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A multi-omic atlas reveals distinct immune landscapes in preterm and term chronic placental inflammation

Levenson, Dustyn1; Romero, Roberto2; Pique-Regi, Roger1; Xu, Yi3; Galaz, Jose4; Badhan, Riddhishrree5; Kareus, Eva3; Lee, Seungbaek3; Ino, Hajime3; Niesen, Sarah3; Monticolo, Francesco6; Shu, Jian6; Myers, Luke7; Wylie, Kristine3; Bhatti, Gaurav1; Tarca, Adi1; Gomez-Lopez, Nardhy3

Published Sep 25, 2026 on Dryad. https://doi.org/10.5061/dryad.np5hqc084

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Abstract

Chronic placental inflammation (CPI) comprises a spectrum of chronic inflammatory lesions associated with preterm birth (PTB), yet its cellular and molecular determinants across gestation remain poorly defined. Here, we constructed an integrated multi-omic atlas of CPI by profiling placental and extraplacental tissues from preterm and term pregnancies using imaging mass cytometry, single-cell RNA sequencing, spatial transcriptomics, TCR repertoire mining, and DNA methylation analysis. CPI emerged as a gestational age-dependent immune continuum rather than a uniform inflammatory state. Preterm CPI exhibited unrestricted infiltration of cytotoxic CD8⁺ T cells, activated macrophages, and NK cells forming self-amplifying inflammatory circuits in the extraplacental membranes. In contrast, term CPI exhibited spatially confined immune niches enriched for homeostatic myeloid cells and regulatory T cells, preserving maternal–fetal tolerance despite persistent inflammation. Multi-omic integration revealed active contributions from the developing fetal immune system in preterm CPI, including macrophages, T cells, and mast cells of fetal origin that reshaped maternal–fetal immune communication. Cell–cell communication analyses uncovered pro-inflammatory signaling programs in preterm CPI and resolution-phase pathways in term CPI, while TCR repertoire profiling identified memory clonotypes with viral epitope similarity, consistent with antigen-agnostic activation. Genome-wide DNA methylation analysis revealed CPI-associated epigenetic remodeling linked to developmental and neurocognitive pathways in PTB. Together, this atlas defines the cellular, spatial, and transcriptional architecture of CPI and explains how chronic inflammation drives prematurity and offspring injury, or alternatively remains compatible with term delivery, providing a framework for translational biomarker discovery and therapeutic intervention development.