{"gene":"LILRB4","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1997,"finding":"ILT3/LILRB4 co-ligation with stimulatory receptors on APCs dramatically blunts calcium influx and tyrosine phosphorylation triggered by those receptors; signal extinction involves recruitment of SH2-containing protein tyrosine phosphatase 1 (SHP-1) to ILT3 upon cross-linking. ILT3 also mediates antigen internalization and delivery to intracellular compartments for MHC-II processing and T cell presentation.","method":"Co-ligation assays with calcium flux and tyrosine phosphorylation readouts; SHP-1 co-immunoprecipitation after cross-linking; internalization and antigen presentation assays in primary monocytes/DCs","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal biochemical methods (calcium signaling, phosphorylation, co-IP of SHP-1, functional antigen presentation) in a single rigorous founding paper","pmids":["9151699"],"is_preprint":false},{"year":2002,"finding":"CD8+CD28− alloantigen-specific T suppressor cells induce upregulation of ILT3 and ILT4 on monocytes and dendritic cells, rendering APCs tolerogenic with reduced costimulatory molecule expression and capacity to induce antigen-specific unresponsiveness in CD4+ T helper cells.","method":"In vitro co-culture of T suppressor cells with APCs; flow cytometry for ILT3/ILT4 and costimulatory molecules; allogeneic T cell proliferation and anergy assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional co-culture experiments with phenotypic and functional readouts, replicated in human transplant recipients","pmids":["11875462"],"is_preprint":false},{"year":2003,"finding":"Tolerogenic DCs with high ILT3 and ILT4 expression anergize alloreactive CD4+CD45RO+CD25+ T cells and convert them into regulatory T cells; IL-10 and IFN-α also induce ILT3 and ILT4 upregulation in DCs, rendering them tolerogenic, indicating a common cytokine-driven mechanism.","method":"In vitro cytokine stimulation (IL-10, IFN-α) of DCs; co-culture with T cells; flow cytometry and functional suppression assays","journal":"Transplant immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays with cytokine stimulation, single lab, multiple readouts","pmids":["12967778"],"is_preprint":false},{"year":2004,"finding":"Alloantigen-specific CD8+CD28−FOXP3+ T suppressor cells interact with endothelial cells and induce upregulation of ILT3 and ILT4 on endothelial cells, downregulating costimulatory/adhesion molecules and rendering endothelial cells tolerogenic; tolerized endothelial cells in turn elicit differentiation of additional CD8+CD28−FOXP3+ T suppressor cells.","method":"RT-PCR; in vitro co-culture of T suppressor cells with HUVECs; flow cytometry; luciferase transcription assays","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional co-culture with phenotypic and transcriptional readouts, single lab","pmids":["15226269"],"is_preprint":false},{"year":2006,"finding":"IL-10 stimulation of human endothelial cells upregulates ILT3 and ILT4 surface expression via STAT-3 signaling and involves glucocorticoid-induced leucine zipper (GILZ); blocking ILT3/ILT4 with antibodies nearly completely restores T cell proliferation inhibited by IL-10-pretreated endothelial cells, and overexpression of ILT3 in co-cultures significantly reduces T cell proliferation.","method":"IL-10 stimulation of HUVECs; blocking antibody experiments in endothelial-T cell co-cultures; ILT3 overexpression; STAT-3 signaling analysis","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional gain- and loss-of-function experiments with ILT3 in endothelial-T cell co-cultures, single lab","pmids":["17163451"],"is_preprint":false},{"year":2007,"finding":"Overexpression of membrane ILT3 in APCs inhibits NF-κB activation and transcription of costimulatory molecules; soluble ILT3 (sILT3) released by alternative splicing that eliminates the transmembrane domain is immunosuppressive, inducing CD8+ T suppressor cells and impairing T cell responses, effects reversible by anti-ILT3 mAb or sILT3 depletion.","method":"Humanized SCID mouse model; soluble ILT3 protein from patient serum; mixed lymphocyte culture; anti-ILT3 mAb blocking; immunohistochemistry; RT-PCR for splice variants","journal":"JOP : Journal of the pancreas","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model plus functional reversal by antibody, single lab","pmids":["17993722"],"is_preprint":false},{"year":2009,"finding":"LILRB4 co-ligation with FcγRI (CD64) on THP-1 monocytic cells potently inhibits TNFα production and reduces phosphorylation of Lck, Syk, LAT, Erk, and c-Cbl but not α-actinin-4; LILRB4 aggregates to sites of CD64 activation upon co-ligation; phosphatase inhibitor pervanadate reverses inhibition but SHP-1-specific inhibitor sodium stibogluconate does not, implicating phosphatase(s) other than SHP-1.","method":"Co-ligation assays on THP-1 cells and primary monocytes; TNFα ELISA; phospho-protein western blotting; phosphatase inhibitor experiments; confocal microscopy of receptor aggregation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal biochemical methods including kinase phosphorylation, functional cytokine assays, and pharmacological dissection in one rigorous study","pmids":["19833736"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of the LILRB4 ectodomain resolved to 1.7 Å reveals two immunoglobulin domains; D2 domain (most similar to D4 of other LILRs) contains unique 3(10) helices; reduced D1-D2 interdomain contacts produce an obtuse interdomain angle (~107°); electrostatic and conformational analysis indicates LILRB4 is unsuited to MHC class I ligation, consistent with binding non-MHC class I ligands; distinctive surface patches on D1 and D1-D2 hinge region are candidate ligand-binding sites.","method":"Protein crystallography (1.7 Å resolution); engineered disulfide bond in D2 for stability; structural comparison with MHC-binding LILRs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with mutagenesis (engineered disulfide) and comparative structural analysis","pmids":["21454581"],"is_preprint":false},{"year":2010,"finding":"Overexpression of membrane ILT3 in APCs inhibits tyrosine phosphorylation, NF-κB and MAPK p38 activity, and transcription of costimulatory molecules, cytokines, and chemokines; soluble ILT3-Fc (containing only the extracellular Ig-like domain fused to mutated IgG1 Fc) acts extracellularly to induce CD4 T helper anergy and differentiation of antigen-specific CD8 T suppressor cells in vitro and in vivo.","method":"ILT3 overexpression in dendritic cell lines; ILT3-Fc recombinant protein treatment; NF-κB reporter assays; in vitro and in vivo (humanized NOD/SCID) tolerance models","journal":"International reviews of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression with multiple signaling readouts and in vivo validation, single lab","pmids":["20132030"],"is_preprint":false},{"year":2006,"finding":"ILT3 cytoplasmic deletion mutant (ILT3Δ) retains suppressive activity in T cell proliferation and cytotoxicity assays (unlike ILT4Δ which loses activity), demonstrating that the extracellular domain of ILT3 mediates suppression independently of the cytoplasmic ITIMs; soluble recombinant ILT3 inhibits T helper and cytotoxic function and induces CD8+ T suppressor cell differentiation.","method":"Cytoplasmic deletion mutants transfected into KG1 dendritic-like cell line; T cell proliferation and cytotoxicity assays; recombinant soluble ILT3 treatment","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function mutagenesis with functional T cell assays, single lab","pmids":["17161342"],"is_preprint":false},{"year":2012,"finding":"ILT3-Fc-induced CD8+ T suppressor cells show significant upregulation of BCL6 (a transcriptional repressor of IL-2, IFN-γ, IL-5, and granzyme B), SOCS1, and DUSP10; these genes define the Ts signature and are targeted by miRNAs suppressed by ILT3-Fc; ILT3-Fc induces tolerance to allogeneic human islets and reverses rejection in a humanized NOD/SCID model.","method":"Gene expression profiling; ILT3-Fc treatment of CD8+ T cells; BCL6 functional analysis; humanized NOD/SCID mouse model; miRNA analysis","journal":"Experimental and molecular pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene profiling with in vivo validation, single lab, multiple readouts","pmids":["23018130"],"is_preprint":false},{"year":2017,"finding":"ILT3.Fc binds to CD166/ALCAM on the surface of activated T cells (identified by flow cytometry, mass spectrometry, and Biacore); CD166 knockdown abrogates ILT3.Fc-mediated inhibition of CD4+ T helper proliferation and induction of CD8+CD28− T suppressor cells; ILT3.Fc-CD166 interaction inhibits tumor cell growth via inactivation of the p70S6K signaling pathway; CRISPR-Cas9 knockout of CD166 abolishes ILT3.Fc binding and tumor-inhibitory effect.","method":"Flow cytometry; mass spectrometry; Biacore binding kinetics; nucleofection-based CD166 knockdown; CRISPR-Cas9 knockout; p70S6K western blotting; in vivo NOD.Cg-Prkdc Il-2rg/SzJ mouse xenograft","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ligand identified by three orthogonal methods, functional validation by genetic knockdown and CRISPR KO, in vivo confirmation","pmids":["29263213"],"is_preprint":false},{"year":2017,"finding":"In CLL B cells, ILT3 is ectopically expressed driven by the transcription factor Deltex1 (a suppressor of antigen receptor signaling); ILT3 triggering inhibits Akt kinase activation upon BCR stimulation by forming inhibitory clusters of ILT3, BCRs, and SHIP1 (INPP5D) at the cell surface.","method":"Transcriptional profiling of p66Shc-deficient CLL cells; Deltex1 overexpression; BCR stimulation with anti-IgM; Akt phosphorylation western blotting; co-immunoprecipitation of ILT3-BCR-SHIP1 clusters; flow cytometry","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic dissection with genetic driver identified, co-IP of signaling complex, and functional kinase readout","pmids":["28931525"],"is_preprint":false},{"year":2018,"finding":"LILRB4 on monocytic AML cells supports tumor infiltration