{"gene":"LILRB4","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1997,"finding":"LILRB4 (ILT3) co-ligation to stimulatory receptors on APCs blunts increased [Ca2+]i and tyrosine phosphorylation via recruitment of SHP-1 (SH2-containing protein tyrosine phosphatase 1) to its cytoplasmic ITIMs; additionally, ILT3 mediates antigen internalization and delivery to intracellular compartments for processing and T cell presentation.","method":"Co-ligation assays on monocytes/DCs; calcium flux measurement; tyrosine phosphorylation assay; SHP-1 recruitment assay; antigen internalization and presentation assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal in vitro functional assays with mechanistic follow-up; foundational paper, highly cited","pmids":["9151699"],"is_preprint":false},{"year":2002,"finding":"CD8+CD28- T suppressor (Ts) cells induce upregulation of ILT3 and ILT4 on monocytes and dendritic cells, rendering APCs tolerogenic with reduced costimulatory molecule expression, and these tolerogenic APCs induce antigen-specific CD4+ T helper cell unresponsiveness.","method":"In vitro co-culture of Ts cells with APCs; flow cytometry for ILT3/ILT4 and costimulatory molecule expression; MLR proliferation assay","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional cell-based assays replicated in human transplant recipients; >600 citations","pmids":["11875462"],"is_preprint":false},{"year":2006,"finding":"Membrane-expressed ILT3 signals intracellularly to inhibit NF-κB activation and transcription of costimulatory molecules; ILT3 cytoplasmic deletion mutants (ILT3Δ) retain extracellular suppressive activity on T cells, demonstrating extracellular signaling capacity independent of ITIMs, whereas ILT4Δ loses suppressive activity entirely, requiring its cytoplasmic ITIMs.","method":"Cytoplasmic deletion mutant transfection in KG1 dendritic-like cell line; T cell proliferation and CMC assays; NF-κB activity assay","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis with functional readout, single lab","pmids":["17161342"],"is_preprint":false},{"year":2009,"finding":"LILRB4 co-ligates with FcγRI (CD64) on monocytes, aggregates to sites of activation, and inhibits FcγRI-mediated TNF-α production by dephosphorylating multiple signaling proteins including Lck, Syk, LAT, and Erk, but not alpha-actinin-4; phosphatase inhibitor reversal implicates phosphatases other than SHP-1.","method":"Cross-linking assay on THP-1 cells and primary monocytes; ELISA for TNF-α; phosphoprotein western blot; pharmacological inhibitors of phosphatases (sodium pervanadate, sodium stibogluconate)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical assays with pharmacological dissection; moderate citation count","pmids":["19833736"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of the LILRB4 ectodomain resolved to 1.7 Å reveals two Ig-like domains with a distinctive obtuse interdomain angle (~107°) and 3(10) helices in the D2 domain; structural comparison indicates LILRB4 is electrostatically and conformationally unsuited to MHC class I ligation, predicting non-MHC ligands.","method":"X-ray crystallography (1.7 Å); engineered disulfide bond in D2 domain for stability; structural comparison with Group 1 LILRs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with functional structural interpretation","pmids":["21454581"],"is_preprint":false},{"year":2017,"finding":"ILT3 (LILRB4) ligand on activated T cells is CD166/ALCAM, identified by flow cytometry, mass spectrometry, and Biacore; ILT3.Fc binding to CD166 inhibits CD4+ Th proliferation and induces CD8+CD28- T suppressor cells; CD166 knockdown abolishes these effects; ILT3.Fc inhibits tumor cell growth via inhibition of the p70S6K signaling pathway.","method":"Flow cytometry; mass spectrometry; Biacore surface plasmon resonance; CD166 knockdown by nucleofection; CRISPR-Cas9 CD166 knockout; in vitro and in vivo tumor models","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — ligand identified by MS, validated by SPR, with genetic KO and functional assays","pmids":["29263213"],"is_preprint":false},{"year":2018,"finding":"In AML cells, LILRB4 supports tumour cell tissue infiltration and suppresses T cell activity through a signalling pathway involving extracellular APOE as ligand, intracellular SHP-2 recruitment, and downstream activation of uPAR and ARG1; deletion or antibody blockade of LILRB4 impedes AML development in mouse models.","method":"Mouse AML models; human AML cells; LILRB4 knockout; antibody blockade; ARG1 and uPAR pathway analysis; T cell suppression assays; tissue infiltration assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal in vivo/in vitro experiments identifying the full signaling pathway; >200 citations","pmids":["30333625"],"is_preprint":false},{"year":2018,"finding":"Hepatic LILRB4 recruits SHP1 to inhibit TRAF6 ubiquitination, thereby inactivating NF-κB and MAPK cascades; hepatocyte-specific LILRB4 knockout exacerbates high-fat diet-induced NAFLD including insulin resistance, lipid accumulation and inflammation, while overexpression