Affinage

KIR2DL4

Killer cell immunoglobulin-like receptor 2DL4 · UniProt Q99706

Length
377 aa
Mass
41.5 kDa
Annotated
2026-06-10
74 papers in source corpus 21 papers cited in narrative 21 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KIR2DL4 (CD158d) is an NK-cell receptor that, unlike its inhibitory KIR relatives, principally drives cytokine production rather than cytotoxicity, inducing IFN-γ and other proinflammatory mediators through MAPK- and NF-κB-dependent signaling (PMID:11489965, PMID:18292514). It signals through two structurally separable modules: a transmembrane arginine that recruits the FcεRI-γ adaptor to support cytolytic and calcium responses, and a second arginine-independent module that activates JNK, ERK, p38, and the IKKβ–IκBα–NF-κB axis to drive cytokine transcription (PMID:15778339, PMID:18292514). Its cytoplasmic ITIM is dispensable for activation but, when phosphorylated, recruits SHP-1 and SHP-2 to confer inhibitory potential (PMID:12055234). KIR2DL4 resides predominantly in endosomes of resting NK cells, where internalized soluble HLA-G triggers signaling via DNA-PKcs, Akt, and NF-κB, and through a noncanonical JAK1–IRF7–STAT2 cascade—JAK1 binding to an IFN-receptor-like sequence in the cytoplasmic tail—that drives type I interferon-stimulated gene transcription (PMID:20854369, PMID:41632833). The crystal structure reveals an unusual D0–D2 architecture that self-associates into tetramers through the D0 domain, the same domain that binds heparan sulfate proteoglycans and syndecan-4 to modulate endosomal trafficking and cytokine output (PMID:24127555, PMID:25759384). Engagement induces an NK-cell senescence program with a proangiogenic secretory phenotype relevant to vascular remodeling at the maternal-fetal interface (PMID:23184984). Expression is governed by 9A/10A transmembrane polymorphism determining membrane versus secreted receptor (PMID:12902476, PMID:17171757), by promoter DNA methylation and histone marks, and by Runx3/Ets1 transcription factors (PMID:18586981, PMID:22467658).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2001 High

    Established that KIR2DL4 engagement uncouples cytokine production from cytotoxicity, defining it as a functionally distinct NK receptor whose signal selectively drives IFN-γ via p38 MAPK.

    Evidence Redirected lysis and cytokine ELISA with pharmacological MAPK inhibitors on resting NK cells

    PMID:11489965

    Open questions at the time
    • Did not identify the membrane adaptor or proximal signaling module
    • Mechanism of selective IFN-γ induction unresolved
  2. 2002 High

    Mapped the activating signal to a transmembrane arginine-tyrosine motif and showed the ITIM is dispensable for activation but recruits SHP-1/SHP-2 when phosphorylated, defining a dual activating/inhibitory potential.

    Evidence Site-directed mutagenesis, GST pull-down with phospho-tail, redirected lysis

    PMID:12055234

    Open questions at the time
    • Identity of the transmembrane-associated adaptor not yet defined
    • Physiological conditions favoring inhibitory vs activating output unknown
  3. 2003 High

    Confirmed the ITIM is not required for the activating function across full-length and truncated isoforms, and showed the 9A frameshift allele abolishes surface expression, linking allelic polymorphism to receptor availability.

    Evidence cDNA construct comparison, surface staining of genotype-stratified primary NK cells, redirected lysis

    PMID:12902476 PMID:14500636

    Open questions at the time
    • Fate of the 9A transcript product not characterized at this stage
    • Post-transcriptional control of surface expression not addressed
  4. 2005 High

    Identified FcεRI-γ as the adaptor recruited via the transmembrane arginine, distinguishing KIR2DL4 from DAP12-associated activating KIRs, and located the HLA-G recognition determinants and a RUNX-based promoter repressor.

    Evidence Co-IP and mutagenesis for FcεRI-γ; HLA-G α1 mutagenesis with Fc-fusion binding and cytotoxicity; promoter reporter, footprinting, and AML-2 site mutation

    PMID:15778339 PMID:15778373 PMID:15780179

    Open questions at the time
    • Stoichiometry of γ association versus signaling output incompletely defined
    • Later structural work questioned direct HLA-G binding
  5. 2007 Medium

    Resolved isoform complexity by showing the 9A allele yields a secreted receptor and that surface expression is lost post-activation despite stable mRNA, revealing post-transcriptional control of surface display.

    Evidence RT-PCR of splice variants, flow cytometry, in vitro NK activation, genotyping

    PMID:17171757

    Open questions at the time
    • Identity of the post-transcriptional negative regulator unknown
    • Function of the secreted/ΔD0 forms not established
  6. 2008 High

    Defined two structurally separable signaling modules—arginine/FcεRI-γ for cytolysis and calcium, and an arginine-independent module for MAPK/NF-κB-driven cytokine production—and showed transcriptional licensing depends on promoter methylation and histone state.