and T cell suppression via a signaling pathway involving APOE as extracellular ligand, SHP-2 recruitment, uPAR upregulation, and ARG1 expression; deletion of LILRB4 or antibody blockade impedes AML development in mouse models.","method":"Mouse AML models (syngeneic and human cell xenograft); LILRB4 knockout; APOE-LILRB4 binding; SHP-2 co-immunoprecipitation; uPAR and ARG1 functional assays; T cell suppression co-culture; tissue infiltration assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ligand-receptor-signaling axis defined by multiple orthogonal methods including KO, co-IP, and in vivo models, replicated in human cells and mouse","pmids":["30333625"],"is_preprint":false},{"year":2018,"finding":"Hepatic LILRB4 recruits SHP-1 to inhibit TRAF6 ubiquitination, subsequently inactivating NF-κB and MAPK cascades; hepatocyte-specific LILRB4 knockout exacerbates HFD-induced insulin resistance, hepatic lipid accumulation, and inflammation, while overexpression reverses these phenotypes.","method":"Hepatocyte-specific LILRB4 knockout mice; LILRB4 overexpression in ob/ob mice; SHP-1 co-immunoprecipitation; TRAF6 ubiquitination assay; NF-κB and MAPK activation western blotting; metabolic phenotyping","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — gain- and loss-of-function in vivo models with defined molecular mechanism (SHP-1 recruitment, TRAF6 ubiquitination) validated by co-IP","pmids":["29091299"],"is_preprint":false},{"year":2019,"finding":"LILRB4 ITIMs: Y412 and Y442 phosphorylation sites are required for T cell suppression, while Y360 is not; all three ITIMs (Y360, Y412, Y442) are required for leukemia cell tissue infiltration; the intracellular domain of LILRB4 (not LILRB1) specifically mediates T cell suppression and AML cell migration in chimeric protein swap experiments.","method":"Site-directed mutagenesis of LILRB4 ITIM tyrosines; chimeric LILRB4/LILRB1 intracellular domain swap constructs; in vitro T cell suppression co-culture; in vivo AML infiltration mouse models","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — systematic mutagenesis of all three ITIMs with both in vitro and in vivo functional validation, and domain-swap controls","pmids":["31700117"],"is_preprint":false},{"year":2019,"finding":"Humanized anti-LILRB4 antibody h128-3 blocks LILRB4-APOE interaction and exerts anti-AML activity through four mechanisms: reversal of T cell suppression, inhibition of AML cell tissue infiltration, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis.","method":"LILRB4-APOE blocking assay; patient-derived xenograft mice; syngeneic immunocompetent AML mice; ADCC and ADCP functional assays; T cell co-culture","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple mechanistic readouts validated in multiple in vivo models with a defined blocking antibody","pmids":["31213474"],"is_preprint":false},{"year":2017,"finding":"LILRB4 deficiency in macrophages promotes atherosclerosis by decreasing SHP-1 phosphorylation, which enhances NF-κB signaling-mediated inflammatory responses; bone marrow-specific LILRB4 deficiency recapitulates the pro-atherosclerotic phenotype.","method":"LILRB4−/−ApoE−/− double-knockout mice on HFD; bone marrow transplantation; SHP-1 phosphorylation western blotting; NF-κB activation assays; in vitro macrophage stimulation","journal":"Clinical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with bone marrow transplant and defined SHP-1/NF-κB mechanism, single lab","pmids":["28743735"],"is_preprint":false},{"year":2021,"finding":"Fibronectin is a functional ligand for ILT3/LILRB4; fibronectin-ILT3 interaction polarizes myeloid cells toward a suppressive state; anti-ILT3 antibody blocking this interaction reprograms tumor-associated myeloid cells toward a stimulatory phenotype in human tumor explants.","method":"Ligand screening approach; myeloid cell polarization assays; anti-ILT3 blocking antibody; ex vivo human tumor explant treatment; phenotypic cytokine/surface marker analysis","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional ligand identified by screening with mechanistic follow-up in primary human tumor explants, replicated in mouse models","pmids":["34426457"],"is_preprint":false},{"year":2021,"finding":"Human LILRB4 and murine gp49B bind fibronectin with sub-micromolar affinity; the major binding site is the N-terminal 30-kDa module (FN30), distinct from the integrin-binding site; blockade of LILRB4-fibronectin interaction with anti-LILRB4 antibodies or recombinant FN30-Fc ameliorates autoimmune disease in lupus-prone BXSB/Yaa mice.","method":"Bio-layer interferometry binding kinetics; FN domain mapping; LILRB4-KO and blocking antibody in BXSB/Yaa mice; functional autoimmunity readouts","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — quantitative binding kinetics with domain mapping, functional in vivo validation with KO and antibody blockade","pmids":["34089617"],"is_preprint":false},{"year":2022,"finding":"LILRB4/gp49B co-tethers fibronectin in cooperation with integrin β1 in cis on macrophages, forming a regulatory triplet; adherence to immobilized FN induces Syk phosphorylation that is augmented in gp49B-deficient macrophages, demonstrating that gp49B suppresses integrin-mediated pro-inflammatory Syk signaling at focal adhesions.","method":"FN pull-down co-immunoprecipitation with gp49B and integrin β1; confocal co-localization microscopy; Syk phosphorylation western blotting in WT vs gp49B-KO macrophages; RAW264.7 and THP-1 cell models","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and KO with defined signaling readout, single lab","pmids":["35689642"],"is_preprint":false},{"year":2023,"finding":"Fibronectin on target cells attenuates NK cell natural cytotoxicity via gp49B/LILRB4; gp49B-deficient NK cells show augmented Syk phosphorylation upon FN binding and enhanced killing of fibronectin-rich Lewis lung carcinoma cells (but not FN30-knockout cells), demonstrating that LILRB4 senses fibronectin on target cells in trans to deliver inhibitory signals in NK cells.","method":"gp49B-KO NK cells; cytotoxicity assays against FN-rich and FN-poor tumor cells; FN30-knockout target cells; Syk phosphorylation analysis; confocal and flow cytometric analysis of gp49B/integrin co-engagement","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic KO with functional cytotoxicity assay, FN30-KO target cell controls, and biochemical Syk readout","pmids":["37083755"],"is_preprint":false},{"year":2023,"finding":"Fibronectin-LILRB4/gp49B interaction negatively regulates osteoclastogenesis: gp49B-deficient mice show reduced trabecular bone; FN N-terminal 30-kDa fragment promotes gp49B-mediated inhibition of osteoclast differentiation by increasing SHP-1 phosphorylation and TRAF6-SHP-1 association, thereby suppressing RANKL-induced TAK1/NF-κB/MAPK signaling.","method":"gp49B-KO mice with bone phenotyping (micro-CT, histology); RAW264.7 osteoclastogenesis assays with FN30; SHP-1 phosphorylation; TRAF6-SHP-1 co-immunoprecipitation; TAK1/NF-κB/MAPK western blotting","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo KO with defined mechanism validated by co-IP and signaling cascade analysis in vitro","pmids":["36331874"],"is_preprint":false},{"year":2020,"finding":"ILT3/LILRB4 promotes the suppressive phenotype of tumor-educated monocytic MDSCs; anti-ILT3 antibody treatment impairs acquisition of MDSC suppressor phenotype and reduces T cell suppression; combined ILT3 blockade with anti-PD1 enhances T cell IFNγ secretion.","method":"SK-MEL-5 cancer cell/PBMC co-culture MDSC generation; anti-ILT3 antibody blockade; T cell proliferation and IFNγ assays; flow cytometry phenotyping; anti-PD1 combination","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional antibody blockade with multiple readouts, single lab","pmids":["33372059"],"is_preprint":false},{"year":2021,"finding":"In solid tumors, LILRB4-knockout mice or anti-LILRB4 antibody treatment reduces tumor burden and increases survival; LILRB4 absence increases tumor immune infiltrates, raises Teff/Treg ratio, shifts TAMs toward less suppressive phenotype, and reduces CD8+ T cell exhaustion; murine gp49B is the LILRB4 ortholog with two cytoplasmic ITIMs (vs three in human).","method":"LILRB4−/− mice; anti-LILRB4 antibody treatment; syngeneic tumor models; flow cytometry of tumor-infiltrating lymphocytes and macrophages; survival analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with antibody blockade in multiple tumor models with comprehensive immune phenotyping","pmids":["33974041"],"is_preprint":false},{"year":2022,"finding":"gp49B (murine LILRB4) deficiency inhibits tumor metastasis and reduces monocytic MDSC tumor infiltration; gp49B-KO MDSCs show impaired pro-tumor functions (Treg activation, cancer cell migration, tumor angiogenesis) and increased plasma exosome miR-1 family miRNAs with anti-tumor properties.","method":"gp49B−/− tumor-bearing mice; tumor metastasis assays; MDSC transfer experiments; exosome miRNA profiling; functional MDSC co-culture assays","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with adoptive transfer validation, single lab","pmids":["35402083"],"is_preprint":false},{"year":2024,"finding":"Galectin-8 (Gal-8) is a high-affinity functional ligand of LILRB4 that drives M-MDSC induction by activating STAT3 and inhibiting NF-κB; Gal-8 and APOE bind LILRB4 noncompetitively at distinct sites; LILRB4 knockout attenuates Gal-8-driven tumor growth in vivo.","method":"Ligand screening; binding affinity measurements; STAT3 and NF-κB activation assays in MDSC induction; competitive binding assays; LILRB4-KO mouse tumor models","journal":"Cell reports. Medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — new ligand identified with binding characterization, mechanistic signaling readouts, and in vivo KO validation","pmids":["38232701"],"is_preprint":false},{"year":2024,"finding":"Microglia-specific LILRB4 conditional knockout exacerbates ischemic brain injury by promoting CD8+ T cell infiltration; LILRB4-KD microglia show increased CCL2 secretion mediating CD8+ T cell