Immune cellular homeostasis and its breakdown at the maternal–fetal interface

Pregnancy requires dynamic immune adaptations that balance tolerance, homeostasis, and defense at the maternal–fetal interface. Recent advances integrating findings from human placental samples with those from refined animal models now enable a detailed analysis of how cellular responses in mid and late gestation contribute to major obstetrical complications - with distinct clinical manifestations - such as preterm birth, fetal growth restriction, and pre-eclampsia. In this Opinion article we propose a unifying paradigm: the breakdown of maternal–fetal immune homeostasis. We highlight regulatory T cells and decidual macrophages as complementary regulators of antigen-specific tolerance and nonspecific homeostasis, whereas effector T cell infiltration in chronic placental inflammation and neutrophil-driven inflammation in acute chorioamnionitis exemplify pathological immune activation. Together, these examples illustrate how immune programs that sustain mid-to-late pregnancy, when dysregulated, drive pathology and open new therapeutic opportunities.