Non-canonical innate immune regulation in pregnancy

The innate immune system has evolved complex mechanisms to protect organisms from infection, maintain tissue homeostasis, and promote tissue remodeling. The success of pregnancy depends on appropriate innate immune modulation at the feto-maternal interface and in the periphery. The mammalian innate immune system is largely driven by granulocytes and mononuclear phagocytes. Here, we explore the functional potential of myeloid cells in humans and mice, with a particular focus on pregnancy, by applying single-cell analytical tools to dissect cellular proteomic composition. We applied single-cell mass cytometry to deeply phenotype human granulocytes at the single-cell level. Basophils, one of the least abundant granulocytes, presented four distinct phenotypes. Based on their distinct protein profiles in response to in vitro stimulation, we determined two basophil subsets exhibited neutrophil-like behavior. Upon sorting these cells and studying their morphology, one of these subsets appeared to be neutrophilic, while the other exhibited a classic basophil morphology. Our findings suggest that subsets of basophils may serve roles beyond their inflammatory responses. In addition to functioning in allergic responses and pathogen clearance, granulocytes are needed for successful pregnancy. We sought to study their potential roles at the feto-maternal interface and assess their changes across mouse gestation in comparison to those of other immune cells. Our analysis revealed compartmentalized specialization of innate immune cells based on their location within the feto-maternal interface, suggesting that innate immune cells have a dominant role in mouse pregnancy beyond placentation and may function to suppress inflammatory responses at mid-gestation. Our analysis of the immune composition of the mouse uterus and lymphoid organs in non-pregnant and pregnant animals revealed dramatic changes in myeloid proliferation outside the bone marrow in pregnancy. Extramedullary myeloid proliferation is a condition typically associated with inflammatory diseases and has never been reported to occur in pregnancy. These results suggest that the feto-maternal interface increases demand for specialized, tolerogenic myeloid cells, to aid in maternal immune modulation. Uncontrolled maternal inflammatory responses during pregnancy can have deleterious consequences. Maternal infections have long been implicated in the etiology of several neuropsychiatric disorders. We hypothesized that aberrant expression of genes that function in multiple biological processes, such as in brain development, immune system, or the feto-maternal interface negatively impact pregnancy outcomes. Using a mouse model, we tested maternal deficiencies in genes associated with neuropsychiatric disorders. Two of the tested genes dramatically impacted fetal resilience to maternal inflammation. The association between traditional "brain" genes that function in pregnancy either through the maternal immune system or placentation has not been previously studied. Our findings point to genes with potential synergistic roles across organ systems that worsen disease outcomes

Keywords: Immunology.
Advisor: Bendall Sean
Palmer Theo
Blish Catherine
Galli Stephen J.
Winn Virginia