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Type: Thesis
Title: Progesterone control of regulatory T cell abundance, phenotype and stability for pregnancy success
Author: Green, Ella Shana
Issue Date: 2020
School/Discipline: Adelaide Medical School
Abstract: Early pregnancy is characterised by adaptations in the maternal immune system to allow development of genetically disparate embryos. Maternal immune tolerance is mediated by a subset of anti-inflammatory T cells known as CD4+Foxp3+ regulatory T (Treg) cells. Absence or reduced function of Treg cells at embryo implantation causes infertility in mice and is implicated as a cause of reproductive disorders in women. 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 well understood. One candidate regulator of Treg cells is the hormone progesterone (P4). We aimed to investigate how early pregnancy P4 exposure regulates Treg cell abundance, phenotype and stability, and the significance of this for pregnancy success. The impact of a peri-implantation disruption in P4 bioavailability on the Treg cell response was investigated by administering the P4 antagonist RU486 to allogeneically mated females. At mid-gestation, a reduction in CD4+ T cells and Foxp3+ Treg cells was evident in the uterus-draining lymph nodes (udLNs) of females treated with low-dose RU486. These immune perturbations were evident at implantation, indicating a failure of normal Treg expansion following mating, suggesting that adequate P4 bioavailability from the outset of pregnancy is a requirement for robust Treg cell induction. Investigation of late-gestational outcomes revealed RU486-treated females had a reduction in pregnancy rate, and in females that retained their pregnancies, fetal growth restriction was evident. RU486-treated females additionally failed to show the normal P4 decline in late gestation, and had an extended gestation length compared to controls. As RU486 treatment perturbed the Treg cell response, we assessed the contribution of Treg cells to pregnancy success following P4 signalling disruption, by adoptively transferring Treg cells into RU486-treated females. Treg cell transfer, but not nonTreg cell transfer, improved both pregnancy rate and fetal weight in RU486 treated mice. In vitro, P4 was found to suppress IFNγ expression in Treg and T effector cells cultured under inflammatory-polarising (Th1, Th17) and non-polarising (Th0) conditions, independent of the classical P4 receptor (PR). Using a membrane-impermeable form of P4 we demonstrated that T cells have the capacity to bind P4 at the membrane, and this capacity increases in early gestation in udLN Treg cells. Finally, we investigated Treg cell stability during pregnancy using Treg cell fate-mapper Foxp3GFPCre.R26RFP mice. Preliminary results show that both Treg and exTreg cells increase in late-gestation. Whether exTreg cells are implicated in the inflammatory process of parturition and whether P4 bioavailability regulates Treg cell stability in pregnancy will be further investigated. Overall, these studies demonstrate that P4 is a key regulator of Treg cells in early pregnancy and that Treg cells are an effector mechanism of P4 action for optimal fetal viability and growth. We show that P4 is a determinant of Treg cell abundance and phenotype and suggest this regulation occurs through both direct and indirect mechanisms of action. We propose that luteal-phase and early pregnancy P4 is essential to drive a robust Treg cell response necessary for pregnancy success.
Advisor: Robertson, Sarah
Moldenhauer, Lachlan
McColl, Shaun
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2020
Keywords: Reproductive immunology
regulatory T cells
fetal maternal tolerance
Provenance: This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at:
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