    Evidence Arginine mutagenesis, Western blot for MAPK/IκBα, pharmacological inhibitors, cytokine ELISA; bisulfite sequencing and ChIP for histone marks

    PMID:18292514 PMID:18586981

    Open questions at the time
    • Molecular identity of the second signaling module's proximal effector unclear
    • How the two modules are coordinately engaged by ligand not defined
  7. 2009 Medium

    Extended the 9A/10A genotype-phenotype relationship to decidual NK cells and showed IL-2 activation is required to license IFN-γ responses in 10A donors, linking receptor function to the tissue context.

    Evidence Flow cytometry, anti-KIR2DL4 ligation, IFN-γ ELISA on genotyped decidual NK cells

    PMID:19509110

    Open questions at the time
    • Mechanism of IL-2-dependent licensing not defined
    • Endogenous decidual ligand engagement not directly demonstrated
  8. 2010 Medium

    Relocalized the receptor's signaling platform to endosomes, showing soluble HLA-G is internalized and signals from this intracellular compartment via DNA-PKcs and Akt to a proinflammatory/proangiogenic output.

    Evidence Endosomal fractionation, internalization assays, DNA-PKcs/Akt inhibitor studies

    PMID:20854369

    Open questions at the time
    • Review summary of original data
    • How endosomal targeting selects signaling output not detailed
  9. 2012 High

    Connected endosomal KIR2DL4 signaling to a DNA-damage-response-driven NK senescence program with a proangiogenic secretome relevant to maternal-fetal vascular remodeling, and defined Runx3/Ets1 as essential activators of constitutive transcription.

    Evidence CD158d agonist stimulation, p21/phospho-HP1-γ Westerns, SASP profiling, vascular permeability and tube formation assays; promoter mutagenesis, EMSA, ChIP for Runx3/Ets1

    PMID:22467658 PMID:23184984

    Open questions at the time
    • In vivo contribution to placentation not directly established
    • Link between senescence induction and the two signaling modules unresolved
  10. 2013 High

    Identified heparan sulfate proteoglycans, including syndecan-4, as D0-domain ligands that direct receptor trafficking to Rab5/Rab7 endosomes and tune cytokine output and degradation.

    Evidence Genome-wide siRNA screen (HS3ST3B1), direct binding assays, D0 deletion mutants, confocal Rab5/Rab7 localization, KIR2DL4–syndecan-4 co-IP, cytokine ELISA

    PMID:24127555

    Open questions at the time
    • Relative physiological roles of HSPG versus HLA-G ligation unclear
    • Whether HSPG binding initiates signaling or only modulates trafficking not fully resolved
  11. 2015 High

    Determined the extracellular structure as a D0–D2 arrangement that self-associates into D0-mediated tetramers and showed D0 residues required for oligomerization preclude a classical HLA-binding mode, challenging direct HLA-G recognition.

    Evidence 2.8 Å crystal structure validated by SEC, DLS, AUC, SAXS, and direct HLA binding studies

    PMID:25759384

    Open questions at the time
    • Reconciliation with prior HLA-G functional data not achieved
    • Functional consequence of tetramerization for signaling not tested
  12. 2018 Medium

    Demonstrated a non-canonical functional context in which NK KIR2DL4 engaging oligodendrocyte HLA-G drives IFN-γ polarization that reduces myelin protein content, independent of KIR2DL1-mediated MHC inhibition.

    Evidence NK-oligodendrocyte conjugate assay, intracellular IFN-γ staining, anti-KIR2DL4 blockade, MOG/MAG Westerns

    PMID:30482463

    Open questions at the time
    • Signaling module responsible not dissected
    • In vivo relevance to demyelinating disease not shown
  13. 2020 Medium

    Showed KIR2DL4 expression and function extend beyond NK cells to mast cells, where agonism modulates KIT- and FcεRI-mediated responses and induces secretion of LIF and serine proteases.

    Evidence Flow cytometry and agonistic antibody stimulation of primary and LAD2 mast cells, functional response assays, ELISA

    PMID:32023940

    Open questions at the time
    • Signaling pathway in mast cells not mapped
    • Physiological mast-cell ligand context not defined
  14. 2021 Medium

    Defined a feed-forward circuit in which IFN-γ upregulates KIR2DL4 via JAK2/STAT1 and KIR2DL4 synergizes with FcγR for IFN-γ secretion, and showed HLA-G/KIR2DL4 engagement suppresses ADCC against HER2+ tumors that blockade restores.