recruitment, which is reversed by CCL2 inhibition; LILRB4 overexpression in microglia is neuroprotective.","method":"Microglia-specific Cre-loxP LILRB4 conditional KO and TG overexpression mice; tMCAO model; flow cytometry; scRNA-seq; spatial transcriptomics; T cell migration assays; CCL2 inhibition; recombinant arginase-1","journal":"Journal of neuroinflammation","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO and TG with mechanistic rescue experiments (CCL2 inhibition, arginase-1), multiple orthogonal methods","pmids":["39217343"],"is_preprint":false},{"year":2023,"finding":"LILRB4 regulates decidual MDSC function via a SHP-2/STAT6 pathway: T. gondii infection reduces STAT3 phosphorylation, decreasing LILRB4 expression on dMDSCs, which reduces p-SHP2 and p-STAT6 levels; SHP-2 directly binds STAT6, which binds the Arg-1 and IL-10 gene promoters to regulate their expression.","method":"LILRB4−/− pregnant mice infected with T. gondii; anti-LILRB4 neutralizing antibody in human dMDSCs; SHP-2/STAT6 co-immunoprecipitation; STAT6 ChIP on Arg-1 and IL-10 promoters; western blotting","journal":"Parasites & vectors","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic in vitro co-IP and ChIP with in vivo KO model, single lab","pmids":["37461040"],"is_preprint":false},{"year":2025,"finding":"Secretogranin 2 (SCG2) is a functional ligand of LILRB4 on monocytic cells; tumor-derived SCG2 promotes tumor growth in myeloid-specific LILRB4 transgenic mice in a T cell-dependent manner; LILRB4 blockade abrogates SCG2-induced immunosuppression; mechanistically, SCG2-LILRB4 interaction triggers SHP recruitment and SHP-independent STAT3 activation.","method":"LILRB4-SCG2 binding assay; myeloid-specific LILRB4 transgenic mice; SCG2-knockout host mice; T cell depletion; anti-LILRB4 blockade; SHP co-immunoprecipitation; STAT3 activation assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — new ligand identified with genetic and pharmacological validation, defined dual signaling mechanism (SHP-dependent and SHP-independent STAT3), in vivo confirmation","pmids":["40707822"],"is_preprint":false},{"year":2024,"finding":"LILRB4 on multiple myeloma cells promotes osteoclastogenesis and bone lesion by secreting RELT cytokine through a p-SHP2/NF-κB/RELT signaling pathway; LILRB4-KO conditioned medium does not promote osteoclast differentiation; exogenous RELT restores bone damage in LILRB4-KO cells.","method":"Conditioned medium osteoclast differentiation assays; xenograft and PDX models with micro-CT; cytokine array; RNA-seq; Co-IP; luciferase reporter; CRISPR-Cas9 LILRB4 deletion; RELT rescue experiments","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic pathway defined by co-IP, cytokine array, rescue experiments, and multiple in vivo models","pmids":["38951916"],"is_preprint":false},{"year":2025,"finding":"In myocardial ischemia-reperfusion injury, LILRB4 promotes inflammation and pyroptosis via SHP-2 phosphorylation/activation, increasing TXNIP, NLRP3, Caspase-1, and GSDMD expression; SHP2 inhibitor PHPS1 mitigates LILRB4-driven inflammation; LILRB4-KO mice show reduced pyroptosis markers and inflammatory cytokines after I/R.","method":"LILRB4 overexpression and knockdown in H9C2 cells and rat myocardium; LILRB4-KO mice; I/R and H/R models; SHP-2 phosphorylation western blotting; NLRP3/Caspase-1/GSDMD expression; SHP2 inhibitor PHPS1","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice and pharmacological inhibition defining SHP-2/TXNIP/NLRP3 axis, single lab","pmids":["40550372"],"is_preprint":false},{"year":2024,"finding":"In multiple myeloma, IKZF1 transactivates LILRB4 expression to activate downstream STAT3-PFKFB1 signaling supporting MM cell proliferation; LILRB4 knockdown delays MM cell growth in vitro and in vivo.","method":"IKZF1 ChIP/luciferase reporter for LILRB4 transcription; LILRB4 knockdown; STAT3 and PFKFB1 western blotting; in vivo MM xenograft models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional driver identified with functional pathway validation in vitro and in vivo, single lab","pmids":["39025844"],"is_preprint":false},{"year":2020,"finding":"ILT3-Fc treatment inhibits release of inflammatory microRNA-containing exosomes from alloactivated CD4+ T cells; these inflammatory exosomes can diminish the suppressive activity of ILT3-Fc-induced CD8+ T suppressor cells at high effector-to-suppressor ratios.","method":"Exosome isolation from mixed lymphocyte cultures ± ILT3-Fc; miRNA profiling; suppressor cell activity assays with exosome addition","journal":"Human immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect functional assay, limited mechanistic detail in abstract","pmids":["24862932"],"is_preprint":false},{"year":2025,"finding":"Homoharringtonine (HHT) suppresses LILRB4 expression in monocytic AML by promoting FTO degradation, which increases global m6A RNA methylation, subsequently reducing expression of MLL1 and LILRB4; reduced LILRB4 enhances CD8+ T cell cytotoxicity against THP-1 cells.","method":"RNA-seq; FTO protein degradation assays; m6A level measurement; LILRB4 mRNA/protein western blotting; CD8+ T cell cytotoxicity assays; in vivo AML xenograft mouse models","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined FTO/m6A/LILRB4 regulatory axis with in vivo validation, single lab","pmids":["40590394"],"is_preprint":false}],"current_model":"LILRB4 is an ITIM-containing inhibitory receptor on myeloid cells (monocytes, macrophages, DCs, AML blasts) that, upon binding extracellular ligands (APOE, fibronectin, galectin-8, CD166/ALCAM, SCG2), recruits SHP-1 or SHP-2 to its cytoplasmic ITIMs (with Y412 and Y442 required for T cell suppression and all three ITIMs needed for tissue infiltration), leading to dephosphorylation of activating kinases (Lck, Syk, Erk), inhibition of NF-κB and MAPK signaling, and downstream immunosuppressive outputs including T cell suppression (via ARG1 and uPAR), MDSC polarization (via STAT3/NF-κB), and regulation of osteoclastogenesis (via TRAF6-SHP-1-TAK1/NF-κB/MAPK); its extracellular domain can also signal in trans to suppress T cell Akt activation (through SHIP1 clustering at the BCR) and NK cell cytotoxicity (by sensing fibronectin on target cells), while soluble ILT3-Fc acts through CD166 to inhibit p70S6K and induce T suppressor cell differentiation via BCL6 upregulation."},"narrative":{"mechanistic_narrative":"LILRB4 (ILT3) is an ITIM-bearing inhibitory receptor of myeloid cells (monocytes, dendritic cells, macrophages) that, upon engagement, dampens activating immunoreceptor signaling and drives tolerogenic and immunosuppressive programs [PMID:9151699, PMID:19833736]. The founding mechanism is recruitment of SH2-containing tyrosine phosphatases to its cytoplasmic ITIMs upon co-ligation with stimulatory receptors, extinguishing calcium flux and the tyrosine phosphorylation of activating kinases (Lck, Syk, LAT, Erk) and suppressing NF-κB/MAPK output and inflammatory cytokine production [PMID:9151699, PMID:19833736, PMID:29091299]. Systematic ITIM mutagenesis established that Y412 and Y442 are required for T cell suppression while all three ITIMs (Y360, Y412, Y442) are needed for leukemic tissue infiltration, and domain-swap experiments showed the LILRB4 intracellular tail specifically confers these functions [PMID:31700117]. A crystal structure of the two-Ig-domain ectodomain showed an obtuse interdomain angle incompatible with MHC class I binding, predicting non-MHC ligands [PMID:21454581]; subsequent screens identified APOE, fibronectin, CD166/ALCAM, galectin-8, and secretogranin-2 as functional ligands that act through SHP-1/SHP-2 recruitment and, for some, SHP-independent STAT3 activation [PMID:29263213, PMID:30333625, PMID:34426457, PMID:38232701, PMID:40707822]. Through these axes LILRB4 polarizes myeloid-derived suppressor cells and tumor-associated myeloid cells, upregulates ARG1 and uPAR, and suppresses T cells, supporting AML and solid tumor immune evasion such that genetic deletion or antibody blockade reduces tumor burden and restores T cell function [PMID:30333625, PMID:31213474, PMID:34426457, PMID:33372059, PMID:33974041]. The same inhibitory machinery operates beyond cancer: it restrains hepatic and macrophage inflammation (limiting insulin resistance and atherosclerosis via SHP-1/TRAF6/NF-κB) [PMID:29091299, PMID:28743735], curbs NK cytotoxicity and osteoclastogenesis by sensing fibronectin [PMID:37083755, PMID:36331874], and protects against ischemic brain injury [PMID:39217343]. A soluble/extracellular form (soluble ILT3, ILT3-Fc) acts in trans through CD166 to inhibit p70S6K and induce CD8+ T suppressor cells via BCL6 upregulation [PMID:17161342, PMID:29263213, PMID:28931525].","teleology":[{"year":1997,"claim":"Established LILRB4/ILT3 as an inhibitory receptor by showing co-ligation extinguishes activating-receptor signaling through phosphatase recruitment, defining its core mechanism.","evidence":"Co-ligation calcium/phosphorylation assays and SHP-1 co-IP in primary monocytes/DCs, plus antigen presentation assays","pmids":["9151699"],"confidence":"High","gaps":["Ligand(s) unknown at this stage","Relative contribution of individual ITIMs not resolved"]},{"year":2002,"claim":"Connected ILT3 upregulation to tolerance induction, showing CD8+ T suppressor cells render APCs tolerogenic, framing ILT3 as an effector of immune tolerance.","evidence":"T suppressor cell–APC co-cultures with flow cytometry and anergy assays, validated in transplant recipients","pmids":["11875462"],"confidence":"High","gaps":["Molecular signaling linking upregulation to tolerogenic output not dissected","Ligand still unidentified"]},{"year":2006,"claim":"Showed the extracellular domain alone mediates suppression independent of cytoplasmic ITIMs, revealing a trans-acting/soluble mode of action distinct from classical ITIM signaling.","evidence":"Cytoplasmic deletion mutants in KG1 cells and recombinant soluble ILT3 in T cell assays","pmids":["17161342"],"confidence":"Medium","gaps":["Receptor on T cells for the ectodomain not identified here","Single