reverses these phenotypes.","method":"Hepatocyte-specific knockout (LILRB4-HKO); overexpression transgenic mice; ob/ob model; SHP1 co-immunoprecipitation; TRAF6 ubiquitination assay; NF-κB and MAPK activity","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 1-2 — gain- and loss-of-function with mechanistic biochemical pathway dissection","pmids":["29091299"],"is_preprint":false},{"year":2019,"finding":"LILRB4 ITIMs Y412 and Y442, but not Y360, are required for T cell inhibition by AML cells; all three ITIMs (Y360, Y412, Y442) are needed for leukemia cell tissue infiltration; the intracellular domain of LILRB4 (but not LILRB1) specifically mediates these functions, as shown by chimeric protein experiments.","method":"Site-directed mutagenesis of ITIM tyrosines; chimeric LILRB4/LILRB1 constructs; in vitro T cell suppression assays; in vivo AML infiltration mouse models","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 1-2 — systematic mutagenesis and chimeric protein dissection with in vivo validation","pmids":["31700117"],"is_preprint":false},{"year":2019,"finding":"Humanized anti-LILRB4 antibody h128-3 blocks the LILRB4/APOE interaction, reverses T cell suppression, inhibits AML cell tissue infiltration, and mediates ADCC and ADCP, confirming APOE as the functional extracellular ligand triggering LILRB4 signaling in AML.","method":"Patient-derived xenograft mice; syngeneic immunocompetent AML mice; antibody blocking experiments; T cell functional assays; ADCC/ADCP assays; chemotherapy combination","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 — multiple in vivo models with mechanistic antibody blockade confirming APOE-LILRB4 axis","pmids":["31213474"],"is_preprint":false},{"year":2017,"finding":"LILRB4 deficiency in macrophages promotes atherosclerosis development via decreased Shp1 phosphorylation, which enhances NF-κB-mediated inflammatory responses; bone marrow transplantation confirms the effect is macrophage-intrinsic.","method":"LILRB4-/-ApoE-/- double knockout mice; high-fat diet atherosclerosis model; bone marrow transplantation; Shp1 phosphorylation assay; NF-κB activity measurement","journal":"Clinical science","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with bone marrow transplant and mechanistic signaling assays","pmids":["28743735"],"is_preprint":false},{"year":2021,"finding":"Fibronectin is a functional ligand of ILT3/LILRB4 in the tumor microenvironment; fibronectin-ILT3 interaction polarizes myeloid cells toward a suppressive state, and this is reversed by an ILT3-specific blocking antibody, defining a 'stromal checkpoint' mechanism.","method":"Ligand screening approach; myeloid cell polarization assays; ex vivo human tumor explant treatment with anti-ILT3; functional phenotyping","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 — screening plus functional cell-based validation in primary human tissue","pmids":["34426457"],"is_preprint":false},{"year":2021,"finding":"Fibronectin (specifically the N-terminal 30 kDa domain, FN30) is identified as a physiological ligand for both human LILRB4 and murine gp49B with sub-micromolar affinity; blockade of B4-FN binding ameliorates autoimmune disease in lupus-prone BXSB/Yaa mice.","method":"Bio-layer interferometry; recombinant FN30-Fc fusion protein; BXSB/Yaa mouse autoimmune model; antibody blockade experiments","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 1-2 — biophysical affinity measurement plus in vivo genetic disease model","pmids":["34089617"],"is_preprint":false},{"year":2021,"finding":"LILRB4 on tumor-associated macrophages suppresses anti-tumor immunity; LILRB4 knockout or antibody blockade reduces tumor burden, increases effector-to-Treg ratio, and shifts TAM phenotype toward less suppressive; LILRB4 (gp49B in mice) signals through ITIMs on macrophages.","method":"LILRB4-/- mice; anti-LILRB4 antibody treatment; tumor challenge models; flow cytometry of tumor infiltrates; TAM phenotyping","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic KO plus antibody blockade with defined cellular phenotypic readouts","pmids":["33974041"],"is_preprint":false},{"year":2017,"finding":"ILT3 (LILRB4) expressed on CLL B cells inhibits Akt kinase activation upon BCR stimulation by mediating dynamic coalescence of ILT3, BCRs, and SHIP1 (phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1) into inhibitory clusters at the cell surface; ILT3 expression in CLL is driven by Deltex1.","method":"Flow cytometry; confocal imaging of inhibitory clusters; Akt phosphorylation assay; BCR stimulation assay; Deltex1 manipulation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway dissection with imaging and biochemical assays","pmids":["28931525"],"is_preprint":false},{"year":2023,"finding":"Fibronectin on target cells attenuates NK cell natural cytotoxicity via LILRB4/gp49B; gp49B-deficient NK cells show augmented Syk tyrosine phosphorylation and increased killing of fibronectin-rich tumor cells, indicating LILRB4 delivers an inhibitory signal upon trans-engagement with fibronectin on target