    Evidence Co-culture and cytotoxicity assays, JAK2/STAT1 inhibition, blocking antibodies, xenograft model, cytokine ELISA

    PMID:34158475

    Open questions at the time
    • Single-lab in vivo model
    • Mechanism by which HLA-G ligation desensitizes ADCC not fully resolved
  15. 2022 Medium

    Showed an intrinsic tumor-cell role for KIR2DL4 in renal cell carcinoma, promoting proliferation through PI3K/Akt signaling, distinct from its immune-receptor function.

    Evidence shRNA knockdown and overexpression, MTT and soft agar assays, xenograft, RNA-seq, phospho-AKT Westerns, wortmannin treatment

    PMID:35063466

    Open questions at the time
    • Upstream ligand/activation in tumor cells unknown
    • Single-lab finding in one cancer type
  16. 2026 High

    Resolved a non-canonical interferon-like signaling mechanism in which the KIR2DL4 cytoplasmic tail binds JAK1 through an IFN-receptor-like sequence and, upon soluble HLA-G binding, drives IRF7/STAT2 nuclear phosphorylation and type I ISG transcription, preferentially in CD56bright NK cells.

    Evidence Soluble HLA-G vs agonist stimulation, RNA-seq/scRNA-seq, JAK1 inhibition, tail mutagenesis, KIR2DL4–JAK1 co-IP, nuclear phospho-IRF7/STAT2 Westerns

    PMID:41632833

    Open questions at the time
    • How JAK1–IRF7–STAT2 integrates with the MAPK/NF-κB and DNA-PKcs/Akt arms unclear
    • In vivo function of ISG induction at the maternal-fetal interface not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the structurally distinct signaling modules (FcεRI-γ/cytolytic, MAPK/NF-κB cytokine, DNA-PKcs/Akt senescence, JAK1/IRF7/STAT2 interferon) and the multiple ligands (HLA-G, HSPGs) are coordinately selected to produce a given functional outcome.
  • No unified model linking ligand identity, endosomal localization, and output module
  • Reconciliation of structural absence of HLA-G binding with functional HLA-G responses unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0001618 virus receptor activity 2 GO:0060090 molecular adaptor activity 2 GO:0008289 lipid binding 1
Localization
GO:0005768 endosome 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-8953897 Cellular responses to stimuli 1
Partners
FCER1GHLA-GJAK1PTPN11PTPN6SDC4