lab"]},{"year":2009,"claim":"Demonstrated LILRB4 co-ligation with FcγRI suppresses kinase phosphorylation and cytokine output, but pharmacology implicated phosphatases beyond SHP-1, refining the signaling model.","evidence":"Co-ligation assays in THP-1/monocytes with phospho-blotting, TNFα ELISA, and phosphatase inhibitor dissection","pmids":["19833736"],"confidence":"High","gaps":["Identity of non-SHP-1 phosphatase not pinned down","Endogenous physiological co-ligand unknown"]},{"year":2011,"claim":"Solved the ectodomain structure, showing it is unsuited to MHC class I and predicting non-MHC ligands, redirecting ligand discovery.","evidence":"1.7 Å crystal structure with engineered disulfide and comparative structural analysis","pmids":["21454581"],"confidence":"High","gaps":["Actual ligand-binding surface confirmed only by inference","No ligand co-crystal"]},{"year":2017,"claim":"Identified CD166/ALCAM as the receptor for soluble ILT3-Fc on T cells, providing the missing ligand for the ectodomain-mediated suppression and a tumor-inhibitory p70S6K axis.","evidence":"Mass spec/Biacore ligand ID, CD166 knockdown and CRISPR KO, p70S6K blotting, xenograft","pmids":["29263213"],"confidence":"High","gaps":["Whether membrane LILRB4 uses CD166 in cis not addressed","Downstream of p70S6K incomplete"]},{"year":2017,"claim":"Showed ectopic ILT3 in CLL B cells forms inhibitory ILT3-BCR-SHIP1 clusters to block Akt, extending inhibitory function to lymphoid contexts via a defined phosphatase complex.","evidence":"Deltex1-driven expression, BCR stimulation, Akt blotting, co-IP of ILT3-BCR-SHIP1","pmids":["28931525"],"confidence":"High","gaps":["Physiological relevance outside CLL unclear","Ligand triggering in this setting not defined"]},{"year":2018,"claim":"Defined the APOE–LILRB4–SHP-2–uPAR–ARG1 axis in monocytic AML, establishing LILRB4 as a druggable driver of leukemic T cell suppression and tissue infiltration.","evidence":"Mouse AML models, LILRB4 KO, APOE binding, SHP-2 co-IP, ARG1/uPAR assays","pmids":["30333625"],"confidence":"High","gaps":["How APOE selectively engages over other ligands unclear","Quantitative ligand affinity not given"]},{"year":2018,"claim":"Showed hepatic LILRB4 restrains metabolic inflammation via SHP-1–TRAF6–NF-κB/MAPK, extending the inhibitory mechanism to a protective non-immune-cell role.","evidence":"Hepatocyte-specific KO and overexpression mice, SHP-1 co-IP, TRAF6 ubiquitination assay, metabolic phenotyping","pmids":["29091299"],"confidence":"High","gaps":["Activating ligand in liver not identified","Receptor-proximal events upstream of SHP-1 unclear"]},{"year":2019,"claim":"Dissected the ITIM code, mapping Y412/Y442 to T cell suppression and all three ITIMs to infiltration, and proved the intracellular domain is functionally specific to LILRB4.","evidence":"Site-directed ITIM mutagenesis and LILRB4/LILRB1 domain-swap chimeras in T cell and AML models","pmids":["31700117"],"confidence":"High","gaps":["Differential phosphatase recruitment by each ITIM not resolved","Structural basis of ITIM selectivity unknown"]},{"year":2021,"claim":"Identified fibronectin (FN30 module) as a high-affinity ligand mediating myeloid suppression and inhibitory signaling, broadening LILRB4 ligand repertoire to ECM.","evidence":"Ligand screening, BLI/binding kinetics, domain mapping, blocking antibody in tumor explants and lupus-prone mice","pmids":["34426457","34089617"],"confidence":"High","gaps":["Cis vs trans engagement context-dependent","Integration with APOE signaling not resolved here"]},{"year":2022,"claim":"Showed LILRB4/gp49B co-tethers fibronectin with integrin β1 to suppress FN-induced Syk signaling at focal adhesions, revealing a cis-regulatory triplet.","evidence":"FN pull-down co-IP with integrin β1, confocal co-localization, Syk blotting in WT vs KO macrophages","pmids":["35689642"],"confidence":"Medium","gaps":["Single lab","Direct vs integrin-bridged FN binding not fully separated"]},{"year":2023,"claim":"Extended fibronectin sensing to NK cells and bone, showing LILRB4 senses FN on target cells in trans to limit NK cytotoxicity and inhibits osteoclastogenesis via SHP-1–TRAF6–TAK1/NF-κB/MAPK.","evidence":"gp49B-KO NK cytotoxicity with FN30-KO controls and Syk blotting; gp49B-KO bone phenotyping with TRAF6-SHP-1 co-IP","pmids":["37083755","36331874"],"confidence":"High","gaps":["Threshold of FN density for trans signaling unclear","Crosstalk with activating NK receptors not mapped"]},{"year":2024,"claim":"Identified galectin-8 and secretogranin-2 as additional ligands acting through SHP recruitment plus SHP-independent STAT3 to drive MDSC induction, showing multiple ligands engage noncompetitively.","evidence":"Ligand screening, binding/competition assays, STAT3/NF-κB readouts, LILRB4-KO and transgenic tumor models","pmids":["38232701","40707822"],"confidence":"High","gaps":["Hierarchy among multiple ligands in vivo unknown","Structural basis of distinct binding sites not solved"]},{"year":2024,"claim":"Revealed LILRB4 cell-intrinsic oncogenic and protective roles, transactivated by IKZF1 to drive MM proliferation via STAT3-PFKFB1 and secreting RELT to drive myeloma bone lesions, while microglial LILRB4 protects against ischemic injury.","evidence":"IKZF1 ChIP/reporter and STAT3-PFKFB1 blotting in MM; CRISPR KO with RELT rescue and micro-CT; microglia-specific conditional KO/TG in stroke model with CCL2 inhibition","pmids":["39025844","38951916","39217343"],"confidence":"High","gaps":["Whether ligand engagement is required for these intrinsic outputs unclear","Tissue-specific signaling divergence not unified"]},{"year":2025,"claim":"Defined therapeutic and regulatory leverage points: SHP-2-driven cardiomyocyte pyroptosis and homoharringtonine-mediated FTO/m6A suppression of LILRB4, indicating both signaling and expression are targetable.","evidence":"LILRB4-KO and SHP2 inhibitor PHPS1 in cardiac I/R; FTO degradation/m6A assays with CD8 cytotoxicity in AML","pmids":["40550372","40590394"],"confidence":"Medium","gaps":["Single-lab mechanisms","Cardiac ligand and upstream trigger undefined"]},{"year":null,"claim":"How distinct ligands (APOE, fibronectin, CD166, galectin-8, SCG2) are integrated to select between SHP-dependent and SHP-independent STAT3 outputs, and the structural basis for their noncompetitive binding, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No ligand-bound structure","Rules governing context-specific signaling output unknown","Relative in vivo dominance of each ligand undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,6,14,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,6,15]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[13,18,26,29]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[12,22]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6,7,11]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[5,9,11]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,13,24]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,14,13,29]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,14,17,30]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[31]}],"complexes":["LILRB4-BCR-SHIP1 inhibitory cluster","LILRB4/gp49B-integrin β1 fibronectin co-tethering triplet"],"partners":["PTPN6 (SHP-1)","PTPN11 (SHP-2)","INPP5D (SHIP1)","TRAF6","APOE","ALCAM (CD166)","ITGB1","FN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NHJ6","full_name":"Leukocyte immunoglobulin-like receptor subfamily B member 4","aliases":["CD85 antigen-like family member K","Immunoglobulin-like transcript 3","ILT-3","Leukocyte immunoglobulin-like receptor 5","LIR-5","Monocyte inhibitory receptor HM18"],"length_aa":448,"mass_kda":49.4,"function":"Inhibitory receptor involved in the down-regulation of the immune response and the development of immune tolerance (PubMed:11875462). Receptor for FN1 (PubMed:34089617). Receptor for apolipoprotein APOE (PubMed:30333625). Receptor for ALCAM/CD166 (PubMed:29263213). Inhibits receptor-mediated phosphorylation of cellular proteins and mobilization of intracellular calcium ions (PubMed:9151699). Inhibits FCGR1A/CD64-mediated monocyte activation by inducing phosphatase-mediated down-regulation of the phosphorylation of multiple proteins including LCK, SYK, LAT and ERK, leading to a reduction in TNF production (PubMed:19833736). This inhibition of monocyte activation occurs at least in part via binding to FN1 (PubMed:34089617). Inhibits T cell proliferation, inducing anergy, suppressing the differentiation of IFNG-producing CD8+ cytotoxic T cells and enhancing the generation of CD8+ T suppressor cells (PubMed:16493035, PubMed:19833736, PubMed:29263213). Induces up-regulation of CD86 on dendritic cells (PubMed:19860908). Interferes with TNFRSF5-signaling and NF-kappa-B up-regulation (PubMed:11875462)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8NHJ6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LILRB4","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LILRB4","total_profiled":1310},"omim":[{"mim_id":"607517","title":"LEUKOCYTE IMMUNOGLOBULIN-LIKE RECEPTOR, SUBFAMILY A, MEMBER 4; LILRA4","url":"https://www.omim.org/entry/607517"},{"mim_id":"606047","title":"LEUKOCYTE IMMUNOGLOBULIN-LIKE RECEPTOR, SUBFAMILY A, MEMBER 5; LILRA5","url":"https://www.omim.org/entry/606047"},{"mim_id":"604821","title":"LEUKOCYTE IMMUNOGLOBULIN-LIKE RECEPTOR, SUBFAMILY B, MEMBER 4; LILRB4","url":"https://www.omim.org/entry/604821"},{"mim_id":"604820","title":"LEUKOCYTE IMMUNOGLOBULIN-LIKE RECEPTOR, SUBFAMILY B, MEMBER 3; LILRB3","url":"https://www.omim.org/entry/604820"},{"mim_id":"604815","title":"LEUKOCYTE IMMUNOGLOBULIN-LIKE RECEPTOR, SUBFAMILY B, MEMBER 2; LILRB2","url":"https://www.omim.org/entry/604815"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":13.5},{"tissue":"lung","ntpm":13.1},{"tissue":"lymphoid tissue","ntpm":17.7}],"url":"https://www.proteinatlas.org/search/LILRB4"},"hgnc":{"alias_symbol":["LIR-5","ILT3","HM18","LIR5","CD85k"],"prev_symbol":[]},"alphafold":{"accession":"Q8NHJ6","domains":[{"cath_id":"2.60.40.10","chopping":"31-118","consensus_level":"high","plddt":92.5619,"start":31,"end":118},{"cath_id":"2.60.40.10","chopping":"123-219","consensus_level":"high","plddt":85.3359,"start":123,"end":219}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NHJ6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NHJ6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NHJ6-F1-predicted_aligned_error_v6.png","plddt_mean":65.