High-resolution characterizion of immune dynamics during pregnancy

Pregnancy requires the parent and fetus to coexist for nine months despite the semi-allogeneic nature of the fetus that would otherwise prompt immune rejection. At the center of this immunological paradox lies the fetal-derived placenta, a critical interface comprised of maternal and fetal tissues. Recent and growing evidence suggests that the placenta actively prevents immune cell infiltration into the fetal compartment, creating a protective barrier for the fetus to receive the necessary gas and nutrient exchange without the dangerous immune infiltration. The immune system and placenta have a dynamic relationship across gestation to accommodate fetal growth and development. The placenta's ability to regulate immune cell access while simultaneously taking on the role of all organs for the fetus is remarkable, yet remains largely unexplained. High resolution characterization of this maternal-fetal interface is necessary to better understand the immunology of pregnancy so that we can better address its complications. While the growth of the placenta is an essential development in pregnancy, every organ system is affected in the pregnant parent. Pregnancy requires a number of anatomical and physiological changes and the degree of change is constantly adjusting to meet the needs as a single cell transitions to a fetus. Parent and fetal health depend on extensive and coordinated hormonal, metabolic, and immunological changes throughout pregnancy. While advances in detecting cell types, cell response, and genetic material in peripheral blood during pregnancy has led to the prediction of certain pregnancy complications, we are missing all of the information that is not available in circulation. High resolution characterization of how these organ systems change throughout gestation is foundational to understanding why pregnancy increases susceptibility to severe illness from flu, or why pregnancy can exacerbate one autoimmune disease while ameliorating others. Furthermore, retrospective studies have shown that systemic infections and allergy/asthma in early gestation can result in pregnancy and postnatal complications for both the fetus and the parent. Therefore, there appears to be a critical time during pregnancy when the fetus is susceptible to immune activation. Pregnancy needs to be studied both locally and systemically, and these studies will be of most value if gestation is regarded as ever-changing and its dynamics are monitored for the length of pregnancy. We first developed a gestational immune-monitoring platform with the capability of simultaneously characterizing circulating, endovascular, and tissue resident cells at the maternal-fetal interface throughout gestation, discriminating maternal and fetal contributions. Our analysis of approximately 3 million cells reveals distinct immune profiles across the endovascular and tissue compartments at the interface, and distinct immune profiles between the blood in the periphery and the endovascular compartments. Furthermore, the immune profiles were dynamic throughout gestation and responded to a systemic immune challenge in a gestationally-dependent manner. We also uncover that mononuclear phagocytes and neutrophils drive the temporal dynamics of the immune composition in the placenta with remarkably diverse populations, including PD-L1-expressing populations that have compartmental and early gestational bias. Overall, we developed a gestational immune monitoring platform that can be used to study pregnancy locally, at the maternal-fetal interface, or systemically, in the peripheral blood, throughout gestation. Our approach and accompanying datasets provide a resource for further investigation into gestational immunology and strengthens the innate immune system's regulatory role in establishing the microenvironment of early pregnancy

Keywords: Immunology.
Advisor: Bendall Sean
Palmer Theo
Martinez Olivia
Winn Virginia