# Crosstalk between decidual natural killer cells and extravillous trophoblasts at the maternal-fetal interface: current status and future perspectives

**Authors:** Yeqi Qiu, Mingye Chen, Rong Lin, Xiaoyan Chen, Lichun He, Hui Yin, Xian Chen

PMC · DOI: 10.3389/fimmu.2025.1703156 · 2025-10-22

## TL;DR

This review explores how decidual natural killer cells and trophoblasts interact to support a healthy pregnancy by maintaining immune tolerance.

## Contribution

The paper provides an updated overview of the dynamic interactions between dNKs and EVTs at the maternal-fetal interface.

## Key findings

- dNKs influence the invasion and migration of EVTs.
- EVTs modulate the immunological functions of dNKs and the immune microenvironment.
- Understanding these interactions is crucial for reproductive medicine research and clinical applications.

## Abstract

The immune tolerance microenvironment is essential for the establishment and maintenance of pregnancy at the maternal-fetal interface. The maternal-fetal interface is a complex system containing various cells, including decidual stromal cells, lymphocytes, and trophoblasts. Decidual natural killer cells (dNKs) are the largest leukocytes and play a critical role in maintaining maternal-fetal immune tolerance and regulating the biological behaviors of extravillous trophoblasts (EVTs). Numerous studies have investigated the crosstalk between dNKs and EVTs at the maternal-fetal interface. On the one hand, dNKs can affect the invasion and migration of EVTs. On the other hand, EVTs can influence the immunological function of dNKs and the state of the maternal-fetal immune microenvironment. This review aims to summarize the most recent advancements in comprehending the phenotypes and functions of dNKs and EVTs, as well as their dynamic interactions that are crucial for the establishment and maintenance of pregnancy. Further developments in this area will greatly enhance both basic research and clinical applications in the field of reproductive medicine.