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LILRB4","jax_strain_url":"https://www.jax.org/strain/search?query=LILRB4"},"sequence":{"accession":"Q8NHJ6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NHJ6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NHJ6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NHJ6"}},"corpus_meta":[{"pmid":"11875462","id":"PMC_11875462","title":"Tolerization 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signal extinction involves recruitment of SH2-containing protein tyrosine phosphatase 1 (SHP-1) to ILT3 upon cross-linking. ILT3 also mediates antigen internalization and delivery to intracellular compartments for MHC-II processing and T cell presentation.\",\n      \"method\": \"Co-ligation assays with calcium flux and tyrosine phosphorylation readouts; SHP-1 co-immunoprecipitation after cross-linking; internalization and antigen presentation assays in primary monocytes/DCs\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal biochemical methods (calcium signaling, phosphorylation, co-IP of SHP-1, functional antigen presentation) in a single rigorous founding paper\",\n      \"pmids\": [\"9151699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD8+CD28− alloantigen-specific T suppressor cells induce upregulation of ILT3 and ILT4 on monocytes and dendritic cells, rendering APCs tolerogenic with reduced costimulatory molecule expression and capacity to induce antigen-specific unresponsiveness in CD4+ T helper cells.\",\n      \"method\": \"In vitro co-culture of T suppressor cells with APCs; flow cytometry for ILT3/ILT4 and costimulatory molecules; allogeneic T cell proliferation and anergy assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional co-culture experiments with phenotypic and functional readouts, replicated in human transplant recipients\",\n      \"pmids\": [\"11875462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Tolerogenic DCs with high ILT3 and ILT4 expression anergize alloreactive CD4+CD45RO+CD25+ T cells and convert them into regulatory T cells; IL-10 and IFN-α also induce ILT3 and ILT4 upregulation in DCs, rendering them tolerogenic, indicating a common cytokine-driven mechanism.\",\n      \"method\": \"In vitro cytokine stimulation (IL-10, IFN-α) of DCs; co-culture with T cells; flow cytometry and functional suppression assays\",\n      \"journal\": \"Transplant immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays with cytokine stimulation, single lab, multiple readouts\",\n      \"pmids\": [\"12967778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Alloantigen-specific CD8+CD28−FOXP3+ T suppressor cells interact with endothelial cells and induce upregulation of ILT3 and ILT4 on endothelial cells, downregulating costimulatory/adhesion molecules and rendering endothelial cells tolerogenic; tolerized endothelial cells in turn elicit differentiation of additional CD8+CD28−FOXP3+ T suppressor cells.\",\n      \"method\": \"RT-PCR; in vitro co-culture of T suppressor cells with HUVECs; flow cytometry; luciferase transcription assays\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional co-culture with phenotypic and transcriptional readouts, single lab\",\n      \"pmids\": [\"15226269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-10 stimulation of human endothelial cells upregulates ILT3 and ILT4 surface expression via STAT-3 signaling and involves glucocorticoid-induced leucine zipper (GILZ); blocking ILT3/ILT4 with antibodies nearly completely restores T cell proliferation inhibited by IL-10-pretreated endothelial cells, and overexpression of ILT3 in co-cultures significantly reduces T cell proliferation.\",\n      \"method\": \"IL-10 stimulation of HUVECs; blocking antibody experiments in endothelial-T cell co-cultures; ILT3 overexpression; STAT-3 signaling analysis\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional gain- and loss-of-function experiments with ILT3 in endothelial-T cell co-cultures, single lab\",\n      \"pmids\": [\"17163451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Overexpression of membrane ILT3 in APCs inhibits NF-κB activation and transcription of costimulatory molecules; soluble ILT3 (sILT3) released by alternative splicing that eliminates the transmembrane domain is immunosuppressive, inducing CD8+ T suppressor cells and impairing T cell responses, effects reversible by anti-ILT3 mAb or sILT3 depletion.\",\n      \"method\": \"Humanized SCID mouse model; soluble ILT3 protein from patient serum; mixed lymphocyte culture; anti-ILT3 mAb blocking; immunohistochemistry; RT-PCR for splice variants\",\n      \"journal\": \"JOP : Journal of the pancreas\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model plus functional reversal by antibody, single lab\",\n      \"pmids\": [\"17993722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LILRB4 co-ligation with FcγRI (CD64) on THP-1 monocytic cells potently inhibits TNFα production and reduces phosphorylation of Lck, Syk, LAT, Erk, and c-Cbl but not α-actinin-4; LILRB4 aggregates to sites of CD64 activation upon co-ligation; phosphatase inhibitor pervanadate reverses inhibition but SHP-1-specific inhibitor sodium stibogluconate does not, implicating phosphatase(s) other than SHP-1.\",\n      \"method\": \"Co-ligation assays on THP-1 cells and primary monocytes; TNFα ELISA; phospho-protein western blotting; phosphatase inhibitor experiments; confocal microscopy of receptor aggregation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal biochemical methods including kinase phosphorylation, functional cytokine assays, and pharmacological dissection in one rigorous study\",\n      \"pmids\": [\"19833736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of the LILRB4 ectodomain resolved to 1.7 Å reveals two immunoglobulin domains; D2 domain (most similar to D4 of other LILRs) contains unique 3(10) helices; reduced D1-D2 interdomain contacts produce an obtuse interdomain angle (~107°); electrostatic and conformational analysis indicates LILRB4 is unsuited to MHC class I ligation, consistent with binding non-MHC class I ligands; distinctive surface patches on D1 and D1-D2 hinge region are candidate ligand-binding sites.\",\n      \"method\": \"Protein crystallography (1.7 Å resolution); engineered disulfide bond in D2 for stability; structural comparison with MHC-binding LILRs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with mutagenesis (engineered disulfide) and comparative structural analysis\",\n      \"pmids\": [\"21454581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Overexpression of membrane ILT3 in APCs inhibits tyrosine phosphorylation, NF-κB and MAPK p38 activity, and transcription of costimulatory molecules, cytokines, and chemokines; soluble ILT3-Fc (containing only the extracellular Ig-like domain fused to mutated IgG1 Fc) acts extracellularly to induce CD4 T helper anergy and differentiation of antigen-specific CD8 T suppressor cells in vitro and in vivo.\",\n      \"method\": \"ILT3 overexpression in dendritic cell lines; ILT3-Fc recombinant protein treatment; NF-κB reporter assays; in vitro and in vivo (humanized NOD/SCID) tolerance models\",\n      \"journal\": \"International reviews of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression with multiple signaling readouts and in vivo validation, single lab\",\n      \"pmids\": [\"20132030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ILT3 cytoplasmic deletion mutant (ILT3Δ) retains suppressive activity in T cell proliferation and cytotoxicity assays (unlike ILT4Δ which loses activity), demonstrating that the extracellular domain of ILT3 mediates suppression independently of the cytoplasmic ITIMs; soluble recombinant ILT3 inhibits T helper and cytotoxic function and induces CD8+ T suppressor cell differentiation.\",\n      \"method\": \"Cytoplasmic deletion mutants transfected into KG1 dendritic-like cell line; T cell proliferation and cytotoxicity assays; recombinant soluble ILT3 treatment\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function mutagenesis with functional T cell assays, single lab\",\n      \"pmids\": [\"17161342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ILT3-Fc-induced CD8+ T suppressor cells show significant upregulation of BCL6 (a transcriptional repressor of IL-2, IFN-γ, IL-5, and granzyme B), SOCS1, and DUSP10; these genes define the Ts signature and are targeted by miRNAs suppressed by ILT3-Fc; ILT3-Fc induces tolerance to allogeneic human islets and reverses rejection in a humanized NOD/SCID model.\",\n      \"method\": \"Gene expression profiling; ILT3-Fc treatment of CD8+ T cells; BCL6 functional analysis; humanized NOD/SCID mouse model; miRNA analysis\",\n      \"journal\": \"Experimental and molecular pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene profiling with in vivo validation, single lab, multiple readouts\",\n      \"pmids\": [\"23018130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ILT3.Fc binds to CD166/ALCAM on the surface of activated T cells (identified by flow cytometry, mass spectrometry, and Biacore); CD166 knockdown abrogates ILT3.Fc-mediated inhibition of CD4+ T helper proliferation and induction of CD8+CD28− T suppressor cells; ILT3.Fc-CD166 interaction inhibits tumor cell growth via inactivation of the p70S6K signaling pathway; CRISPR-Cas9 knockout of CD166 abolishes ILT3.Fc binding and tumor-inhibitory effect.