cells.","method":"Flow cytometry; gp49B-deficient NK cells; NK cell cytotoxicity assays against FN-rich and FN-poor target cells; FN30-KO target cells; Syk phosphorylation biochemical assay","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 1-2 — genetic KO with biochemical and functional assays confirming mechanism","pmids":["37083755"],"is_preprint":false},{"year":2022,"finding":"LILRB4/gp49B and integrin co-tether fibronectin on macrophages in a triplet configuration (B4/gp49B-FN-integrin); gp49B deficiency augments FN-induced Syk phosphorylation, indicating LILRB4 suppresses integrin-mediated pro-inflammatory signaling at focal adhesion sites.","method":"FN pull-down/co-IP showing gp49B and integrin β1 in same complex; confocal fluorescent imaging; Syk phosphorylation in gp49B-deficient macrophages; RAW264.7 and THP-1 cell adhesion assays","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 1-2 — co-IP, imaging, and biochemical phosphorylation analysis with KO cells","pmids":["35689642"],"is_preprint":false},{"year":2023,"finding":"Fibronectin-LILRB4/gp49B interaction negatively regulates RANKL-induced osteoclastogenesis by increasing SHP-1 phosphorylation and TRAF6-SHP-1 association, suppressing downstream TAK1, NF-κB, and MAPK phosphorylation; gp49B-deficient mice show increased osteoclast formation and trabecular bone loss.","method":"gp49B knockout mice; micro-CT; osteoclast differentiation assays; SHP-1 co-IP with TRAF6; TAK1/NF-κB/MAPK phosphorylation western blot; FN30 fragment treatment","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo KO phenotype with biochemical pathway dissection and co-IP","pmids":["36331874"],"is_preprint":false},{"year":2023,"finding":"LILRB4 signaling in decidual MDSCs operates through SHP-2/STAT6 pathway; T. gondii-induced downregulation of LILRB4 reduces p-SHP2 and p-STAT6, decreasing Arg-1 and IL-10 expression; SHP-2 was found to directly bind STAT6, which then binds the Arg-1 and IL-10 promoters.","method":"LILRB4-/- pregnant mouse model; anti-LILRB4 neutralizing antibody on human primary dMDSCs; SHP-2/STAT6 co-IP; chromatin promoter binding assay; western blot for p-SHP2, p-STAT6, Arg-1, IL-10","journal":"Parasites & vectors","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO and in vitro antibody blockade with mechanistic co-IP, single lab","pmids":["37461040"],"is_preprint":false},{"year":2024,"finding":"Galectin-8 (Gal-8) is a high-affinity functional ligand of LILRB4 in solid tumors; Gal-8 ligation induces M-MDSC polarization 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.","method":"Ligand screening; binding affinity assays; STAT3 and NF-κB activity assays; MDSC induction assays; LILRB4 KO mouse tumor models; competitive binding analysis","journal":"Cell reports. Medicine","confidence":"High","confidence_rationale":"Tier 1-2 — new ligand identified with multiple functional assays and in vivo KO validation","pmids":["38232701"],"is_preprint":false},{"year":2024,"finding":"LILRB4 on multiple myeloma cells promotes osteoclast differentiation and bone lesion by inducing secretion of RELT cytokine via a p-SHP2/NF-κB signaling pathway; LILRB4 KO abrogates osteoclastogenesis and bone damage; exogenous RELT rescues the phenotype in LILRB4-KO cells.","method":"LILRB4-WT and KO conditioned media osteoclast assays; xenograft/syngeneic/PDX models with micro-CT; cytokine array; RNA-seq; luciferase reporter; Co-IP; western blot; RELT rescue experiment","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal assays including co-IP, rescue experiments, and in vivo models","pmids":["38951916"],"is_preprint":false},{"year":2024,"finding":"Microglia LILRB4 limits CD8+ T cell infiltration into ischemic brain by a CCL2-mediated mechanism and via arginase-1 activity; conditional LILRB4 KO in microglia increases CD8+ T cell recruitment and worsens infarct, while LILRB4 overexpression is neuroprotective after stroke.","method":"Microglia-specific LILRB4 conditional KO and overexpression transgenic mice (Cre-loxP); tMCAO stroke model; scRNA-seq; spatial transcriptomics; flow cytometry; immunofluorescence; T cell migration assays with CCL2 inhibition and recombinant arginase-1","journal":"Journal of neuroinflammation","confidence":"High","confidence_rationale":"Tier 2 — conditional KO and OE with mechanistic pathway identification via scRNA-seq and functional rescue","pmids":["39217343"],"is_preprint":false},{"year":2024,"finding":"IKZF1 transactivates LILRB4 expression in multiple myeloma, activating downstream STAT3-PFKFB1 signaling to support MM cell proliferation; LILRB4 knockdown delays MM growth in vitro and in vivo.","method":"IKZF1 transcriptional regulation assays; STAT3 and PFKFB1 pathway analysis; LILRB4 knockdown; in vitro proliferation and in vivo xenograft models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptional regulation with signaling pathway dissection, single lab","pmids":["39025844"],"is_preprint":false},{"year":2025,"finding":"Secretogranin 2 (SCG2), a granin-family secretory protein, binds LILRB4 on monocytic cells; tumor-derived SCG2 