Extracellular vesicles and immune response during pregnancy: A balancing act*

The mechanisms underlying maternal tolerance of the semi- or fully-allogeneic fetus are intensely investigated. Across gestation, feto-placental antigens interact with the maternal immune system locally within the trophoblast-decidual interface and distantly through shed cells and soluble molecules that interact with maternal secondary lymphoid tissues. The discovery of extracellular vesicles (EVs) as local or systemic carriers of antigens and immune-regulatory molecules has added a new dimension to our understanding of immune modulation prior to implantation, during trophoblast invasion, and throughout the course of pregnancy. New data on immune-regulatory molecules, located on EVs or within their cargo, suggest a role for EVs in negotiating immune tolerance during gestation. Lessons from the field of transplant immunology also shed light on possible interactions between feto-placentally derived EVs and maternal lymphoid tissues. These insights illuminate a potential role for EVs in major obstetrical disorders. This review provides updated information on intensely studied, pregnancy-related EVs, their cargo molecules, and patterns of fetal-placental-maternal trafficking, highlighting potential immune pathways that might underlie immune suppression or activation in gestational health and disease. Our summary also underscores the likely need to broaden the definition of the maternal-fetal interface to systemic maternal immune tissues that might interact with circulating EVs.