\",\n      \"method\": \"Flow cytometry; mass spectrometry; Biacore binding kinetics; nucleofection-based CD166 knockdown; CRISPR-Cas9 knockout; p70S6K western blotting; in vivo NOD.Cg-Prkdc Il-2rg/SzJ mouse xenograft\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ligand identified by three orthogonal methods, functional validation by genetic knockdown and CRISPR KO, in vivo confirmation\",\n      \"pmids\": [\"29263213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In CLL B cells, ILT3 is ectopically expressed driven by the transcription factor Deltex1 (a suppressor of antigen receptor signaling); ILT3 triggering inhibits Akt kinase activation upon BCR stimulation by forming inhibitory clusters of ILT3, BCRs, and SHIP1 (INPP5D) at the cell surface.\",\n      \"method\": \"Transcriptional profiling of p66Shc-deficient CLL cells; Deltex1 overexpression; BCR stimulation with anti-IgM; Akt phosphorylation western blotting; co-immunoprecipitation of ILT3-BCR-SHIP1 clusters; flow cytometry\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic dissection with genetic driver identified, co-IP of signaling complex, and functional kinase readout\",\n      \"pmids\": [\"28931525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LILRB4 on monocytic AML cells supports tumor infiltration and T cell suppression via a signaling pathway involving APOE as extracellular ligand, SHP-2 recruitment, uPAR upregulation, and ARG1 expression; deletion of LILRB4 or antibody blockade impedes AML development in mouse models.\",\n      \"method\": \"Mouse AML models (syngeneic and human cell xenograft); LILRB4 knockout; APOE-LILRB4 binding; SHP-2 co-immunoprecipitation; uPAR and ARG1 functional assays; T cell suppression co-culture; tissue infiltration assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ligand-receptor-signaling axis defined by multiple orthogonal methods including KO, co-IP, and in vivo models, replicated in human cells and mouse\",\n      \"pmids\": [\"30333625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hepatic LILRB4 recruits SHP-1 to inhibit TRAF6 ubiquitination, subsequently inactivating NF-κB and MAPK cascades; hepatocyte-specific LILRB4 knockout exacerbates HFD-induced insulin resistance, hepatic lipid accumulation, and inflammation, while overexpression reverses these phenotypes.\",\n      \"method\": \"Hepatocyte-specific LILRB4 knockout mice; LILRB4 overexpression in ob/ob mice; SHP-1 co-immunoprecipitation; TRAF6 ubiquitination assay; NF-κB and MAPK activation western blotting; metabolic phenotyping\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — gain- and loss-of-function in vivo models with defined molecular mechanism (SHP-1 recruitment, TRAF6 ubiquitination) validated by co-IP\",\n      \"pmids\": [\"29091299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LILRB4 ITIMs: Y412 and Y442 phosphorylation sites are required for T cell suppression, while Y360 is not; all three ITIMs (Y360, Y412, Y442) are required for leukemia cell tissue infiltration; the intracellular domain of LILRB4 (not LILRB1) specifically mediates T cell suppression and AML cell migration in chimeric protein swap experiments.\",\n      \"method\": \"Site-directed mutagenesis of LILRB4 ITIM tyrosines; chimeric LILRB4/LILRB1 intracellular domain swap constructs; in vitro T cell suppression co-culture; in vivo AML infiltration mouse models\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — systematic mutagenesis of all three ITIMs with both in vitro and in vivo functional validation, and domain-swap controls\",\n      \"pmids\": [\"31700117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Humanized anti-LILRB4 antibody h128-3 blocks LILRB4-APOE interaction and exerts anti-AML activity through four mechanisms: reversal of T cell suppression, inhibition of AML cell tissue infiltration, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis.\",\n      \"method\": \"LILRB4-APOE blocking assay; patient-derived xenograft mice; syngeneic immunocompetent AML mice; ADCC and ADCP functional assays; T cell co-culture\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple mechanistic readouts validated in multiple in vivo models with a defined blocking antibody\",\n      \"pmids\": [\"31213474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LILRB4 deficiency in macrophages promotes atherosclerosis by decreasing SHP-1 phosphorylation, which enhances NF-κB signaling-mediated inflammatory responses; bone marrow-specific LILRB4 deficiency recapitulates the pro-atherosclerotic phenotype.\",\n      \"method\": \"LILRB4−/−ApoE−/− double-knockout mice on HFD; bone marrow transplantation; SHP-1 phosphorylation western blotting; NF-κB activation assays; in vitro macrophage stimulation\",\n      \"journal\": \"Clinical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with bone marrow transplant and defined SHP-1/NF-κB mechanism, single lab\",\n      \"pmids\": [\"28743735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Fibronectin is a functional ligand for ILT3/LILRB4; fibronectin-ILT3 interaction polarizes myeloid cells toward a suppressive state; anti-ILT3 antibody blocking this interaction reprograms tumor-associated myeloid cells toward a stimulatory phenotype in human tumor explants.\",\n      \"method\": \"Ligand screening approach; myeloid cell polarization assays; anti-ILT3 blocking antibody; ex vivo human tumor explant treatment; phenotypic cytokine/surface marker analysis\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional ligand identified by screening with mechanistic follow-up in primary human tumor explants, replicated in mouse models\",\n      \"pmids\": [\"34426457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human LILRB4 and murine gp49B bind fibronectin with sub-micromolar affinity; the major binding site is the N-terminal 30-kDa module (FN30), distinct from the integrin-binding site; blockade of LILRB4-fibronectin interaction with anti-LILRB4 antibodies or recombinant FN30-Fc ameliorates autoimmune disease in lupus-prone BXSB/Yaa mice.\",\n      \"method\": \"Bio-layer interferometry binding kinetics; FN domain mapping; LILRB4-KO and blocking antibody in BXSB/Yaa mice; functional autoimmunity readouts\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — quantitative binding kinetics with domain mapping, functional in vivo validation with KO and antibody blockade\",\n      \"pmids\": [\"34089617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LILRB4/gp49B co-tethers fibronectin in cooperation with integrin β1 in cis on macrophages, forming a regulatory triplet; adherence to immobilized FN induces Syk phosphorylation that is augmented in gp49B-deficient macrophages, demonstrating that gp49B suppresses integrin-mediated pro-inflammatory Syk signaling at focal adhesions.\",\n      \"method\": \"FN pull-down co-immunoprecipitation with gp49B and integrin β1; confocal co-localization microscopy; Syk phosphorylation western blotting in WT vs gp49B-KO macrophages; RAW264.7 and THP-1 cell models\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and KO with defined signaling readout, single lab\",\n      \"pmids\": [\"35689642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Fibronectin on target cells attenuates NK cell natural cytotoxicity via gp49B/LILRB4; gp49B-deficient NK cells show augmented Syk phosphorylation upon FN binding and enhanced killing of fibronectin-rich Lewis lung carcinoma cells (but not FN30-knockout cells), demonstrating that LILRB4 senses fibronectin on target cells in trans to deliver inhibitory signals in NK cells.\",\n      \"method\": \"gp49B-KO NK cells; cytotoxicity assays against FN-rich and FN-poor tumor cells; FN30-knockout target cells; Syk phosphorylation analysis; confocal and flow cytometric analysis of gp49B/integrin co-engagement\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic KO with functional cytotoxicity assay, FN30-KO target cell controls, and biochemical Syk readout\",\n      \"pmids\": [\"37083755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Fibronectin-LILRB4/gp49B interaction negatively regulates osteoclastogenesis: gp49B-deficient mice show reduced trabecular bone; FN N-terminal 30-kDa fragment promotes gp49B-mediated inhibition of osteoclast differentiation by increasing SHP-1 phosphorylation and TRAF6-SHP-1 association, thereby suppressing RANKL-induced TAK1/NF-κB/MAPK signaling.\",\n      \"method\": \"gp49B-KO mice with bone phenotyping (micro-CT, histology); RAW264.7 osteoclastogenesis assays with FN30; SHP-1 phosphorylation; TRAF6-SHP-1 co-immunoprecipitation; TAK1/NF-κB/MAPK western blotting\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo KO with defined mechanism validated by co-IP and signaling cascade analysis in vitro\",\n      \"pmids\": [\"36331874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ILT3/LILRB4 promotes the suppressive phenotype of tumor-educated monocytic MDSCs; anti-ILT3 antibody treatment impairs acquisition of MDSC suppressor phenotype and reduces T cell suppression; combined ILT3 blockade with anti-PD1 enhances T cell IFNγ secretion.\",\n      \"method\": \"SK-MEL-5 cancer cell/PBMC co-culture MDSC generation; anti-ILT3 antibody blockade; T cell proliferation and IFNγ assays; flow cytometry phenotyping; anti-PD1 combination\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional antibody blockade with multiple readouts, single lab\",\n      \"pmids\": [\"33372059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In solid tumors, LILRB4-knockout mice or anti-LILRB4 antibody treatment reduces tumor burden and increases survival; LILRB4 absence increases tumor immune infiltrates, raises Teff/Treg ratio, shifts TAMs toward less suppressive phenotype, and reduces CD8+ T cell exhaustion; murine gp49B is the LILRB4 ortholog with two cytoplasmic ITIMs (vs three in human).\",\n      \"method\": \"LILRB4−/− mice; anti-LILRB4 antibody treatment; syngeneic tumor models; flow cytometry of tumor-infiltrating lymphocytes and macrophages; survival analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with antibody blockade in multiple tumor models with comprehensive immune phenotyping\",\n      \"pmids\": [\"33974041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"gp49B (murine LILRB4) deficiency inhibits tumor metastasis and reduces monocytic MDSC tumor infiltration; gp49B-KO MDSCs show impaired pro-tumor functions (Treg activation, cancer cell migration, tumor angiogenesis) and increased plasma exosome miR-1 family miRNAs with anti-tumor properties.