Unraveling the complexity of mid-gestation placental immunity

Abstract

Maintenance of healthy pregnancy is reliant on successful balance between the fetal and maternal immune systems. Although maternal mechanisms responsible have been well studied, those used by the fetal immune system remain poorly understood. Using suspension mass cytometry and various imaging modalities, this dissertation reports a complex immune system within the mid-gestation (18-23 weeks) human placental villi (PV). Further, we identified immunosuppressive signatures in innate immune cells and antigen presenting cells that potentially maintain immune homeostasis in utero. Consistent with recent reports in other fetal organs, T cells with memory phenotypes were detected within the PV tissue and vasculature. Moreover, we determined PV T cells could be activated to upregulate CD69 and proliferate after TCR stimulation and when exposed to maternal uterine antigens. In addition, this dissertation explored the role of PV immune cells in a non-human primate model of intra-amniotic inflammation. This study showed that pregnancy-matched choriodecidua and PV have distinct immunological profiles in rhesus pregnancies. In the choriodecidua, the abundance of neutrophils, multiple populations of antigen-presenting cells, and two populations of natural killer (NK) cells changed with prenatal IA LPS exposure. In contrast, in immune cells within the PV we observed alterations in the abundance of B cells, monocytes, and CD8 T cells. Prior work has illustrated that IA inflammation leads to an increase in tumor necrosis factor alpha (TNFα) at the fetal–maternal interface. In this study, pretreatment with a TNF blockade partially reversed inflammation in the PV. Furthermore, immune cells in the PV sensed LPS during our experimental window, and subsequently activated T cells to produce proinflammatory cytokines. Moreover, this study was the first report of memory T cells in third-trimester non-human primate PV and provided evidence that manipulation of immune cells in the PV at the fetal–maternal interface should be considered as a potential therapeutic target for IA inflammation