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 KIR2DL4 engagement on resting NK cells induces IFN-γ production but not cytotoxicity, and this IFN-γ induction is blocked by a p38 MAPK inhibitor, placing p38 MAPK downstream of KIR2DL4 signaling; in contrast, CD16 and 2B4 induced cytotoxicity but not IFN-γ, revealing a functional dichotomy dictated by individual receptor signals. Redirected lysis assay, cytokine ELISA, pharmacological MAPK inhibitors (p38 vs ERK pathway) Journal of immunology High 11489965
2002 The transmembrane arginine-tyrosine motif (not the cytoplasmic ITIM) is required for the activating signal of KIR2DL4; the ITIM tyrosine is dispensable for activation but, when phosphorylated, recruits SHP-1 and SHP-2 (Src homology 2-containing phosphatases), conferring inhibitory potential; an activation-deficient KIR2DL4 mutant can inhibit CD16-mediated signaling. Site-directed mutagenesis of ITIM tyrosine and transmembrane arginine; redirected lysis assay; GST pull-down with phosphorylated cytoplasmic tail and SHP-1/SHP-2 Journal of immunology High 12055234
2003 KIR2DL4 engagement triggers potent IFN-γ production but weak cytotoxicity in NK cells; the ITIM does not influence the activating function of the full-length receptor (2DL4.1), and a truncated form lacking the ITIM (2DL4*) shows similar activation potential, confirming the ITIM is not required for activation. Epitope-tagged receptor transfection into NK-like cell line; antibody cross-linking; cytokine ELISA; redirected lysis assay; comparison of full-length vs. truncated cDNA clones Journal of immunology High 14500636
2003 The 9A allele of KIR2DL4 (single adenine deletion in the transmembrane exon causing a frameshift and premature stop codon) results in loss of cell-surface expression; only individuals with at least one 10A allele show detectable surface KIR2DL4 and activating function in redirected lysis assays. Transfection of 10A vs. 9A cDNA into cell lines; surface staining with anti-KIR2DL4 mAb on primary NK cells stratified by genotype; redirected lysis assay Journal of immunology High 12902476
2005 KIR2DL4 associates with FcεRI-γ (FcepsilonRI-gamma) via its transmembrane arginine residue; this association promotes surface expression and provides signal-transducing function. Weak cytolytic responses correlate with low stoichiometric association with γ. This distinguishes KIR2DL4 from all other activating KIRs, which associate with DAP12. Co-immunoprecipitation; biochemical association assays; functional cytolysis assays; transmembrane arginine mutagenesis Journal of immunology High 15778339
2005 The KIR2DL4 promoter drives NK cell-specific reporter gene expression. An inhibitory element upstream of the core promoter suppresses KIR2DL4 promoter activity. AML-2 (RUNX family) binds a conserved AML site in the KIR2DL4 promoter and acts as a repressor; mutation of this site increases promoter activity. Promoter-reporter transfection assays in NK3.3 cells and primary NK cells; DNase I footprinting; site-directed mutagenesis of transcription factor binding sites; methyltransferase inhibitor treatment Journal of immunology Medium 15778373
2005 Residues Met76 and Gln79 in the α1 domain of HLA-G are critical for KIR2DL4 recognition; mutation of both to Ala reduced binding of a KIR2DL4-IgG Fc fusion protein and altered cytolytic function of KIR2DL4-transfected NK-92 cells against HLA-G-expressing targets. Retroviral transduction of wild-type and mutant HLA-G into K562 cells; KIR2DL4-IgG Fc fusion protein binding assay; cytotoxicity (LDH release) assay with KIR2DL4-transfected NK-92 cells Cell research Medium 15780179
2007 KIR2DL4 encoded by the 9A allele can produce a secreted form of the receptor (lacking the transmembrane domain due to exon skipping); individuals with 10A alleles who lack detectable surface KIR2DL4 express a ΔD0 receptor not recognized by available anti-KIR2DL4 mAbs; surface KIR2DL4 disappears 16 days post-activation despite maintained mRNA, indicating a post-transcriptional negative regulator of surface expression. RT-PCR analysis of splice variants; flow cytometry with anti-KIR2DL4 mAbs; in vitro NK cell culture and activation assays; genotyping European journal of immunology Medium 17171757
