CD47 in pregnancy immune tolerance
The protection of the semi-allogeneic fetus presents a significant challenge for the maternal immune system. During pregnancy, specialized maternal macrophages are in close contact with fetally-derived trophoblast cells in the decidua and intervillous space, and participate in phagocytosis to process apoptotic trophoblast cells, cell debris, and foreign pathogens. It remains unclear; however, how allogeneic and healthy trophoblast cells evade macrophage-mediated recognition for destruction and how macrophages adopt a pro-tolerogenic phenotype. In this study, we have attempted to address these questions by testing the involvement of CD47, a cell surface-expressed immune checkpoint molecule. While CD47 is known to inhibit macrophage phagocytosis through its interaction with signal regulatory protein alpha (SIRPA) on macrophages during cancer development-a process that bears notable similarities to placentation-its significance in reproduction remains largely unexplored. Here, we have shown that CD47 expression is strong on the outer surface of the outermost layer of the chorionic villi, the syncytiotrophoblast (STB), but not the extravillous trophoblast, in first trimester human placental tissue. Blockade of the CD47-SIRPA interactions increased the capacity of THP1-macrophage to engulf STB differentiated in vitro from a human trophoblast stem cell line, CT27 (CT27-STB). The distribution pattern of CD47 was altered during staurosporine-induced apoptosis of CT27-STB, specifically showing reduced CD47 expression on the cell surface. In addition, conditioned medium from CD47-silenced CT27-STB led to upregulation of genes normally associated with interferon-mediated antiviral responses in THP1-macrophages as well as in macrophages derived from peripheral blood mononuclear cells of pregnant women. Collectively, our results reveal that cell surface CD47 protects healthy STB against macrophage phagocytosis and that factors secreted from CD47-expressing STB contribute to macrophage tolerance. These findings suggest that CD47-mediated signaling may help to balance maternal pathogen defense with protection of the allogeneic fetus.