\",\n      \"method\": \"gp49B−/− tumor-bearing mice; tumor metastasis assays; MDSC transfer experiments; exosome miRNA profiling; functional MDSC co-culture assays\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with adoptive transfer validation, single lab\",\n      \"pmids\": [\"35402083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Galectin-8 (Gal-8) is a high-affinity functional ligand of LILRB4 that drives M-MDSC induction by activating STAT3 and inhibiting NF-κB; Gal-8 and APOE bind LILRB4 noncompetitively at distinct sites; LILRB4 knockout attenuates Gal-8-driven tumor growth in vivo.\",\n      \"method\": \"Ligand screening; binding affinity measurements; STAT3 and NF-κB activation assays in MDSC induction; competitive binding assays; LILRB4-KO mouse tumor models\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — new ligand identified with binding characterization, mechanistic signaling readouts, and in vivo KO validation\",\n      \"pmids\": [\"38232701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Microglia-specific LILRB4 conditional knockout exacerbates ischemic brain injury by promoting CD8+ T cell infiltration; LILRB4-KD microglia show increased CCL2 secretion mediating CD8+ T cell recruitment, which is reversed by CCL2 inhibition; LILRB4 overexpression in microglia is neuroprotective.\",\n      \"method\": \"Microglia-specific Cre-loxP LILRB4 conditional KO and TG overexpression mice; tMCAO model; flow cytometry; scRNA-seq; spatial transcriptomics; T cell migration assays; CCL2 inhibition; recombinant arginase-1\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO and TG with mechanistic rescue experiments (CCL2 inhibition, arginase-1), multiple orthogonal methods\",\n      \"pmids\": [\"39217343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LILRB4 regulates decidual MDSC function via a SHP-2/STAT6 pathway: T. gondii infection reduces STAT3 phosphorylation, decreasing LILRB4 expression on dMDSCs, which reduces p-SHP2 and p-STAT6 levels; SHP-2 directly binds STAT6, which binds the Arg-1 and IL-10 gene promoters to regulate their expression.\",\n      \"method\": \"LILRB4−/− pregnant mice infected with T. gondii; anti-LILRB4 neutralizing antibody in human dMDSCs; SHP-2/STAT6 co-immunoprecipitation; STAT6 ChIP on Arg-1 and IL-10 promoters; western blotting\",\n      \"journal\": \"Parasites & vectors\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic in vitro co-IP and ChIP with in vivo KO model, single lab\",\n      \"pmids\": [\"37461040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Secretogranin 2 (SCG2) is a functional ligand of LILRB4 on monocytic cells; tumor-derived SCG2 promotes tumor growth in myeloid-specific LILRB4 transgenic mice in a T cell-dependent manner; LILRB4 blockade abrogates SCG2-induced immunosuppression; mechanistically, SCG2-LILRB4 interaction triggers SHP recruitment and SHP-independent STAT3 activation.\",\n      \"method\": \"LILRB4-SCG2 binding assay; myeloid-specific LILRB4 transgenic mice; SCG2-knockout host mice; T cell depletion; anti-LILRB4 blockade; SHP co-immunoprecipitation; STAT3 activation assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — new ligand identified with genetic and pharmacological validation, defined dual signaling mechanism (SHP-dependent and SHP-independent STAT3), in vivo confirmation\",\n      \"pmids\": [\"40707822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LILRB4 on multiple myeloma cells promotes osteoclastogenesis and bone lesion by secreting RELT cytokine through a p-SHP2/NF-κB/RELT signaling pathway; LILRB4-KO conditioned medium does not promote osteoclast differentiation; exogenous RELT restores bone damage in LILRB4-KO cells.\",\n      \"method\": \"Conditioned medium osteoclast differentiation assays; xenograft and PDX models with micro-CT; cytokine array; RNA-seq; Co-IP; luciferase reporter; CRISPR-Cas9 LILRB4 deletion; RELT rescue experiments\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic pathway defined by co-IP, cytokine array, rescue experiments, and multiple in vivo models\",\n      \"pmids\": [\"38951916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In myocardial ischemia-reperfusion injury, LILRB4 promotes inflammation and pyroptosis via SHP-2 phosphorylation/activation, increasing TXNIP, NLRP3, Caspase-1, and GSDMD expression; SHP2 inhibitor PHPS1 mitigates LILRB4-driven inflammation; LILRB4-KO mice show reduced pyroptosis markers and inflammatory cytokines after I/R.\",\n      \"method\": \"LILRB4 overexpression and knockdown in H9C2 cells and rat myocardium; LILRB4-KO mice; I/R and H/R models; SHP-2 phosphorylation western blotting; NLRP3/Caspase-1/GSDMD expression; SHP2 inhibitor PHPS1\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice and pharmacological inhibition defining SHP-2/TXNIP/NLRP3 axis, single lab\",\n      \"pmids\": [\"40550372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In multiple myeloma, IKZF1 transactivates LILRB4 expression to activate downstream STAT3-PFKFB1 signaling supporting MM cell proliferation; LILRB4 knockdown delays MM cell growth in vitro and in vivo.\",\n      \"method\": \"IKZF1 ChIP/luciferase reporter for LILRB4 transcription; LILRB4 knockdown; STAT3 and PFKFB1 western blotting; in vivo MM xenograft models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional driver identified with functional pathway validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"39025844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ILT3-Fc treatment inhibits release of inflammatory microRNA-containing exosomes from alloactivated CD4+ T cells; these inflammatory exosomes can diminish the suppressive activity of ILT3-Fc-induced CD8+ T suppressor cells at high effector-to-suppressor ratios.\",\n      \"method\": \"Exosome isolation from mixed lymphocyte cultures ± ILT3-Fc; miRNA profiling; suppressor cell activity assays with exosome addition\",\n      \"journal\": \"Human immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect functional assay, limited mechanistic detail in abstract\",\n      \"pmids\": [\"24862932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Homoharringtonine (HHT) suppresses LILRB4 expression in monocytic AML by promoting FTO degradation, which increases global m6A RNA methylation, subsequently reducing expression of MLL1 and LILRB4; reduced LILRB4 enhances CD8+ T cell cytotoxicity against THP-1 cells.\",\n      \"method\": \"RNA-seq; FTO protein degradation assays; m6A level measurement; LILRB4 mRNA/protein western blotting; CD8+ T cell cytotoxicity assays; in vivo AML xenograft mouse models\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined FTO/m6A/LILRB4 regulatory axis with in vivo validation, single lab\",\n      \"pmids\": [\"40590394\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LILRB4 is an ITIM-containing inhibitory receptor on myeloid cells (monocytes, macrophages, DCs, AML blasts) that, upon binding extracellular ligands (APOE, fibronectin, galectin-8, CD166/ALCAM, SCG2), recruits SHP-1 or SHP-2 to its cytoplasmic ITIMs (with Y412 and Y442 required for T cell suppression and all three ITIMs needed for tissue infiltration), leading to dephosphorylation of activating kinases (Lck, Syk, Erk), inhibition of NF-κB and MAPK signaling, and downstream immunosuppressive outputs including T cell suppression (via ARG1 and uPAR), MDSC polarization (via STAT3/NF-κB), and regulation of osteoclastogenesis (via TRAF6-SHP-1-TAK1/NF-κB/MAPK); its extracellular domain can also signal in trans to suppress T cell Akt activation (through SHIP1 clustering at the BCR) and NK cell cytotoxicity (by sensing fibronectin on target cells), while soluble ILT3-Fc acts through CD166 to inhibit p70S6K and induce T suppressor cell differentiation via BCL6 upregulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LILRB4 (ILT3) is an ITIM-bearing inhibitory receptor of myeloid cells (monocytes, dendritic cells, macrophages) that, upon engagement, dampens activating immunoreceptor signaling and drives tolerogenic and immunosuppressive programs [#0, #6]. The founding mechanism is recruitment of SH2-containing tyrosine phosphatases to its cytoplasmic ITIMs upon co-ligation with stimulatory receptors, extinguishing calcium flux and the tyrosine phosphorylation of activating kinases (Lck, Syk, LAT, Erk) and suppressing NF-\\u03baB/MAPK output and inflammatory cytokine production [#0, #6, #14]. Systematic ITIM mutagenesis established that Y412 and Y442 are required for T cell suppression while all three ITIMs (Y360, Y412, Y442) are needed for leukemic tissue infiltration, and domain-swap experiments showed the LILRB4 intracellular tail specifically confers these functions [#15]. A crystal structure of the two-Ig-domain ectodomain showed an obtuse interdomain angle incompatible with MHC class I binding, predicting non-MHC ligands [#7]; subsequent screens identified APOE, fibronectin, CD166/ALCAM, galectin-8, and secretogranin-2 as functional ligands that act through SHP-1/SHP-2 recruitment and, for some, SHP-independent STAT3 activation [#11, #13, #18, #26, #29]. Through these axes LILRB4 polarizes myeloid-derived suppressor cells and tumor-associated myeloid cells, upregulates ARG1 and uPAR, and suppresses T cells, supporting AML and solid tumor immune evasion such that genetic deletion or antibody blockade reduces tumor burden and restores T cell function [#13, #16, #18, #23, #24]. The same inhibitory machinery operates beyond cancer: it restrains hepatic and macrophage inflammation (limiting insulin resistance and atherosclerosis via SHP-1/TRAF6/NF-\\u03baB) [#14, #17], curbs NK cytotoxicity and osteoclastogenesis by sensing fibronectin [#21, #22], and protects against ischemic brain injury [#27]. A soluble/extracellular form (soluble ILT3, ILT3-Fc) acts in trans through CD166 to inhibit p70S6K and induce CD8+ T suppressor cells via BCL6 upregulation [#9, #11, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established LILRB4/ILT3 as an inhibitory receptor by showing co-ligation extinguishes activating-receptor signaling through phosphatase recruitment, defining its core mechanism.