ArticlePloS one2016
Tim-3 Is Upregulated in NK Cells during Early Pregnancy and Inhibits NK Cytotoxicity toward Trophoblast in Galectin-9 Dependent Pathway.
Article in PloS one, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 86 citations in OpenAlex.
- Trial
- Inflammation at the Maternal-Fetal Interface: Mechanisms Linking Maternal-Fetal Immunity to Preeclampsia and Fetal Growth Restriction.International journal of molecular sciences · 2026Review
- Dual Role of Natural Killer Cells in Early Pregnancy: Immunopathological Implications and Therapeutic Potential in Recurrent Spontaneous Abortion and Recurrent Implantation Failure.Cell proliferation · 2025Review
- Role of galectin-9 in the development of gestational diabetes mellitus.Scientific reports · 2025Article
- Investigation of TIGIT, PVRIG, CD112 and CD155 expression in early and late onset preeclampsia.Journal of molecular histology · 2025Article
- JEG-3 Trophoblast Cells Influence ILC-like Transformation of NK Cells In Vitro.International journal of molecular sciences · 2025Article
- The Placenta as an Immunological Environment.British journal of biomedical science · 2025Review
- Involvement of Tim-3 in Maternal-fetal Tolerance: A Review of Current Understanding.International journal of biological sciences · 2025Review
- Dichotomous outcomes of TNFR1 and TNFR2 signaling in NK cell-mediated immune responses during inflammation.Nature communications · 2024Article
- Surface Immune Checkpoints as Potential Biomarkers in Physiological Pregnancy and Recurrent Pregnancy Loss.International journal of molecular sciences · 2024Article
- Harnessing innate immune pathways for therapeutic advancement in cancer.Signal transduction and targeted therapy · 2024Review
- The role of TIM3Journal of translational internal medicine · 2024Article
- Roles of N-linked glycosylation and glycan-binding proteins in placentation: trophoblast infiltration, immunomodulation, angiogenesis, and pathophysiology.Biochemical Society transactions · 2023Review
- Expression changes of Tim-3 as one of supplementary indicators for monitoring prognosis of liver pathological changes in chronic HBV infection.BMC infectious diseases · 2022Article
- Galectins: Important Regulators in Normal and Pathologic Pregnancies.International journal of molecular sciences · 2022Review
- Pro- and Anti-Inflammatory Cytokines in the Context of NK Cell-Trophoblast Interactions.International journal of molecular sciences · 2022Article
- The Role of the Immune Checkpoint Molecules PD-1/PD-L1 and TIM-3/Gal-9 in the Pathogenesis of Preeclampsia-A Narrative Review.Medicina (Kaunas, Lithuania) · 2022Review
- Uterine Natural Killer Cells: A Rising Star in Human Pregnancy Regulation.Frontiers in immunology · 2022Review
- Plasticity of NK cells in Cancer.Frontiers in immunology · 2022Review
- Placental galectins regulate innate and adaptive immune responses in pregnancy.Frontiers in immunology · 2022Article
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
NK cells accumulate at the maternal-fetal interface (MFI) and play essential roles in maintaining immune tolerance during pregnancy. The mechanisms that facilitate NK cells tolerance to fetal tissue are largely unknown. T cell Ig and mucin domain-containing protein 3 (Tim-3) is a newly defined molecule with essential immunological function in many physiological and pathological processes. Recent study showed that Tim-3 was involved in the regulation of immune tolerance at MFI. However, whether Tim-3 regulates NK cells cytotoxicity toward trophoblasts is unclear. Here, we showed Tim-3 was mainly expressed by decidual NK cells (dNK) and Tim-3 level in dNK was higher than peripheral NK cells (pNK). Tim-3(+) dNK expressed more levels of mature markers CD94 and CD69 than Tim-3- dNK cells and blocking Tim-3 significantly inhibited dNK IFN-γ and TNF-α secretion. Furthermore, we found TGF-β1 may contribute to such up-regulation of Tim-3 in NK cells. Interestingly, blocking Tim-3 enhanced NK cytotoxicity toward trophoblast cell line HTR-8 but not K562. We found HTR-8 expressed Tim-3 ligand Galectin-9, in contrast K562 did not. Small interfering RNA-mediated silencing of Galectin-9 expression enhanced NK cytotoxicity toward HTR-8. We further showed Tim-3/Galecin-9 inhibited NK cytotoxicity toward trophoblast partially via impairing the degranulation process. In addition, clinical data showed that abnormal Tim-3 level on pNK might be associated with recurrent spontaneous abortion (RSA). Thus, our data demonstrate Tim-3/Galectin-9 pathway maintains local tolerance by suppressing NK cytotoxicity toward trophoblasts which may represent a new immunologic tolerance mechanism at MFI.
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