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 miscarriage (RM). However, an in-depth understanding of the systematic and decidual immune environment in RM remains largely lacking. In this study, we utilized single-cell RNA-sequencing (scRNA-seq) to comparably analyze the cellular and molecular signatures of decidual and peripheral leukocytes in normal and unexplained RM pregnancies at the early stage of gestation. Integrative analysis identifies 22 distinct cell clusters in total, and a dramatic difference in leukocyte subsets and molecular properties in RM cases is revealed. Specifically, the cytotoxic properties of CD8+ effector T cells, nature killer (NK), and mucosal-associated invariant T (MAIT) cells in peripheral blood indicates apparently enhanced pro-inflammatory status, and the population proportions and ligand–receptor interactions of the decidual leukocyte subsets demonstrate preferential immune activation in RM patients. The molecular features, spatial distribution, and the developmental trajectories of five decidual NK (dNK) subsets have been elaborately illustrated. In RM patients, a dNK subset that supports embryonic growth is diminished in proportion, while the ratio of another dNK subset with cytotoxic and immune-active signature is significantly increased. Notably, a unique pro-inflammatory CD56+CD16+ dNK subset substantially accumulates in RM decidua. These findings reveal a comprehensive cellular and molecular atlas of decidual and peripheral leukocytes in human early pregnancy and provide an in-depth insight into the immune pathogenesis for early pregnancy loss.
研究问题： 不明原因复发性流产（RM）的免疫适应性调节是否存在异常，免疫微环境的破坏主要由哪些免疫细胞造成？? 研究方法： 通过10X Genomics单细胞测序分析、流式分选、免疫荧光等技术，构建了不明原因复发性流产患者的蜕膜及外周血中免疫细胞的单细胞转录组图谱，系统比较了复发流产和正常妊娠免疫细胞亚群分布及分子特性的差异；通过拟时分析推演了蜕膜dNK细胞亚群的发育轨迹。进而利用扩大的临床样本验证了不明原因复发流产患者蜕膜中dNK细胞亚群比例的变化。 ? 主要结果1： RM患者外周血中多个T细胞亚群和NK细胞亚群比例发生改变，综合表现为免疫炎性激活状态。? 主要结果2： RM患者蜕膜局部CD4+和CD8+ T细胞及dNK细胞亚群比例及细胞间互作模式呈现免疫耐受-免疫激活失衡的状态。? 主要结果3： 推演了dNK细胞的发育轨迹，证明dNK1亚群处于发育早期阶段，具有发育为其它dNK亚群的潜能。? 主要结果4： 部分RM患者蜕膜中dNK4细胞亚群比例的显著增高，提示其NK细胞的募集和训导分化异常，并预示了不良妊娠结局的记忆机制。





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