Date of Award
Spring 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Immunobiology
First Advisor
Medzhitov, Ruslan
Abstract
During pregnancy, the maternal immune system must strike a delicate balance between immune tolerance to prevent rejection of the allogeneic fetus and immune activation to support tissue remodeling and anti-pathogen responses. From the first days of pregnancy and implantation to the development of the mature placenta, fetal trophoblasts rapidly invade the maternal uterine decidua and facilitate tissue reorganization through closely regulated mechanisms of maternal-fetal crosstalk. The extracellular matrix, and particularly the basement membrane protein laminin, is an essential mediator of this process. In this thesis, I describe a model of γδ T cells responding to viral inflammation and causing changes to the tissue microenvironment that directly influence pregnancy. This work details a previously unknown role of early placental basement membrane laminin in mediating γδ T cell-dependent neural tube defects. First, using a model of sterile antiviral immune activation in early pregnancy, I further characterize previous work demonstrating that neural tube defects are γδ T cell-dependent. I quantify changes in γδ T cell localization and Vg and Vd usage to show that after poly(I:C) injection, there is a significant increase in the number of γδ T cells in the ectoplacental cone (EPC), the region of early placental development in mice. I also find a concurrent reduction in laminin protein in the EPC after poly(I:C) and specifically, a reduction in Lamc2 by bulk and spatial RNA sequencing. I then establish an in vitro model of EPC explants to more directly interrogate the mechanism of γδ T cell action on Lamc2 production. Through quantitative immunofluorescence imaging of laminin and the Lamc2 transcription factor Cdx2, it appears that IFNγ treatment of EPC cells ex vivo leads to a reduction in laminin that is consistent with the results observed in vivo. Finally, I investigate the potential roles that Lamc2 plays in placentation that could contribute to fetal neural tube defects. Through transmission electron microscopy studies at embryonic day E9.5, I observe no mature basement membrane in the EPC, supporting the hypothesis that Lamc2 binding to its integrin receptors, rather than a solely adhesive function, provides pro-invasion and proliferation signals to fetal trophoblasts. γδ T cells responding at the maternal fetal interface after maternal antiviral immune activation produce cytokines, including IFNγ, which causes a decrease in Lamc2 production by trophoblasts, reducing the pro-invasion and survival signals that the fetus receives. By altering the essential matrix protein and pro-survival signal that is Lamc2, γδ T cells control pregnancy progression and fetal development. This work contributes to our understanding of the biology of early placental development and the role of maternal immune activation in pregnancy. Further studies expanding on this work can help improve treatments for common conditions like infertility, preeclampsia, and neural tube defects as well as help prevent negative maternal and fetal outcomes caused by viral infection during pregnancy.
Recommended Citation
Condiff, Emily Kay, "The Role of Laminin in a Model of Maternal Antiviral Immune Activation During Early Placental Development" (2023). Yale Graduate School of Arts and Sciences Dissertations. 912.
https://elischolar.library.yale.edu/gsas_dissertations/912