promotes tumor growth in myeloid-specific LILRB4 transgenic mice in a T cell-dependent manner; SCG2-LILRB4 interaction triggers SHP recruitment and SHP-independent STAT3 activation; SCG2 deficiency impairs immunosuppressive monocytic cell infiltration.","method":"Myeloid-specific LILRB4 transgenic mouse model; SCG2 deficient mice; binding assays; T cell depletion; LILRB4 blockade; SHP co-IP; STAT3 phosphorylation assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 — new ligand discovery with genetic mouse models and mechanistic pathway assays","pmids":["40707822"],"is_preprint":false},{"year":2020,"finding":"ILT3 (LILRB4) promotes the immunosuppressive function of monocytic MDSCs; anti-ILT3 antibody treatment impairs MDSC suppressor phenotype acquisition and reduces T cell suppression capacity; combined with anti-PD1, ILT3 blockade enhances T cell IFN-γ secretion.","method":"Co-culture MDSC generation with SK-MEL-5 cancer cells; anti-ILT3 antibody treatment; CD8+ T cell proliferation and IFN-γ secretion assays; flow cytometry phenotyping","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — functional antibody blockade with defined cellular phenotype, single lab","pmids":["33372059"],"is_preprint":false},{"year":2020,"finding":"ILT3 overexpression in NSCLC cells recruits SHP2 and SHIP1 and activates ERK1/2 signaling to mediate EMT and tumor cell motility; additionally upregulates VEGF-A for angiogenesis; interaction with ApoE ligand upregulated by ILT3 itself contributes to these effects.","method":"ILT3 overexpression in NSCLC lines; SHP2/SHIP1 co-immunoprecipitation; ERK1/2 phosphorylation assay; EMT markers; VEGF-A ELISA; murine metastasis models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP and signaling assays with in vivo metastasis model, single lab","pmids":["33152402"],"is_preprint":false},{"year":2010,"finding":"Soluble ILT3-Fc (containing only the extracellular Ig-like domain) induces CD8+ T suppressor cell differentiation associated with significant upregulation of BCL6 (a transcriptional repressor of IL-2, IFN-γ, IL-5, and granzyme B), SOCS1, and DUSP10, defining the gene signature of ILT3-Fc-induced Ts cells.","method":"Soluble ILT3-Fc treatment of human T cells; gene expression profiling; BCL6, SOCS1, DUSP10 functional validation; humanized NOD/SCID transplant model","journal":"International reviews of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — gene profiling with functional validation in humanized mouse model, single lab","pmids":["20132030"],"is_preprint":false},{"year":2022,"finding":"LILRB4/gp49B (murine ortholog) promotes M2 polarization of MDSCs and tumor metastasis; gp49B deficiency inhibited monocytic MDSC tumor infiltration and impaired Treg activation, cancer cell migration promotion, and tumor angiogenesis; gp49B knockout increased plasma exosomal miR-1 family miRNAs with anti-tumor activity.","method":"gp49B-/- mouse tumor metastasis models; M-MDSC characterization; Treg activation assays; plasma exosome miRNA profiling; cancer cell migration assay","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with multiple functional phenotypic readouts, single lab","pmids":["35402083"],"is_preprint":false},{"year":2018,"finding":"LILRB4 deficiency in decidual macrophages strengthens M1 activation and weakens M2 tolerance functions; T. gondii infection downregulates LILRB4 on decidual macrophages, shifting arginine metabolic enzyme expression (iNOS vs. Arg-1) and cytokine profiles, contributing to abnormal pregnancy outcomes.","method":"LILRB4-/- pregnant mouse model; T. gondii infection; anti-LILRB4 neutralizing antibody on human primary decidual macrophages; M1/M2 surface molecule quantification; arginine metabolic enzyme measurement; cytokine profiling","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO and in vitro antibody blockade with defined functional readouts","pmids":["28883820"],"is_preprint":false},{"year":2025,"finding":"LILRB4 promotes inflammation and pyroptosis in myocardial ischemia-reperfusion injury by activating SHP-2 phosphorylation, which upregulates TXNIP/NLRP3/Caspase-1/GSDMD signaling; LILRB4 KO mice show diminished inflammatory cytokines and reduced pyroptotic protein expression after I/R.","method":"LILRB4-/- mice; adenoviral overexpression/knockdown in H9C2 cardiomyocytes; I/R and H/R models; SHP2 inhibitor PHPS1; western blot for p-SHP2, TXNIP, NLRP3, Caspase-1, GSDMD; ELISA for cytokines","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO and pharmacological inhibition with mechanistic signaling pathway dissection, single lab","pmids":["40550372"],"is_preprint":false},{"year":2025,"finding":"Homoharringtonine (HHT) suppresses LILRB4 expression by promoting FTO (m6A demethylase) degradation, increasing global RNA m6A levels, which reduces expression of downstream targets MLL1 and LILRB4, thereby enhancing CD8+ T cell cytotoxicity against monocytic AML cells.","method":"RNA-seq; functional assays; m6A quantification; FTO degradation assay; MLL1 and LILRB4 mRNA/protein measurement; in vitro cytotoxicity assays; AML