Oral Presentation The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2017

Reduced progesterone signalling at implantation compromises Treg cell tolerance and impairs fetal growth and viability in later gestation (#167)

Ella S Green 1 , Lachlan M Moldenhauer 1 , Shaun R McColl 2 , Sarah A Robertson 1
  1. Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia
  2. Department of Molecular & Cellular Biology, University of Adelaide , Adelaide, SA, Australia

Implantation and early placental development require the female immune system to tolerate the genetically disparate embryo. Fetal-maternal tolerance is primarily mediated by maternal CD4+Foxp3+ regulatory T (Treg) cells. The importance of adequate Treg cell responses during pregnancy is well recognised, however the factors which control the strength and quality of this response are not defined. The pregnancy hormone, progesterone (P4), has potent immunosuppressive action. We previously demonstrated a key role for P4 in regulating Treg cell abundance and phenotype in early pregnancy. Here, we aimed to investigate the impact on the Treg cell response and pregnancy progression, of P4 suppression in early pregnancy. Low to high doses of the P4 antagonist RU486 (0.5–8.0 mg/kg) or control were administered to allogenically mated C57Bl/6 females on day 1.5 and 3.5 post-coitus (pc). All but the highest doses were insufficient to alter implantation rate measured on d9.5 pc, but all doses reduced the frequency of Treg cells in the uterus-draining lymph nodes measured by flow cytometry. A low dose of 1 mg/kg RU486 caused a 30% reduction in Treg cells. In a second cohort, females were treated with 1 mg/kg RU486 and pregnancy outcomes were measured on d18.5 pc. A 27% reduction in pregnancy rate (29/36 vs 26/49 pregnant in control and RU486-treated females, respectively; P<0.01), with an increase resorptions (P=0.0149), was observed.  Furthermore, amongst viable fetuses, mean fetal weight was reduced by 10% (P<0.001) and fetal-placental weight ratio was 9% lower, indicative of decreased placental efficiency. This work demonstrates that when P4 signalling is compromised in early pregnancy, Treg cells are reduced and this is associated with impaired fetal development in late gestation. Treg cell regulation by P4 may be essential for in the establishment and maintenance of stable, competent maternal tolerance necessary for pregnancy success.