2008 KIR2DL4 signals through two distinct structural modules: (1) the transmembrane arginine mediates FcεRI-γ association, which is required for cytolytic activity and calcium responses; (2) a second domain independent of the transmembrane arginine activates MAPKs (JNK, ERK, p38), the classical NF-κB pathway (IKKβ phosphorylation, IκBα degradation), and cytokine transcription/translation (TNF-α, IFN-γ, MIP1α, MIP1β, IL-8). MAPK inhibitors (JNK, MEK1/2, p38) block cytokine production in a nonredundant manner. Site-directed mutagenesis of transmembrane arginine (R/G mutant); receptor cross-linking; Western blot for MAPK phosphorylation and IκBα; pharmacological inhibitors; cytokine ELISA; co-immunoprecipitation for FcεRI-γ Journal of immunology High 18292514
2008 Epigenetic status of the KIR2DL4 promoter determines transcriptional competency: NK cells have a fully demethylated KIR2DL4 promoter with active histone marks (H3/H4 acetylation, di/trimethyl H3-Lys4, reduced dimethyl H3-Lys9); aging T cells show partial demethylation and increased dimethyl H3-Lys4 that renders the promoter sensitive to DNMT inhibition, enabling KIR2DL4 transcription. Bisulfite sequencing of KIR2DL4 promoter; chromatin immunoprecipitation (ChIP) for histone modifications; DNMT inhibitor treatment; RT-PCR for KIR2DL4 expression in sorted T cell subsets Journal of leukocyte biology Medium 18586981
2010 KIR2DL4 resides in endosomes rather than on the cell surface of resting NK cells. Soluble HLA-G is internalized into KIR2DL4-positive endosomes, and signaling from this intracellular location triggers a proinflammatory and proangiogenic response via the serine/threonine kinases DNA-PKcs and Akt. Endosomal fractionation/localization studies; receptor internalization assays; inhibitor studies targeting DNA-PKcs and Akt; cytokine/angiogenic factor readouts (reviewed/summarized mechanistic findings) Traffic (Copenhagen, Denmark) Medium 20854369
2012 CD158d (KIR2DL4) engagement by agonists triggers a DNA damage response pathway (DNA-PKcs, Akt, NF-κB) and induces cellular senescence in NK cells, characterized by p21 upregulation, HP1-γ phosphorylation, morphological enlargement, survival without cell-cycle entry, and a senescence-associated secretory phenotype (SASP). The secretome of CD158d-stimulated senescent NK cells promoted vascular remodeling and angiogenesis (vascular permeability and endothelial tube formation). CD158d agonist stimulation of primary NK cells; Western blot for p21 and phospho-HP1-γ; cell morphology analysis; transcriptional profiling (SASP signature); functional assays for vascular permeability and endothelial cell tube formation; retrospective transcriptome analysis of decidual NK cells Proceedings of the National Academy of Sciences High 23184984
2012 Transcription factors Runx3 and Ets1 bind the KIR2DL4 promoter in situ and are essential for constitutive 2DL4 transcription; two redundant Runx binding sites and a CRE element are required for basal activity. IL-2/IL-15 stimulation increases 2DL4 promoter activity through functional Runx, CRE, and Ets sites. Promoter mutagenesis; EMSA; cotransfection reporter assays; chromatin immunoprecipitation (ChIP) for Runx3 and Ets1 binding in situ Journal of immunology High 22467658
2013 KIR2DL4 directly interacts with heparan sulfate (HS)/heparin via its D0 domain (identified by genome-wide siRNA screen revealing HS3ST3B1 as a regulator); HS/heparin regulates KIR2DL4-mediated cytokine production; exogenous HS/heparin induces differential KIR2DL4 localization to Rab5+ and Rab7+ endosomes leading to cytokine downregulation and receptor degradation. Syndecan-4 (SDC4) HSPG directly interacts with KIR2DL4 and affects receptor endocytosis and membrane trafficking. Genome-wide high-throughput siRNA screen; direct binding assays (KIR2DL4–HS/heparin); D0 domain deletion mutant analysis; cytokine ELISA; confocal microscopy for Rab5+/Rab7+ endosomal localization; co-immunoprecipitation (KIR2DL4–syndecan-4) Journal of immunology High 24127555
2015 Crystal structure of the KIR2DL4 extracellular domains resolved at 2.8 Å reveals a D0-D2 arrangement (no D1 domain) with C2-type immunoglobulin folds and an acute elbow angle. KIR2DL4 self-associates via the D0 domain in a concentration-dependent manner, forming a tetramer in the crystal lattice confirmed by size exclusion chromatography, dynamic light scattering, analytical ultracentrifugation, and SAXS. D0 residues required for tetramer formation preclude an HLA-binding mode akin to KIR3DL1; no direct HLA interaction was detected in binding studies. X-ray crystallography (2.8 Å); size exclusion chromatography; dynamic light scattering; analytical ultracentrifugation; small-angle X-ray scattering (SAXS); direct HLA binding studies The Journal of biological chemistry High 25759384