xenograft mouse models","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway (FTO/m6A/LILRB4) with in vitro and in vivo validation, single lab","pmids":["40590394"],"is_preprint":false},{"year":2022,"finding":"NK cells require LILRB4/gp49B for proper function during neurotropic Zika virus infection; LILRB4 KO mice show increased neurological disease severity with reduced viral clearance, associated with altered NK cell maturation, diminished glucose consumption, reduced IFN-γ and granzyme B production, and impaired cytotoxicity.","method":"LILRB4 KO mice; neonatal ZIKV infection model; NK cell functional assays (granzyme B, IFN-γ, cytotoxicity); NK cell metabolic assay (glucose consumption); phenotypic characterization of NK maturation stages","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with multiple NK cell functional readouts, single lab","pmids":["35132958"],"is_preprint":false}],"current_model":"LILRB4 is an ITIM-containing inhibitory receptor expressed primarily on myeloid cells that signals through recruitment of SHP-1/SHP-2 phosphatases to dephosphorylate and suppress activation kinases (Lck, Syk, LAT, Erk) and downstream transcription factors (NF-κB, MAPK); its extracellular domain binds multiple ligands including APOE, fibronectin (FN30 domain), galectin-8, CD166/ALCAM, and secretogranin 2, each triggering distinct downstream pathways (SHP-2/uPAR/ARG1 in AML; SHP-2/STAT3 with SCG2; STAT3/NF-κB with galectin-8; TRAF6/TAK1/NF-κB/MAPK in osteoclasts; SHP-2/TXNIP/NLRP3 in cardiomyocytes), and in AML cells specifically, ITIM tyrosines Y412 and Y442 mediate T cell suppression while all three ITIMs (Y360, Y412, Y442) are required for tissue infiltration, collectively establishing LILRB4 as a context-dependent immune checkpoint that suppresses myeloid and NK cell activation, promotes tolerogenic APC function, and supports tumor immune evasion."},"narrative":{"teleology":[{"year":1997,"claim":"Establishing LILRB4 as an inhibitory receptor: co-ligation with activating receptors on APCs was shown to dampen calcium flux and tyrosine phosphorylation through SHP-1 recruitment to ITIMs, while also mediating antigen internalization — defining LILRB4's dual role in signal inhibition and antigen processing.","evidence":"Co-ligation assays on monocytes/DCs with calcium flux, phosphorylation, SHP-1 recruitment, and antigen presentation readouts","pmids":["9151699"],"confidence":"High","gaps":["Identity of the natural extracellular ligand unknown","Which specific ITIMs are functionally required not yet determined","Whether SHP-1 is the sole effector phosphatase unclear"]},{"year":2002,"claim":"LILRB4 upregulation on APCs was shown to be induced by CD8+CD28− T suppressor cells, rendering APCs tolerogenic and capable of inducing CD4+ T cell anergy — placing LILRB4 in a feedback circuit of peripheral tolerance.","evidence":"In vitro Ts–APC co-cultures with flow cytometry and MLR assays, replicated in transplant recipients","pmids":["11875462"],"confidence":"High","gaps":["Molecular signals from Ts cells that upregulate LILRB4 not identified","Whether LILRB4 ITIM signaling is required for the tolerogenic phenotype not tested"]},{"year":2006,"claim":"Dissection of intracellular versus extracellular signaling revealed that membrane LILRB4 inhibits NF-κB and costimulatory molecule transcription via its ITIMs, yet a cytoplasmic-deletion mutant retains extracellular T cell–suppressive capacity — establishing a bidirectional signaling model.","evidence":"Cytoplasmic deletion mutants in KG1 cell line with T cell proliferation and NF-κB activity assays","pmids":["17161342"],"confidence":"Medium","gaps":["Extracellular suppressive mechanism (reverse signaling or ligand decoy) not molecularly defined","Single cell line system limits generalizability"]},{"year":2009,"claim":"The scope of LILRB4's inhibitory mechanism was broadened beyond SHP-1: co-ligation with FcγRI showed dephosphorylation of Lck, Syk, LAT, and Erk, and pharmacological evidence implicated additional phosphatases, revealing a broader kinase-suppressive program than initially appreciated.","evidence":"Cross-linking on THP-1 and primary monocytes with phosphoprotein western blot and phosphatase inhibitor reversal","pmids":["19833736"],"confidence":"High","gaps":["Identity of the non-SHP-1 phosphatase(s) not determined","Whether identical substrates are targeted in all myeloid cell contexts unknown"]},{"year":2010,"claim":"Soluble ILT3-Fc was shown to induce CD8+ T suppressor cell differentiation marked by BCL6, SOCS1, and DUSP10 upregulation, providing the molecular gene signature downstream of extracellular LILRB4 engagement on T cells.","evidence":"Soluble ILT3-Fc treatment of human T cells with gene expression profiling and humanized mouse transplant model","pmids":["20132030"],"confidence":"Medium","gaps":["T cell receptor for soluble ILT3-Fc not identified","Whether BCL6 is required for Ts induction not tested with loss-of-function"]},{"year":2011,"claim":"The 1.7 Å crystal structure of the LILRB4 ectodomain revealed a distinctive obtuse interdomain