dNK3 cells in normal pregnancy and recurrent pregnancy loss: from molecular identity to functional imbalance

Background Decidual natural killer (dNK) cells constitute approximately 70% of first-trimester decidual leukocytes and play critical roles in immune tolerance, angiogenesis, and trophoblast invasion. Single-cell RNA sequencing has revealed substantial heterogeneity within the dNK population, identifying three major subsets—dNK1, dNK2, and dNK3—with distinct transcriptomic profiles and predicted functions. dNK3 Characteristics: dNK3 cells are characterized by a CD160 + KLRB1 + CD103 + CD39 − surface phenotype, T-bet-high/Eomes-intermediate transcription factor profile, and phenotypic resemblance to intraepithelial type 1 innate lymphoid cells (ieILC1). These cells demonstrate the highest effector capacity among dNK subsets, producing multiple cytokines (CCL5, XCL1, IFN-γ, GM-CSF) following stimulation. Predicted ligand-receptor interactions include CCL5–CCR1 with extravillous trophoblasts, XCL1–XCR1 with dendritic cells, and inhibitory axes through KLRB1–CLEC2D and TIGIT–PVR. Notably, dNK3 abundance undergoes dynamic changes across gestation and shows distinct spatial distribution within decidual compartments. Clinical relevance Multiple independent studies have identified a reproducible dNK1-down/dNK3-up shift in recurrent pregnancy loss (RPL), with dNK3 cells showing IFNG upregulation at chromatin, transcriptional, and protein levels. This subset imbalance positions the dNK1/dNK3 ratio as a candidate diagnostic biomarker and identifies potential therapeutic targets including M-CSF supplementation, TGF-β pathway modulation, and iPSC-derived dNK cell therapy. Conclusions While dNK3 represents a promising focus for reproductive immunology and RPL, the current evidence base remains insufficient for clinical translation. Critical questions regarding causality, cross-study comparability, and the dNK3/ieILC1 developmental relationship require resolution through prospective cohorts and rigorous functional validation.