Fetal sex programs immune architecture and cellular differentiation at the maternal–fetal interface in early human pregnancy

Immune adaptation during pregnancy is a complex and tightly regulated process that ensures the survival of both the mother and the fetus. Disruption of this balance can lead to severe pregnancy complications, yet the mechanisms governing immune organization at the maternal–fetal interface remain incompletely understood. Although fetal sex is known to influence pregnancy outcomes, how it shapes immune development during early gestation is unclear. Here, we demonstrate that fetal sex fundamentally programs immune architecture in the human placenta and maternal decidua during the first trimester. By integrating bulk and single-cell transcriptomic analyses across human and mouse tissues, we identify coordinated sex-specific immune differentiation within both fetal and maternal compartments. Progenitor Hofbauer cells give rise to distinct macrophage states in male and female placentas, driven by sex-dependent stromal signaling rather than maternal systemic cues. Concurrently, decidual NK cells and macrophages adopt divergent regulatory and inflammatory programs, establishing distinct immune landscapes in male and female pregnancies. Cross-species analyses further reveal that these patterns arise intrinsically within the conceptus, even under identical maternal environments. Importantly, miscarriage is associated with sex-specific disruption of innate immune organization, uncovering distinct pathways of immune dysregulation in male versus female pregnancies. Together, our findings identify fetal sex as a fundamental determinant of immune development at the maternal–fetal interface and reveal how sex-specific immune programming may shape susceptibility to pregnancy complications. Brief Summary : Fetal sex shapes maternal–fetal immune interactions in early pregnancy, influencing macrophage differentiation, immune signatures, and miscarriage risk, revealing sex-specific immunological pathways and vulnerabilities.