ (Treg) cells upon DT administration. DT was injected (37.5ng/g) on gestational day (GD)3.5 and GD5.5 to deplete FOXP3+ cells; PBS-treated Foxp3DTR mice were controls. Additionally, on GD2.5 and GD4.5 mice received (i.v.) 2-4 x 105 CD4+CD25+ Treg cells (Treg-treated), CD4+CD25- conventional T cells (Tconv), or vehicle. Dams gave birth and offspring cardiometabolic health was evaluated by glucose tolerance test and echocardiography from 16-20 weeks of age. Adult male (but not female) offspring from DT-treated dams exhibited impaired glucose tolerance in adulthood (area under curve (AUC); P=0.02). Pre-treatment with Tregs but not Tconv cells in early pregnancy prevented this impairment, with AUC values like offspring from control dams (AUC; P>0.99). Global longitudinal strain, an early indicator of left ventricular systolic dysfunction, was impaired in male (P=0.001) but not female offspring, and this was mitigated by Treg cell supplementation (P<0.001). These data show that maternal Treg cell deficiency adversely affects fetal programming of cardiometabolic health in a sex-specific manner. These findings strengthen the imperative to consider Treg cells as a candidate target in inflammatory disorders of gestation, with potential to improve pregnancy outcomes and protect cardiometabolic health in offspring.