Spatial Transcriptomics of Human Decidua Identifies Molecular Signatures in Recurrent Pregnancy Loss

Abstract The human decidua establishes immune tolerance at the maternal–fetal interface and is essential for successful embryo implantation and development. Here, we conducted a spatial transcriptomic analysis of human decidua from early pregnancies in both healthy donors and patients with recurrent pregnancy loss (RPL). Our analysis revealed two distinct spatial domains, named implantation zone (IZ) and glandular-secretory zone (GZ), corresponding to the layers of decidua compacta and spongiosa, respectively. The decidual natural killer cell subset (dNK1) and the macrophage subset (dM2), both associated with growth promotion and immune regulation, were predominantly localized in the healthy IZ but were significantly reduced in RPL patients. In contrast, cytotoxic CD8+ T cells, sparsely distributed in the healthy decidual domains, were elevated in both domains under RPL conditions. Spatial cell–cell interaction analysis indicated a broad exhibition but a marked downregulation of immunoregulatory interactions in the IZ of RPL patients. Through integrated single-cell chromatin accessibility and transcription factor occupancy analyses, we identified FOSL2 as a pivotal regulator orchestrating the spatial transformation of dNK1 cells. Decreased FOSL2 expression correlated with compromised IL-15-induced dNK1 cell transformation and diminished immunoregulatory capabilities. Our findings delineate the intricate spatial and regulatory architecture of immune tolerance within the human decidua, providing new insights into immune tolerance dysregulation in RPL.