## Full-text entities

- **Genes:** EOMES (eomesodermin) [NCBI Gene 8320] {aka TBR2}, PGF (placental growth factor) [NCBI Gene 5228] {aka D12S1900, PGFL, PIGF, PLGF, PlGF-2, SHGC-10760}, CD9 (CD9 molecule) [NCBI Gene 928] {aka BTCC-1, DRAP-27, MIC3, MRP-1, TSPAN-29, TSPAN29}, NCR1 (natural cytotoxicity triggering receptor 1) [NCBI Gene 9437] {aka CD335, LY94, NK-p46, NKP46}, KLRC2 (killer cell lectin like receptor C2) [NCBI Gene 3822] {aka CD159c, NKG2-C, NKG2C}, ENTPD1 (ectonucleoside triphosphate diphosphohydrolase 1) [NCBI Gene 953] {aka ATP-DPH, ATPDase, CD39, NTPDase-1, SPG64}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, KIR2DL2 (killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2) [NCBI Gene 3803] {aka CD158B1, CD158b, NKAT-6, NKAT6, p58.2}, IL10 (interleukin 10) [NCBI Gene 3586] {aka CSIF, GVHDS, IL-10, IL10A, TGIF}, CCR1 (C-C motif chemokine receptor 1) [NCBI Gene 1230] {aka CD191, CKR-1, CKR1, CMKBR1, HM145, MIP1aR}, CXCL1 (C-X-C motif chemokine ligand 1) [NCBI Gene 2919] {aka FSP, GRO1, GROa, MGSA, MGSA-a, NAP-3}, CXCL14 (C-X-C motif chemokine ligand 14) [NCBI Gene 9547] {aka BMAC, BRAK, KEC, KS1, MIP-2g, MIP2G}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, CXCL10 (C-X-C motif chemokine ligand 10) [NCBI Gene 3627] {aka C7, IFI10, INP10, IP-10, SCYB10, crg-2}, MMP9 (matrix metallopeptidase 9) [NCBI Gene 4318] {aka CLG4B, GELB, MANDP2, MMP-9}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, KIR2DS1 (killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 1) [NCBI Gene 3806] {aka CD158H, CD158a, p50.1}, NT5E (5'-nucleotidase ecto) [NCBI Gene 4907] {aka CALJA, CD73, E5NT, NT, NT5, NTE}, TEAD3 (TEA domain transcription factor 3) [NCBI Gene 7005] {aka DTEF-1, ETFR-1, TEAD-3, TEAD5, TEF-5, TEF5}, HLA-H (major histocompatibility complex, class I, H (pseudogene)) [NCBI Gene 3136] {aka HLAHP}, HAVCR2 (hepatitis A virus cellular receptor 2) [NCBI Gene 84868] {aka CD366, HAVcr-2, KIM-3, SPTCL, TIM3, TIMD-3}, HLA-DMA (major histocompatibility complex, class II, DM alpha) [NCBI Gene 3108] {aka D6S222E, DMA, HLADM, RING6}, KLRD1 (killer cell lectin like receptor D1) [NCBI Gene 3824] {aka CD94}, STAT5A (signal transducer and activator of transcription 5A) [NCBI Gene 6776] {aka MGF, STAT5}, CSF2 (colony stimulating factor 2) [NCBI Gene 1437] {aka CSF, GMCSF}, TBX21 (T-box transcription factor 21) [NCBI Gene 30009] {aka IMD88, T-PET, T-bet, TBET, TBLYM}, CSF1 (colony stimulating factor 1) [NCBI Gene 1435] {aka CSF-1, MCSF, PG-M-CSF}, CTSS (cathepsin S) [NCBI Gene 1520], GZMA (granzyme A) [NCBI Gene 3001] {aka CTLA3, HFSP}, NCAM1 (neural cell adhesion molecule 1) [NCBI Gene 4684] {aka CD56, MSK39, NCAM}, TIGIT (T cell immunoreceptor with Ig and ITIM domains) [NCBI Gene 201633] {aka VSIG9, VSTM3, WUCAM}, HLA-C (major histocompatibility complex, class I, C) [NCBI Gene 3107] {aka D6S204, HLA-JY3, HLAC, HLC-C, MHC, PSORS1}, CCL2 (C-C motif chemokine ligand 2) [NCBI Gene 6347] {aka GDCF-2, HC11, HSMCR30, MCAF, MCP-1, MCP1}, KIR2DL3 (killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3) [NCBI Gene 3804] {aka CD158B2, CD158b, GL183, KIR-023GB, KIR-K7b, KIR-K7c}, HLA-F (major histocompatibility complex, class I, F) [NCBI Gene 3134] {aka CDA12, HLA-5.4, HLA-CDA12, HLAF}, GNLY (granulysin) [NCBI Gene 10578] {aka D2S69E, LAG-2, LAG2, NKG5, TLA519}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, JAK2 (Janus kinase 2) [NCBI Gene 3717] {aka JTK10}, KLRC1 (killer cell lectin like receptor C1) [NCBI Gene 3821] {aka CD159A, NKG2, NKG2A}, CXCR4 (C-X-C motif chemokine receptor 4) [NCBI Gene 7852] {aka CD184, D2S201E, FB22, HM89, HSY3RR, LCR1}, GJA5 (gap junction protein alpha 5) [NCBI Gene 2702] {aka ATFB11, CX40}, MMP2 (matrix metallopeptidase 2) [NCBI Gene 4313] {aka CLG4, CLG4A, MMP-2, MMP-II, MONA, TBE-1}, PLAU (plasminogen activator, urokinase) [NCBI Gene 5328] {aka ATF, BDPLT5, QPD, UPA, URK, u-PA}, CD160 (CD160 molecule) [NCBI Gene 11126] {aka BY55, NK1, NK28}, CD274 (CD274 molecule) [NCBI Gene 29126] {aka ADMIO5, B7-H, B7H1, PD-L1, PDCD1L1, PDCD1LG1}, CXCL8 (C-X-C motif chemokine ligand 8) [NCBI Gene 3576] {aka GCP-1, GCP1, IL8, LECT, LUCT, LYNAP}, CSF1R (colony stimulating factor 1 receptor) [NCBI Gene 1436] {aka BANDDOS, C-FMS, CD115, CSF-1R, CSFR, FIM2}, MYBL2 (MYB proto-oncogene like 2) [NCBI Gene 4605] {aka B-MYB, BMYB}, ITGB2 (integrin subunit beta 2) [NCBI Gene 3689] {aka CD18, LAD, LCAMB, LFA-1, MAC-1, MF17}, KIR2DL4 (killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 4) [NCBI Gene 3805] {aka CD158D, G9P, KIR-103AS, KIR-2DL4, KIR103, KIR103AS}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, KIR2DS5 (killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 5) [NCBI Gene 3810] {aka CD158G, NKAT-9, NKAT9}, STOX1 (storkhead box 1) [NCBI Gene 219736] {aka C10orf24}, KIR2DS4 (killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 4 (gene/pseudogene)) [NCBI Gene 3809] {aka CD158I, KIR-2DS4, KIR1D, KIR412, KKA3, NKAT-8}, HLA-G (major histocompatibility complex, class I, G) [NCBI Gene 3135] {aka MHC-G}, CDH1 (cadherin 1) [NCBI Gene 999] {aka Arc-1, BCDS1, CD324, CDHE, ECAD, LCAM}, FAM3C (FAM3 metabolism regulating signaling molecule C) [NCBI Gene 10447] {aka GS3786, ILEI}, SERPINE1 (serpin family E member 1) [NCBI Gene 5054] {aka PAI, PAI-1, PAI1, PLANH1}, NCR3 (natural cytotoxicity triggering receptor 3) [NCBI Gene 259197] {aka 1C7, CD337, LY117, MALS, NKp30}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}
- **Diseases:** EVTs (MESH:D014328), FGR (MESH:D005317), PE (MESH:D011225), cytotoxic (MESH:D064420), pregnancy failure (MESH:D051437), RM (MESH:D000026), placental function (MESH:D010922), postpartum hemorrhage (MESH:D006473), stillbirth (MESH:D050497), miscarriage (MESH:D000022), placenta accreta (MESH:D010921), pregnancy disorders (MESH:D011254), choriocarcinoma (MESH:D002822)
- **Chemicals:** oxygen (MESH:D010100), EVTs (-), progesterone (MESH:D011374)
- **Species:** Alocasia macrorrhizos (ape, species) [taxon 4456], Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090], Legionella sp. H (species) [taxon 66966]
- **Mutations:** Y153H
- **Cell lines:** dNK1 — Mus musculus (Mouse), Hybridoma (CVCL_C7RB), HTR-8/SVneo — Homo sapiens (Human), Transformed cell line (CVCL_7162), Bewo — Homo sapiens (Human), Gestational choriocarcinoma, Cancer cell line (CVCL_0044)

## Figures

2 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12586042/full.md

---
Source: https://tomesphere.com/paper/PMC12586042