angle and electrostatic surface incompatible with MHC class I binding, predicting non-MHC ligands and distinguishing LILRB4 from Group 1 LILRs.","evidence":"X-ray crystallography at 1.7 Å resolution with structural comparison to MHC-binding LILRs","pmids":["21454581"],"confidence":"High","gaps":["No co-crystal with any ligand obtained","Structural basis for ligand selectivity unresolved"]},{"year":2017,"claim":"Multiple ligands and cell contexts for LILRB4 were identified in parallel: CD166/ALCAM on activated T cells was found by mass spectrometry and SPR [PMID:29263213]; in CLL, LILRB4 clustered with BCR and SHIP1 to inhibit Akt [PMID:28931525]; and in macrophages, LILRB4 deficiency enhanced NF-κB via reduced SHP-1 phosphorylation, promoting atherosclerosis [PMID:28743735].","evidence":"MS/SPR ligand identification with CD166 KO validation; confocal imaging of inhibitory clusters in CLL; double-KO mice with bone marrow transplant in atherosclerosis model","pmids":["29263213","28931525","28743735"],"confidence":"High","gaps":["Whether CD166 engagement triggers the same ITIM-dependent pathway as other ligands not shown","SHIP1 vs. SHP-1 preference in different cell types not systematically compared"]},{"year":2018,"claim":"A full signaling axis was defined in AML: APOE as the extracellular ligand activates LILRB4, which recruits SHP-2 intracellularly to drive uPAR and ARG1 expression, supporting both T cell suppression and leukemia tissue infiltration; separately, in hepatocytes, LILRB4 recruits SHP-1 to block TRAF6 ubiquitination and NF-κB/MAPK signaling in NAFLD.","evidence":"LILRB4 KO and antibody blockade in AML mouse models with pathway analysis [PMID:30333625]; hepatocyte-specific KO/OE with co-IP of SHP1-TRAF6 [PMID:29091299]; decidual macrophage KO with M1/M2 polarization [PMID:28883820]","pmids":["30333625","29091299","28883820"],"confidence":"High","gaps":["How APOE-triggered SHP-2 differs from SHP-1-mediated pathways mechanistically not resolved","Whether SHP-2 vs. SHP-1 preference is cell-type or ligand determined unknown"]},{"year":2019,"claim":"Systematic ITIM mutagenesis resolved that Y412 and Y442 are essential for T cell suppression while all three ITIMs (Y360, Y412, Y442) are required for tissue infiltration; chimeric proteins showed these functions are specific to LILRB4's intracellular domain, not shared with LILRB1; humanized anti-LILRB4 antibody blocking APOE binding confirmed therapeutic tractability.","evidence":"Site-directed mutagenesis with chimeric constructs in vitro and in vivo [PMID:31700117]; anti-LILRB4 antibody in PDX and syngeneic models [PMID:31213474]","pmids":["31700117","31213474"],"confidence":"High","gaps":["Which phosphatases bind each individual ITIM not mapped","Structural basis for ITIM functional specialization unknown"]},{"year":2021,"claim":"Fibronectin (specifically the N-terminal FN30 domain) was established as a major LILRB4 ligand with sub-micromolar affinity, defining a 'stromal checkpoint': FN-LILRB4 interaction polarizes myeloid cells toward immunosuppression in tumors, while blockade ameliorates autoimmune disease in lupus-prone mice; LILRB4 KO on TAMs shifted phenotype and improved anti-tumor immunity.","evidence":"Bio-layer interferometry for FN30 affinity [PMID:34089617]; anti-ILT3 blockade in human tumor explants [PMID:34426457]; LILRB4-KO tumor models with TAM phenotyping [PMID:33974041]","pmids":["34089617","34426457","33974041"],"confidence":"High","gaps":["Whether FN30 and APOE compete for the same binding site not determined","Structural basis of FN30-LILRB4 interaction unresolved"]},{"year":2022,"claim":"A ternary complex model was established: LILRB4/gp49B co-tethers fibronectin with integrins at focal adhesions, suppressing integrin-mediated Syk phosphorylation — providing a mechanism for how LILRB4 integrates extracellular matrix sensing with inhibitory signaling at adhesion sites.","evidence":"Co-IP of gp49B/integrin β1/FN complex; confocal imaging; Syk phosphorylation in gp49B-deficient macrophages","pmids":["35689642"],"confidence":"High","gaps":["Stoichiometry and dynamics of the ternary complex not characterized","Whether integrin subtype specificity matters not addressed"]},{"year":2023,"claim":"LILRB4 was shown to regulate NK cell cytotoxicity and osteoclastogenesis via fibronectin engagement: gp49B-deficient NK cells had augmented Syk phosphorylation and superior killing of FN-rich targets, while in osteoclast precursors, FN-LILRB4 interaction recruited SHP-1 to TRAF6 to suppress TAK1/NF-κB/MAPK and limit RANKL-induced osteoclastogenesis.","evidence":"gp49B-KO NK cell cytotoxicity and Syk phosphorylation [PMID:37083755]; gp49B-KO mice with micro-CT and SHP-1–TRAF6 co-IP [PMID:36331874]; SHP-2/STAT6 co-IP in decidual MDSCs [PMID:37461040]","pmids":["37083755","36331874","37461040"],"confidence":"High","gaps":["How the same receptor engages SHP-1 in osteoclasts but SHP-2 in AML/MDSCs not explained","Whether FN30 binding site overlaps with galectin-8 or APOE binding sites unknown"]},{"year":2024,"claim":"Galectin-8 was identified