Enrichment of decidual CD11c + CD8 + T cells with altered immune function in early pregnancy loss

• Published in: Nature communications Vol. 16; no. 1; pp. 6678 - 19
• Main Authors: Guo, Ling, Guo, Anliang, Guo, Yaqiu, Han, Shuwen, Klein, Cameron, Chen, Zi-Jiang, Yan, Junhao, Li, Yan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.07.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 13/21; 13/31; 631/250/127/1212; 631/250/1619/554/1834/1269; 692/53/2423; 692/699/2732/1577; Abortion; Abortion, Spontaneous - immunology; Animals; Antigens; Biomarkers; Caspase 1 - metabolism; Caspase-1; CD11c antigen; CD11c Antigen - immunology; CD11c Antigen - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell activation; Cells; Cytotoxicity; Datasets; Decidua; Decidua - immunology; Embryo transfer; Embryos; Female; Fetal resorption; Flow cytometry; Granzyme B; Granzymes - metabolism; Humanities and Social Sciences; Humans; Immune response; Infertility; Interferon-gamma - metabolism; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Microenvironments; multidisciplinary; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Perforin; Prediction models; Pregnancy; Pyroptosis; Pyroptosis - immunology; Science; Science (multidisciplinary); Therapeutic targets; Trophoblasts - immunology; Trophoblasts - metabolism; Tumor necrosis factor-α; Visualization; Womens health; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-61992-8

Early pregnancy loss (EPL) is closely associated with imbalances in the maternal-foetal immune microenvironment. Here we identify CD11c + CD8 + T cells, an unconventional cytotoxic T cell subset, as significantly enriched and activated in EPL cases. These cells contribute to immune dysregulation and inhibit trophoblast invasion through secreting granzyme B, perforin, CD107a, TNF-α, and IFN-γ. Furthermore, we present an effective early prediction model for EPL, based on cytokine and cytotoxic molecule profiles of CD11c + CD8 + T cells in maternal serum, collected 12-16 days post-embryo transfer. Functional assays reveal that IFN-γ triggers trophoblast pyroptosis via the NLRP3/Caspase-1/GSDMD pathway, impairing trophoblast invasion. In vivo validation using abortion-prone mice and an anti-4-1BB antibody-induced model of CD11c + CD8 + T cell activation confirms increased embryo resorption and reduced trophoblast infiltration. These findings highlight the role of dysregulated CD11c + CD8 + T cells at the maternal-foetal interface in EPL, and suggest their potential as biomarkers and therapeutic targets for EPL-management. The maternal-foetal immune microenvironment is important in pregnancy maintenance and its dysregulation could lead to early pregnancy loss (EPL). Here authors identify unconventional CD11c + CD8 + T cells as major players in EPL immune pathology via impairing trophoblast invasion.