2021 KIR2DL4 forms a regulatory circuit with the IFN-γ pathway: IFN-γ upregulates KIR2DL4 expression via JAK2/STAT1 signaling, and KIR2DL4 in turn synergizes with Fcγ receptor to increase IFN-γ secretion by NK cells. HLA-G binding to KIR2DL4 desensitizes NK cells to trastuzumab by disrupting antibody-dependent cell-mediated cytotoxicity (ADCC). Blockade of HLA-G/KIR2DL4 signaling restored NK cell cytotoxicity against HER2+ breast cancer in vivo. Co-culture assays; NK cell cytotoxicity assays; JAK2/STAT1 pathway inhibition; anti-KIR2DL4/HLA-G blocking antibodies; in vivo xenograft mouse model; cytokine ELISA (IFN-γ, TGF-β) Signal transduction and targeted therapy Medium 34158475
2018 KIR2DL4 expressed on NK cells interacts with HLA-G expressed on oligodendrocytes; this KIR2DL4–HLA-G interaction is required for NK-cell-mediated IFN-γ polarization toward oligodendrocytes, which in turn reduces myelin oligodendrocyte glycoprotein (MOG) and myelin associated glycoprotein (MAG) content. This activity is independent of KIR2DL1-mediated MHC class I inhibition. NK cell–oligodendrocyte conjugate assay; intracellular cytokine staining for IFN-γ; anti-KIR2DL4 blocking antibody; Western blot for MOG and MAG; flow cytometry for KIR2DL4+ NK cell frequency Molecular immunology Medium 30482463
2020 KIR2DL4 is expressed on human mast cells (peripheral blood-derived and LAD2 cell line). Agonistic antibodies to KIR2DL4 negatively regulate KIT-mediated and FcεRI-mediated mast cell responses. HLA-G (natural KIR2DL4 ligand) and agonistic antibodies induce secretion of leukemia inhibitory factor and serine proteases from human mast cells. Flow cytometry for KIR2DL4 on mast cells; agonistic anti-KIR2DL4 antibody stimulation; functional assays for KIT-mediated and FcεRI-mediated responses; ELISA for leukemia inhibitory factor and serine proteases International journal of molecular sciences Medium 32023940
2022 KIR2DL4 is expressed in renal cell carcinoma (RCC) cells and promotes RCC cell proliferation; knockdown reduces proliferation/viability while overexpression promotes it in vitro and in vivo. The mechanism involves activation of the PI3K/Akt signaling pathway, as AKT phosphorylation levels correlate with KIR2DL4 expression levels, and combined PI3K inhibitor (wortmannin) plus KIR2DL4-shRNA further reduces phospho-AKT and proliferation. MTT viability assay; soft agar colony formation; KIR2DL4 knockdown (shRNA) and overexpression; xenograft mouse model; RNA sequencing; Western blot for phospho-AKT; PI3K inhibitor (wortmannin) treatment Life sciences Medium 35063466
2026 Soluble HLA-G activates transcription of type I interferon-stimulated genes (ISGs) in primary NK cells through KIR2DL4 via a noncanonical pathway requiring transcription factor IRF7 and kinase JAK1. The C-terminal portion of the KIR2DL4 cytoplasmic tail contains a sequence analogous to conserved JAK1 binding sites in IFN receptors and is required for JAK1 binding to KIR2DL4. HLA-G stimulation leads to nuclear phosphorylation of IRF7 and JAK substrate STAT2, linking KIR2DL4 signaling to ISG transcription. scRNA-seq showed HLA-G induces a broader response in CD56bright than CD56dim NK cells, and ISG expression was detected at the early maternal-fetal interface. Primary NK cell stimulation with soluble HLA-G vs. agonistic anti-KIR2DL4 antibody; RNA-seq and scRNA-seq; pharmacological JAK1 inhibition; cytoplasmic tail mutagenesis/deletion constructs; co-immunoprecipitation (KIR2DL4–JAK1); Western blot for nuclear phospho-IRF7 and phospho-STAT2; comparison with decidual NK scRNA-seq dataset Science signaling High 41632833
2009 In decidual NK (dNK) cells, KIR2DL4 surface expression is controlled by the 9A/10A transmembrane polymorphism (as in peripheral blood NK cells). Freshly isolated dNK cells do not secrete IFN-γ in response to KIR2DL4 ligation regardless of genotype, but IL-2 activation in vitro enables IFN-γ secretion only in donors with at least one 10A allele. Flow cytometry for KIR2DL4 surface expression on freshly isolated decidual NK cells; anti-KIR2DL4 ligation; IFN-γ ELISA; genotyping for 9A/10A polymorphism Molecular human reproduction Medium 19509110

