Uncovering the immune landscape of uterus-draining lymph nodes in human pregnancy 9249

Abstract Description Immunological tolerance is fundamental to the maintenance of human health, where its aberrant induction or loss has the potential to issue life-threatening consequences. During pregnancy, maternal tolerance to the genetically semi-foreign fetus is instrumental for delivery of a healthy infant. Despite this known requirement, the processes that establish immune tolerance to fetal alloantigen remain incompletely understood. Research in animal models have illustrated that immune tolerance arises through a spatially coordinated process involving lymph nodes (LNs); however, uterus-draining (ud) LNs remain understudied in the context of pregnancy. Here, we employed a 477-gene panel to construct a spatial transcriptomic atlas of udLNs during human pregnancy. Our analysis revealed an enrichment of a CD8+ Tex-like cells and a sinusoidal macrophage subset characterized by upregulated expression of immunoregulatory genes (CD163, CD5L, etc.) and the erythropoietin receptor (EPOR). Stimulation of human PBMCs with extravillous trophoblast-conditioned media induced EPOR expression on myeloid cells, demonstrating that the placental secretome can equip myeloid cells with immunoregulatory properties. In EPOR-reporter mice, we observed a similar macrophage subset emerge in pregnant mice. This has prompted ongoing experiments in which EPOR is conditionally knocked out in mature myeloid cells to deconvolute how EPOR+ macrophages modulate maternal-fetal immune tolerance and pregnancy outcomes. Funding Sources Supported by Stanford Maternal and Child Health Research Institute; Canadian Institutes of Health Research 187865. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)