\",\n      \"evidence\": \"Co-ligation calcium/phosphorylation assays and SHP-1 co-IP in primary monocytes/DCs, plus antigen presentation assays\",\n      \"pmids\": [\"9151699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand(s) unknown at this stage\", \"Relative contribution of individual ITIMs not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected ILT3 upregulation to tolerance induction, showing CD8+ T suppressor cells render APCs tolerogenic, framing ILT3 as an effector of immune tolerance.\",\n      \"evidence\": \"T suppressor cell\\u2013APC co-cultures with flow cytometry and anergy assays, validated in transplant recipients\",\n      \"pmids\": [\"11875462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular signaling linking upregulation to tolerogenic output not dissected\", \"Ligand still unidentified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed the extracellular domain alone mediates suppression independent of cytoplasmic ITIMs, revealing a trans-acting/soluble mode of action distinct from classical ITIM signaling.\",\n      \"evidence\": \"Cytoplasmic deletion mutants in KG1 cells and recombinant soluble ILT3 in T cell assays\",\n      \"pmids\": [\"17161342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor on T cells for the ectodomain not identified here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated LILRB4 co-ligation with Fc\\u03b3RI suppresses kinase phosphorylation and cytokine output, but pharmacology implicated phosphatases beyond SHP-1, refining the signaling model.\",\n      \"evidence\": \"Co-ligation assays in THP-1/monocytes with phospho-blotting, TNF\\u03b1 ELISA, and phosphatase inhibitor dissection\",\n      \"pmids\": [\"19833736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of non-SHP-1 phosphatase not pinned down\", \"Endogenous physiological co-ligand unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Solved the ectodomain structure, showing it is unsuited to MHC class I and predicting non-MHC ligands, redirecting ligand discovery.\",\n      \"evidence\": \"1.7 \\u00c5 crystal structure with engineered disulfide and comparative structural analysis\",\n      \"pmids\": [\"21454581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Actual ligand-binding surface confirmed only by inference\", \"No ligand co-crystal\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified CD166/ALCAM as the receptor for soluble ILT3-Fc on T cells, providing the missing ligand for the ectodomain-mediated suppression and a tumor-inhibitory p70S6K axis.\",\n      \"evidence\": \"Mass spec/Biacore ligand ID, CD166 knockdown and CRISPR KO, p70S6K blotting, xenograft\",\n      \"pmids\": [\"29263213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether membrane LILRB4 uses CD166 in cis not addressed\", \"Downstream of p70S6K incomplete\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed ectopic ILT3 in CLL B cells forms inhibitory ILT3-BCR-SHIP1 clusters to block Akt, extending inhibitory function to lymphoid contexts via a defined phosphatase complex.\",\n      \"evidence\": \"Deltex1-driven expression, BCR stimulation, Akt blotting, co-IP of ILT3-BCR-SHIP1\",\n      \"pmids\": [\"28931525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance outside CLL unclear\", \"Ligand triggering in this setting not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the APOE\\u2013LILRB4\\u2013SHP-2\\u2013uPAR\\u2013ARG1 axis in monocytic AML, establishing LILRB4 as a druggable driver of leukemic T cell suppression and tissue infiltration.\",\n      \"evidence\": \"Mouse AML models, LILRB4 KO, APOE binding, SHP-2 co-IP, ARG1/uPAR assays\",\n      \"pmids\": [\"30333625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How APOE selectively engages over other ligands unclear\", \"Quantitative ligand affinity not given\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed hepatic LILRB4 restrains metabolic inflammation via SHP-1\\u2013TRAF6\\u2013NF-\\u03baB/MAPK, extending the inhibitory mechanism to a protective non-immune-cell role.\",\n      \"evidence\": \"Hepatocyte-specific KO and overexpression mice, SHP-1 co-IP, TRAF6 ubiquitination assay, metabolic phenotyping\",\n      \"pmids\": [\"29091299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Activating ligand in liver not identified\", \"Receptor-proximal events upstream of SHP-1 unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Dissected the ITIM code, mapping Y412/Y442 to T cell suppression and all three ITIMs to infiltration, and proved the intracellular domain is functionally specific to LILRB4.\",\n      \"evidence\": \"Site-directed ITIM mutagenesis and LILRB4/LILRB1 domain-swap chimeras in T cell and AML models\",\n      \"pmids\": [\"31700117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Differential phosphatase recruitment by each ITIM not resolved\", \"Structural basis of ITIM selectivity unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified fibronectin (FN30 module) as a high-affinity ligand mediating myeloid suppression and inhibitory signaling, broadening LILRB4 ligand repertoire to ECM.\",\n      \"evidence\": \"Ligand screening, BLI/binding kinetics, domain mapping, blocking antibody in tumor explants and lupus-prone mice\",\n      \"pmids\": [\"34426457\", \"34089617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cis vs trans engagement context-dependent\", \"Integration with APOE signaling not resolved here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed LILRB4/gp49B co-tethers fibronectin with integrin \\u03b21 to suppress FN-induced Syk signaling at focal adhesions, revealing a cis-regulatory triplet.\",\n      \"evidence\": \"FN pull-down co-IP with integrin \\u03b21, confocal co-localization, Syk blotting in WT vs KO macrophages\",\n      \"pmids\": [\"35689642\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct vs integrin-bridged FN binding not fully separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended fibronectin sensing to NK cells and bone, showing LILRB4 senses FN on target cells in trans to limit NK cytotoxicity and inhibits osteoclastogenesis via SHP-1\\u2013TRAF6\\u2013TAK1/NF-\\u03baB/MAPK.\",\n      \"evidence\": \"gp49B-KO NK cytotoxicity with FN30-KO controls and Syk blotting; gp49B-KO bone phenotyping with TRAF6-SHP-1 co-IP\",\n      \"pmids\": [\"37083755\", \"36331874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Threshold of FN density for trans signaling unclear\", \"Crosstalk with activating NK receptors not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified galectin-8 and secretogranin-2 as additional ligands acting through SHP recruitment plus SHP-independent STAT3 to drive MDSC induction, showing multiple ligands engage noncompetitively.\",\n      \"evidence\": \"Ligand screening, binding/competition assays, STAT3/NF-\\u03baB readouts, LILRB4-KO and transgenic tumor models\",\n      \"pmids\": [\"38232701\", \"40707822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among multiple ligands in vivo unknown\", \"Structural basis of distinct binding sites not solved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed LILRB4 cell-intrinsic oncogenic and protective roles, transactivated by IKZF1 to drive MM proliferation via STAT3-PFKFB1 and secreting RELT to drive myeloma bone lesions, while microglial LILRB4 protects against ischemic injury.\",\n      \"evidence\": \"IKZF1 ChIP/reporter and STAT3-PFKFB1 blotting in MM; CRISPR KO with RELT rescue and micro-CT; microglia-specific conditional KO/TG in stroke model with CCL2 inhibition\",\n      \"pmids\": [\"39025844\", \"38951916\", \"39217343\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ligand engagement is required for these intrinsic outputs unclear\", \"Tissue-specific signaling divergence not unified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined therapeutic and regulatory leverage points: SHP-2-driven cardiomyocyte pyroptosis and homoharringtonine-mediated FTO/m6A suppression of LILRB4, indicating both signaling and expression are targetable.\",\n      \"evidence\": \"LILRB4-KO and SHP2 inhibitor PHPS1 in cardiac I/R; FTO degradation/m6A assays with CD8 cytotoxicity in AML\",\n      \"pmids\": [\"40550372\", \"40590394\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab mechanisms\", \"Cardiac ligand and upstream trigger undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct ligands (APOE, fibronectin, CD166, galectin-8, SCG2) are integrated to select between SHP-dependent and SHP-independent STAT3 outputs, and the structural basis for their noncompetitive binding, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ligand-bound structure\", \"Rules governing context-specific signaling output unknown\", \"Relative in vivo dominance of each ligand undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 6, 14, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 6, 15]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [13, 18, 26, 29]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [12, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6, 7, 11]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5, 9, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 13, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 14, 13, 29]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 14, 17, 30]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [31]}\n    ],\n    \"complexes\": [\n      \"LILRB4-BCR-SHIP1 inhibitory cluster\",\n      \"LILRB4/gp49B-integrin \\u03b21 fibronectin co-tethering triplet\"\n    ],\n    \"partners\": [\n      \"PTPN6 (SHP-1)\",\n      \"PTPN11 (SHP-2)\",\n      \"INPP5D (SHIP1)\",\n      \"TRAF6\",\n      \"APOE\",\n      \"ALCAM (CD166)\",\n      \"ITGB1\",\n      \"FN1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}