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.