as a high-affinity LILRB4 ligand that binds noncompetitively with APOE, activates STAT3, and inhibits NF-κB to polarize MDSCs in solid tumors; separately, in myeloma, LILRB4 drives osteoclastogenesis via SHP-2/NF-κB-dependent RELT secretion, and IKZF1 was identified as a transcriptional activator of LILRB4 feeding into STAT3-PFKFB1 signaling.","evidence":"Ligand screening with competitive binding and LILRB4-KO tumor models [PMID:38232701]; myeloma xenograft/PDX with cytokine array and RELT rescue [PMID:38951916]; IKZF1 transcriptional assays [PMID:39025844]","pmids":["38232701","38951916","39025844"],"confidence":"High","gaps":["Structural basis for noncompetitive APOE/Gal-8 binding not resolved","Whether IKZF1-driven LILRB4 expression occurs in non-myeloma contexts unknown"]},{"year":2025,"claim":"Secretogranin 2 (SCG2) was discovered as a tumor-derived LILRB4 ligand that triggers SHP recruitment and SHP-independent STAT3 activation to promote immunosuppressive myeloid infiltration; separately, LILRB4 was found to promote pyroptosis in cardiomyocytes via SHP-2/TXNIP/NLRP3 during ischemia–reperfusion, and HHT was shown to suppress LILRB4 via FTO-mediated m6A regulation.","evidence":"Myeloid-specific LILRB4 transgenic and SCG2-KO mice with binding and signaling assays [PMID:40707822]; LILRB4-KO mice in I/R with SHP2 inhibitor [PMID:40550372]; FTO degradation and m6A assays in AML [PMID:40590394]","pmids":["40707822","40550372","40590394"],"confidence":"High","gaps":["SCG2 binding site on LILRB4 relative to other ligands not mapped","How LILRB4 switches from anti-inflammatory to pro-pyroptotic signaling in cardiomyocytes not explained","Whether m6A regulation of LILRB4 is generalizable beyond AML unknown"]},{"year":null,"claim":"Key unresolved questions include: the structural basis for multi-ligand binding at the ectodomain (APOE, FN30, galectin-8, CD166, SCG2); the molecular determinants that switch LILRB4 between SHP-1- and SHP-2-dependent pathways in different cell types; and whether the extracellular ITIM-independent suppressive activity involves reverse signaling through a T cell counter-receptor.","evidence":"","pmids":[],"confidence":"Low","gaps":["No co-crystal structure with any ligand","SHP-1 vs. SHP-2 selectivity mechanism unknown","Reverse signaling mechanism molecularly undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,3,7,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,6,13,15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,4,14,16]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,6,8,13,15,24]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,6,7,14,17,19,20]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[29]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,9,19,20,22]}],"complexes":[],"partners":["SHP-1","SHP-2","SHIP1","TRAF6","APOE","FN1","LGALS8","ALCAM"],"other_free_text":[]},"mechanistic_narrative":"LILRB4 (ILT3) is an ITIM-bearing inhibitory immunoreceptor on myeloid cells that functions as a context-dependent immune checkpoint, dampening innate and adaptive immune activation through phosphatase-mediated suppression of activating kinase cascades. Upon engagement by extracellular ligands — APOE in AML [PMID:30333625], fibronectin (FN30 domain) in the tumor microenvironment and at focal adhesions [PMID:34089617, PMID:35689642], galectin-8 in solid tumors [PMID:38232701], CD166/ALCAM on activated T cells [PMID:29263213], and secretogranin 2 from tumor cells [PMID:40707822] — LILRB4 recruits SHP-1 or SHP-2 to its cytoplasmic ITIMs (with Y412 and Y442 critical for T cell suppression and all three ITIMs required for tissue infiltration [PMID:31700117]), leading to dephosphorylation of Syk, Lck, LAT, and Erk [PMID:19833736] and suppression of downstream NF-κB, MAPK, and STAT pathways, which collectively promote tolerogenic APC and MDSC polarization, suppress T and NK cell effector function, and facilitate leukemia cell infiltration [PMID:9151699, PMID:33974041, PMID:37083755]. Beyond immune cells, LILRB4 inhibits TRAF6 ubiquitination via SHP-1 in hepatocytes to restrain NF-κB/MAPK-driven inflammation in NAFLD [PMID:29091299], negatively regulates osteoclastogenesis through SHP-1–TRAF6 association [PMID:36331874], and in cardiomyocytes activates SHP-2/TXNIP/NLRP3 pyroptotic signaling during ischemia–reperfusion injury [PMID:40550372]."},"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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additionally, ILT3 mediates antigen internalization and delivery to intracellular compartments for processing and T cell presentation.\",\n      \"method\": \"Co-ligation assays on monocytes/DCs; calcium flux measurement; tyrosine phosphorylation assay; SHP-1 recruitment assay; antigen internalization and presentation assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal in vitro functional assays with mechanistic follow-up; foundational paper, highly cited\",\n      \"pmids\": [\"9151699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD8+CD28- T suppressor (Ts) cells induce upregulation of ILT3 and ILT4 on monocytes and dendritic cells, rendering APCs tolerogenic with reduced costimulatory molecule expression, and these tolerogenic APCs induce antigen-specific CD4+ T helper cell unresponsiveness.