Source papers

Stage 0 corpus · 74 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 HLA-G up-regulates ILT2, ILT3, ILT4, and KIR2DL4 in antigen presenting cells, NK cells, and T cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 246 15670976
2002 KIR2DL4 (CD158d), an NK cell-activating receptor with inhibitory potential. Journal of immunology (Baltimore, Md. : 1950) 192 12055234
2001 Cutting edge: induction of IFN-gamma production but not cytotoxicity by the killer cell Ig-like receptor KIR2DL4 (CD158d) in resting NK cells. Journal of immunology (Baltimore, Md. : 1950) 188 11489965
2012 KIR2DL4 (CD158d): An activation receptor for HLA-G. Frontiers in immunology 152 22934097
2012 Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling. Proceedings of the National Academy of Sciences of the United States of America 139 23184984
2003 KIR2DL4 is an IL-2-regulated NK cell receptor that exhibits limited expression in humans but triggers strong IFN-gamma production. Journal of immunology (Baltimore, Md. : 1950) 139 14500636
2005 Cutting edge: KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. Journal of immunology (Baltimore, Md. : 1950) 111 15778339
2003 KIR2DL4 (CD158d) genotype influences expression and function in NK cells. Journal of immunology (Baltimore, Md. : 1950) 98 12902476
2021 Interaction between HLA-G and NK cell receptor KIR2DL4 orchestrates HER2-positive breast cancer resistance to trastuzumab. Signal transduction and targeted therapy 93 34158475
2005 Residues Met76 and Gln79 in HLA-G alpha1 domain involve in KIR2DL4 recognition. Cell research 77 15780179
2005 Three structurally and functionally divergent kinds of promoters regulate expression of clonally distributed killer cell Ig-like receptors (KIR), of KIR2DL4, and of KIR3DL3. Journal of immunology (Baltimore, Md. : 1950) 67 15778373
2005 The silent KIR3DP1 gene (CD158c) is transcribed and might encode a secreted receptor in a minority of humans, in whom the KIR3DP1, KIR2DL4 and KIR3DL1/KIR3DS1 genes are duplicated. European journal of immunology 66 15580659
2007 Three common alleles of KIR2DL4 (CD158d) encode constitutively expressed, inducible and secreted receptors in NK cells. European journal of immunology 54 17171757
2003 Recognition of HLA-G by the NK cell receptor KIR2DL4 is not essential for human reproduction. European journal of immunology 52 12616484
2010 Endosomal signaling and a novel pathway defined by the natural killer receptor KIR2DL4 (CD158d). Traffic (Copenhagen, Denmark) 46 20854369
2007 Possible roles of KIR2DL4 expression on uNK cells in human pregnancy. American journal of reproductive immunology (New York, N.Y. : 1989) 46 17362384
2002 Alleles of the KIR2DL4 receptor and their lack of association with pre-eclampsia. European journal of immunology 44 11754000
2003 Different and divergent regulation of the KIR2DL4 and KIR3DL1 promoters. Journal of immunology (Baltimore, Md. : 1950) 43 12794136
2000 Detection of KIR2DL4 alleles by sequencing and SSCP reveals a common allele with a shortened cytoplasmic tail. Tissue antigens 40 11034561
2013 Genome-wide siRNA screen reveals a new cellular partner of NK cell receptor KIR2DL4: heparan sulfate directly modulates KIR2DL4-mediated responses. Journal of immunology (Baltimore, Md. : 1950) 36 24127555
2015 The structure of the atypical killer cell immunoglobulin-like receptor, KIR2DL4. The Journal of biological chemistry 33 25759384
2008 KIR2DL4 differentially signals downstream functions in human NK cells through distinct structural modules. Journal of immunology (Baltimore, Md. : 1950) 31 18292514
2022 Roles of HLA-G/KIR2DL4 in Breast Cancer Immune Microenvironment. Frontiers in immunology 30 35185887
2008 Epigenetic mechanisms of age-dependent KIR2DL4 expression in T cells. Journal of leukocyte biology 28 18586981
2004 Investigation of killer cell immunoglobulinlike receptor gene diversity: I. KIR2DL4. Human immunology 28 14700593
2015 Genetic polymorphisms and expression of HLA-G and its receptors, KIR2DL4 and LILRB1, in non-small cell lung cancer. Tissue antigens 27 25855135
2009 The genotype of the NK cell receptor, KIR2DL4, influences INFgamma secretion by decidual natural killer cells. Molecular human reproduction 25 19509110
2020 Possible roles of HLA-G regulating immune cells in pregnancy and endometrial diseases via KIR2DL4. Journal of reproductive immunology 21 32711226
2008 Human leukocyte antigen-G, a ligand for the natural killer receptor KIR2DL4, is expressed by eutopic endometrium only in the menstrual phase. Fertility and sterility 21 18314122
2016 Possible Role of HLA-G, LILRB1 and KIR2DL4 Gene Polymorphisms in Spontaneous Miscarriage. Archivum immunologiae et therapiae experimentalis 20 26973020
2009 Possible gene-gene interaction of KIR2DL4 with its cognate ligand HLA-G in modulating risk for preeclampsia. Reproductive sciences (Thousand Oaks, Calif.) 19 19700612
2005 Genomic characterization of KIR2DL4 in families and unrelated individuals reveals extensive diversity in exon and intron sequences including a common frameshift variation occurring in several alleles. Tissue antigens 18 15853895
2009 Evidence for balancing selection acting on KIR2DL4 genotypes in rhesus macaques of Indian origin. Immunogenetics 17 19506858
2020 Killer Immunoglobulin-Like Receptor 2DL4 (CD158d) Regulates Human Mast Cells both Positively and Negatively: Possible Roles in Pregnancy and Cancer Metastasis. International journal of molecular sciences 15 32023940
2013 KIR2DL4 copy number variation is associated with CD4+ T-cell depletion and function of cytokine-producing NK cell subsets in SIV-infected Mamu-A*01-negative rhesus macaques. Journal of virology 13 23449795
