Reframing the paradigm-rethinking placental and fetal immunity

Preterm birth (PTB), defined as delivery before 37 weeks of gestation, is a leading cause of infant mortality worldwide, with nearly 10 % of births in the U.S. being preterm. PTB leads to various complications, including respiratory, neurological, and immunological issues, along with long-term health problems. It also costs the U.S. healthcare system approximately $25 billion annually, impacting families with lost productivity and long-term care needs. Understanding fetal and placental immunity is critical in addressing PTB. The immune system plays a vital role in maternal tolerance to the fetus and fetal immune development. Research into immune cells and signaling within the placenta may help prevent complications leading to PTB. Additionally, the interaction between maternal and fetal immune systems could reveal therapeutic targets to reduce preterm labor. Although animal models, especially mice, have advanced our understanding of fetal immunity, their differences from humans limit their applicability. Human studies, particularly those examining cord blood, had shown that neonatal immune cells are naïve at birth. However closer examination of preterm infants' blood demonstrated that they exhibit memory T cells linked to preterm labor. Building on this discovery, data demonstrates that fetal memory T cells exist in numerous fetal organs including the placenta. As such, research indicates that the fetus actively shapes the immune environment within the placenta. Disruptions in this process may contribute to PTB. Future investigations into fetal trained immunity and how to improve fetal immune responses could enhance neonatal protection. Understanding immune development in utero could lead to interventions that optimize neonatal health and prevent infections.