Spatiotemporal Dynamics of NK Cell Immune Checkpoints Tim-3 and Lag-3 in Human Pregnancy: An Integrated Peripheral and Decidual Compartment Analysis.

Authors

Daojing Li, Xianhong Tong, Yanyan Yang, Fangting Lu, Zuojun Shen, Yajing Liu, Yanshi Wang

Published in

Biology of reproduction. Jun 22, 2026. Epub Jun 22, 2026.

Abstract

Pregnancy represents a unique state of immune adaptation requiring precise regulation to maintain tolerance toward the semi-allogeneic fetus. Although natural killer (NK) cells and T cells play central roles in maternal-fetal immunity, gestational stage-specific expression patterns of immune checkpoint molecules Tim-3 and Lag-3, especially regarding their soluble forms, remain poorly characterized. This study comprehensively investigates T-cell immunoglobulin and mucin domain-3 (Tim-3) and Lymphocyte-activation gene 3 (Lag-3) in maternal immune regulation by integrating peripheral blood and decidual tissue analyses. In decidual NK (dNK) cells, single-cell RNA sequencing identified four distinct subsets (dNK1, dNK2, dNK3, and proliferating NKp cells) and revealed subset-specific immune checkpoint profiles: Tim-3 was highly expressed in dNK1 and dNK2, whereas Lag-3 showed consistently low expression. Patients with recurrent pregnancy loss (RPL) exhibited significantly reduced Tim-3 expression in key dNK subsets. Gene set enrichment analysis (GSEA) of Tim-3+ dNK cells identified significant enrichment in immune-related pathways, including chemokine signaling, cytokine-cytokine receptor interaction, and apoptosis. Peripheral analyses revealed dynamic gestational changes: Tim-3+ NK cells peaked early and declined, while Tim-3+ T cells gradually increased. Soluble Tim-3 (sTim-3) levels negatively correlated with membrane-bound Tim-3 on NK cells, suggesting shedding-mediated regulation. Collectively, these findings underscore the spatial and temporal specificity of immune checkpoint regulation during pregnancy and indicate that dysregulated Tim-3 expression in both decidual and peripheral NK cells may contribute to impaired maternal-fetal immune tolerance in RPL.

PMID:
42324764
Bibliographic data and abstract were imported from PubMed on 22 Jun 2026.

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