Single-Cell Immune Landscape of Human Recurrent Spontaneous Abortion

Abstract

Successful pregnancy in placental mammals substantially depends on the establishment of maternal immune tolerance to the semi-allogenic fetus. Disorders in this process are tightly associated with adverse pregnancy outcomes including recurrent spontaneous abortion (RSA). However, an in-depth understanding of the disorders from the aspect of systematic and decidual immune environment in RSA remains largely lacking. In this study, we utilized single-cell RNA-sequencing to comparably analyze the cellular and molecular signatures of decidual and peripheral leukocytes in normal and RSA pregnancies at the early stage of gestation. Integrative analysis identified 22 distinct cell clusters in total, and a dramatic difference in leukocyte subsets and molecular properties in RSA cases was revealed. Specifically, the cytotoxic properties of CD8T effector, NK, and MAIT cells in peripheral blood indicated apparently enhanced immune inflammatory status, and the subpopulation proportions and ligand-receptor interactions of the decidual leukocyte subsets demonstrated preferential immune activation in RSA patients. The molecular features, spatial distribution and the developmental trajectories of five decidual NK (dNK) subsets were illustrated. The proportion of a dNK subset responsible for fetal protection was reduced, while the ratio of another dNK subset with cytotoxic and immune-active signature was significantly increased. Notably, a unique pro-inflammatory CD56+CD16+ dNK subpopulation was substantially accumulated in RSA decidua. These findings reveal a comprehensive cellular and molecular atlas of decidual and peripheral leukocytes in human early pregnancy, which provides an in-depth insight into the immune pathogenesis for early pregnancy loss.