A multiomic atlas reveals distinct immune landscapes in preterm and term chronic placental inflammation

Abstract

Chronic placental inflammation (CPI), an umbrella term encompassing chronic chorioamnionitis, chronic villitis, and chronic deciduitis, is associated with preterm birth (PTB), yet its cellular and molecular determinants across gestation remain poorly defined. Here, we constructed an integrated multiomic atlas of CPI by profiling placental and extraplacental tissues from preterm and term pregnancies using imaging mass cytometry, single-cell RNA sequencing, spatial transcriptomics, and T cell receptor (TCR) repertoire mining. CPI emerged as a gestational age–dependent immune continuum rather than a uniform inflammatory state. Preterm CPI was characterized by infiltration of cytotoxic CD8⁺ T cells, activated macrophages, and natural killer (NK) cells in the extraplacental membranes. In contrast, term CPI exhibited spatially confined immune niches enriched for homeostatic myeloid cells and regulatory T cells. Multiomic integration revealed active contributions from the developing fetal immune system in preterm CPI, including macrophages, T cells, and mast cells that reshaped maternal-fetal immune cross-talk. Cell-cell–communication analyses uncovered proinflammatory signaling states in preterm CPI and resolution-phase pathways in term CPI, whereas TCR repertoire profiling identified memory clonotypes with viral epitope similarity, consistent with antigen-agnostic activation. Overall, this atlas defines the cellular, spatial, and transcriptional architecture of CPI and provides a framework for translational biomarker discovery and therapeutic intervention development.