2006 Investigation of killer cell immunoglobulin-like receptor KIR2DL4 diversity by sequence-based typing in Chinese population. Tissue antigens 13 16573558
2006 Rapid production of human KIR2DL4 extracellular domain and verification of its interaction with HLA-G. Biochemistry. Biokhimiia 12 16487070
2022 KIR2DL4 promotes the proliferation of RCC cell associated with PI3K/Akt signaling activation. Life sciences 10 35063466
2017 The Influence of Cytomegalovirus on Expression of HLA-G and its Ligand KIR2DL4 by Human Peripheral Blood Leucocyte Subsets. Scandinavian journal of immunology 10 28817184
2011 Lack of KIR2DL4 gene in a fertile Caucasian woman. Tissue antigens 10 21623736
2007 Allelic diversity in KIR2DL4 in a bone marrow transplant population: description of three novel alleles. Tissue antigens 10 17610421
2007 The elucidation of KIR2DL4 gene polymorphism. Molecular immunology 10 18082267
2018 KIR2DL4-HLAG interaction at human NK cell-oligodendrocyte interfaces regulates IFN-γ-mediated effects. Molecular immunology 8 30482463
2012 Differential transcription factor use by the KIR2DL4 promoter under constitutive and IL-2/15-treated conditions. Journal of immunology (Baltimore, Md. : 1950) 8 22467658
2024 Combined maternal KIR2DL4 and fetal HLA-G polymorphisms were associated with preeclampsia in a Han Chinese population. Frontiers in genetics 7 39144721
2015 Genetic polymorphism of KIR2DL4 in the Polish population. Tissue antigens 7 25818657
2014 Two new cases of KIR3DP1, KIR2DL4-negative genotypes, one of which is also lacking KIR3DL2. Archivum immunologiae et therapiae experimentalis 7 25033772
2009 High levels of molecular polymorphism at the KIR2DL4 locus in French and Congolese populations: impact for anthropology and clinical studies. Human immunology 7 19679155
2007 Enrichment of individual KIR2DL4 sequences from genomic DNA using long-template PCR and allele-specific hybridization to magnetic bead-bound oligonucleotide probes. Tissue antigens 7 17498270
2007 Cloning and sequencing alleles of the KIR2DL4 gene from genomic DNA samples. Tissue antigens 6 17445175
2023 KIR2DL4/HLA-G polymorphisms were associated with HCV infection susceptibility among Chinese high-risk population. Journal of medical virology 5 36890645
2023 The effects of KIR2DL4 stimulated NK-92 cells on the apoptotic pathways of HER2 + /HER-breast cancer cells. Medical oncology (Northwood, London, England) 5 37027073
2013 Genetic polymorphism of KIR2DL4 (CD158d), a putative NK cell receptor for HLA-G, does not influence susceptibility to asthma. Tissue antigens 5 24033084
2009 KIR2DL4 (CD158d) polymorphisms and susceptibility to multiple sclerosis. Journal of neuroimmunology 5 19304328
2020 Expression of HLA-G and KIR2DL4 receptor in chorionic villous in missed abortion. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 3 33305671
2021 KIR2DL4 genetic diversity in a Brazilian population sample: implications for transcription regulation and protein diversity in samples with different ancestry backgrounds. Immunogenetics 2 33595694
2025 Emerging roles of KIR2DL4 in cancer immunotherapy. Breast cancer (Tokyo, Japan) 1 40549069
2016 Description of the novel KIR2DL4*035 allele identified using high-throughput sequencing. HLA 1 26917249
2015 KIR2DL4 expression rather than its single nucleotide polymorphisms correlates with pre-eclampsia. International journal of clinical and experimental pathology 1 26823774
2026 The fetal trophoblast cell marker HLA-G activates a type I interferon response in primary NK cells through the receptor KIR2DL4. Science signaling 0 41632833
2025 Mechanism of microRNA-152 Regulating Decidual Natural Killer Cell Viability and Affecting Trophoblast Cell Invasiveness via the HLA-G/KIR2DL4 Axis. The Kaohsiung journal of medical sciences 0 40309956
2022 Modularisation of published and novel models toward a complex KIR2DL4 pathway in pbNK cell. MethodsX 0 35774414
2022 The novel KIR2DL4*00108 allele identified by sequencing-based typing in a Chinese Han individual. HLA 0 36256498
2020 Quantitative Multiplex Real-Time Reverse Transcriptase-Polymerase Chain Reaction with Fluorescent Probe Detection of Killer Immunoglobulin-Like Receptors, KIR2DL4/3DL3. Diagnostics (Basel, Switzerland) 0 32823754
2019 Description of the novel KIR2DL4*00603 allele identified in a Chinese Hani individual. HLA 0 31041847
2019 Characterization of the novel KIR2DL4*037 allele identified in a Chinese Hani individual. HLA 0 31044496
2019 Identification of the novel KIR2DL4*036 allele in a Chinese Hani individual. HLA 0 31069992
2019 The novel KIR2DL4*038 allele identified by sequencing-based typing in a Chinese Naxi individual. HLA 0 31070014
2018 Description of the novel KIR2DL4*039 allele identified in a southern Chinese Han individual. HLA 0 29292865
2018 Identification of the novel KIR2DL4*040 allele in a southern Chinese Han individual. HLA 0 29316382
2018 [Association of polymorphisms of KIR2DL4 gene with leukemia among ethnic Hans from southern China]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 29419875
2018 Identification of the novel KIR2DL4*00106 allele in a southern Chinese Han individual. HLA 0 29577675
2017 [Allelic diversity of KIR2DL4 gene and identification of five novel alleles among southern Han Chinese population]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 28397235
2016 Identification of the novel KIR2DL4*00503 allele from a southern Chinese Han individual. HLA 0 27748071

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