HLA-C allotypes interactions with KIR on dNK cells (WP5580)

Homo sapiens

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In decidual NK (dNK) cells, killer-cell immunoglobulin-like receptors (KIRs) interact with HLA-C allotypes on extravillous trophoblast (EVT) cells to modulate immune responses at the maternal–fetal interface. Inhibitory KIRs transmit signals through immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which recruit SHP-1 and SHP-2 phosphatases to suppress activation pathways. Conversely, activating KIRs signal via the adaptor protein DAP12, whose ITAM motifs recruit SYK kinase, leading to downstream activation of LAT, SLP-76, VAV1, PLC-γ1, and NF-κB. This cascade promotes cytokine production and functional activation of dNK cells. Additionally, KIR signaling has been linked to repeated pregnancy loss (RPL), suggesting coordination between immune signaling and placental development mediated by dNK cells. The exact origin of dNK cells (phenotype CD56⁺⁺ (bright) CD16⁻) is still uncertain. Some studies suggest they may arise from CD34⁺ progenitor cells, while others propose that peripheral blood NK (pbNK) cells or local NK precursors give rise to uterine NK (uNK) cells. These uNK cells may then differentiate into either endometrial NK (eNK) cells, which are present before pregnancy, or decidual NK (dNK) cells, which appear during early pregnancy.

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Authors

Johidi Rog , Denise Slenter , and Egon Willighagen

Activity

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Organisms

Homo sapiens

Communities

Annotations

Pathway Ontology

altered tumor necrosis factor mediated signaling pathway tumor necrosis factor superfamily mediated signaling pathway signaling pathway

Disease Ontology

female reproductive system disease

Cell Type Ontology

Participants
Query Drugst.One

Label Type Compact URI Comment
HLA-C Protein uniprot:P10321
GM-CSF Protein uniprot:P04141 Enhances trophoblast motility
Transwell assays with conditioned media
DAG Protein uniprot:P17252
SLP-76 Protein uniprot:Q13094
IFN-γ Protein uniprot:P01579 Robustly produced following activating KIR engagement.
IFN-γ inhibits trophoblast invasion by inducing apoptosis and suppressing protease activity
Transcriptome profiling via microarray
Syk Protein uniprot:P43405
NLRP2 Protein uniprot:Q9NX02 Expression: Differentially expressed (significant) Measurement: RNA-seq Role: upstream regulator of HLA-C Source: GSE241792 (ELF3/NLRP7 KO vs WT)
PLC-γ1 Protein uniprot:P19174
VAV1 Protein uniprot:P15498
SHP-1 Protein uniprot:P29350
SHP-2 Protein uniprot:P17706
PKC Protein uniprot:Q04759
TNF-α Protein uniprot:P01375 Via its action on endometrial stromal cells, TNF-α can also indirectly promote trophoblast invasion by creating a supportive inflammatory environment
Elevated TNF-α impairs trophoblast migration and invasion
This duality highlights the importance of tightly regulated TNF-α signaling for successful implantation and placental development
KIR2DL1 Protein uniprot:P43626 Cytoplasmic tail contains ITIM motif
ELF3 Protein uniprot:Q5SR36 Expression: Differentially expressed Measurement: RNA-seq Role: Transcription factor that may regulate HLA-C Source: GSE241792 (ELF3/NLRP7 KO vs WT)
FYN Protein uniprot:P06241
LAT Protein uniprot:O43561
RAC1 Protein uniprot:P63000
NLRP7 Protein uniprot:Q8WX94 Expression: Differentially expressed (significant) Measurement: RNA-seq Role: upstream regulator of HLA-C Source: GSE241792 (ELF3/NLRP7 KO vs WT)
IP3 Protein uniprot:Q14643
DAP12 Protein uniprot:O43914 Contains immunoreceptor tyrosine-based activation motif (ITAM)
KIR2DL2 Protein uniprot:P43627
KIR2DS1 Protein uniprot:Q14954
KIR2DL3 Protein uniprot:P43628

References

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