The maternal-fetal interface as an immunological barrier: Structure, regulation, and breakdown

Eva Kareus; Dustyn Levenson; Seungbaek Lee; Nardhy Gomez-Lopez

doi:10.1016/j.celrep.2026.117164

The maternal-fetal interface as an immunological barrier: Structure, regulation, and breakdown

Cell Rep. 2026 Mar 26;45(4):117164. doi: 10.1016/j.celrep.2026.117164. Online ahead of print.

Authors

Eva Kareus¹, Dustyn Levenson², Seungbaek Lee³, Nardhy Gomez-Lopez⁴

Affiliations

¹ Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA; Center for Reproductive Health Sciences, Department of Obstetrics and Gynecology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.
² Center for Reproductive Health Sciences, Department of Obstetrics and Gynecology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA; Wayne State University School of Medicine, Detroit, MI 48201, USA.
³ Center for Reproductive Health Sciences, Department of Obstetrics and Gynecology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.
⁴ Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA; Center for Reproductive Health Sciences, Department of Obstetrics and Gynecology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA. Electronic address: nardhy@wustl.edu.

PMID: 41903132
DOI: 10.1016/j.celrep.2026.117164

Abstract

The maternal-fetal interface is a specialized immunological barrier composed of the decidua, the intervillous space, and the fetal membranes, each forming distinct sites of the maternal-fetal interaction. Across gestation, these compartments coordinate tolerance to the semi-allogeneic fetus, antimicrobial defense, and the inflammatory signaling required for labor. This review integrates human and murine studies to describe how immune populations function within this barrier. Early gestation depends on macrophages, regulatory T cells, and uterine natural killer cells to support implantation and vascular remodeling. Mid- and late gestation feature sustained Treg activity, homeostatic macrophages, Hofbauer cells, and reduced, tolerogenic dendritic cells that together maintain immune quiescence. Near term, a programmed shift toward inflammation facilitates parturition, with exhausted decidual T cells acting as restrained modulators. Finally, we discuss chronic placental inflammation as a breach of the maternal-fetal barrier, characterized by maternal T cell infiltration into fetal tissues and acquisition of cytotoxic effector phenotypes.

Keywords: CP: immunology; T cells; decidua; fetus; immune cells; placenta; pregnancy; tolerance.

Publication types

Review