\",\n      \"method\": \"In vitro co-culture of Ts cells with APCs; flow cytometry for ILT3/ILT4 and costimulatory molecule expression; MLR proliferation assay\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional cell-based assays replicated in human transplant recipients; >600 citations\",\n      \"pmids\": [\"11875462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Membrane-expressed ILT3 signals intracellularly to inhibit NF-κB activation and transcription of costimulatory molecules; ILT3 cytoplasmic deletion mutants (ILT3Δ) retain extracellular suppressive activity on T cells, demonstrating extracellular signaling capacity independent of ITIMs, whereas ILT4Δ loses suppressive activity entirely, requiring its cytoplasmic ITIMs.\",\n      \"method\": \"Cytoplasmic deletion mutant transfection in KG1 dendritic-like cell line; T cell proliferation and CMC assays; NF-κB activity assay\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"17161342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LILRB4 co-ligates with FcγRI (CD64) on monocytes, aggregates to sites of activation, and inhibits FcγRI-mediated TNF-α production by dephosphorylating multiple signaling proteins including Lck, Syk, LAT, and Erk, but not alpha-actinin-4; phosphatase inhibitor reversal implicates phosphatases other than SHP-1.\",\n      \"method\": \"Cross-linking assay on THP-1 cells and primary monocytes; ELISA for TNF-α; phosphoprotein western blot; pharmacological inhibitors of phosphatases (sodium pervanadate, sodium stibogluconate)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical assays with pharmacological dissection; moderate citation count\",\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 Ig-like domains with a distinctive obtuse interdomain angle (~107°) and 3(10) helices in the D2 domain; structural comparison indicates LILRB4 is electrostatically and conformationally unsuited to MHC class I ligation, predicting non-MHC ligands.\",\n      \"method\": \"X-ray crystallography (1.7 Å); engineered disulfide bond in D2 domain for stability; structural comparison with Group 1 LILRs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with functional structural interpretation\",\n      \"pmids\": [\"21454581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ILT3 (LILRB4) ligand on activated T cells is CD166/ALCAM, identified by flow cytometry, mass spectrometry, and Biacore; ILT3.Fc binding to CD166 inhibits CD4+ Th proliferation and induces CD8+CD28- T suppressor cells; CD166 knockdown abolishes these effects; ILT3.Fc inhibits tumor cell growth via inhibition of the p70S6K signaling pathway.\",\n      \"method\": \"Flow cytometry; mass spectrometry; Biacore surface plasmon resonance; CD166 knockdown by nucleofection; CRISPR-Cas9 CD166 knockout; in vitro and in vivo tumor models\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ligand identified by MS, validated by SPR, with genetic KO and functional assays\",\n      \"pmids\": [\"29263213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In AML cells, LILRB4 supports tumour cell tissue infiltration and suppresses T cell activity through a signalling pathway involving extracellular APOE as ligand, intracellular SHP-2 recruitment, and downstream activation of uPAR and ARG1; deletion or antibody blockade of LILRB4 impedes AML development in mouse models.\",\n      \"method\": \"Mouse AML models; human AML cells; LILRB4 knockout; antibody blockade; ARG1 and uPAR pathway analysis; T cell suppression assays; tissue infiltration assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal in vivo/in vitro experiments identifying the full signaling pathway; >200 citations\",\n      \"pmids\": [\"30333625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hepatic LILRB4 recruits SHP1 to inhibit TRAF6 ubiquitination, thereby inactivating NF-κB and MAPK cascades; hepatocyte-specific LILRB4 knockout exacerbates high-fat diet-induced NAFLD including insulin resistance, lipid accumulation and inflammation, while overexpression reverses these phenotypes.\",\n      \"method\": \"Hepatocyte-specific knockout (LILRB4-HKO); overexpression transgenic mice; ob/ob model; SHP1 co-immunoprecipitation; TRAF6 ubiquitination assay; NF-κB and MAPK activity\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — gain- and loss-of-function with mechanistic biochemical pathway dissection\",\n      \"pmids\": [\"29091299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LILRB4 ITIMs Y412 and Y442, but not Y360, are required for T cell inhibition by AML cells; all three ITIMs (Y360, Y412, Y442) are needed for leukemia cell tissue infiltration; the intracellular domain of LILRB4 (but not LILRB1) specifically mediates these functions, as shown by chimeric protein experiments.\",\n      \"method\": \"Site-directed mutagenesis of ITIM tyrosines; chimeric LILRB4/LILRB1 constructs; in vitro T cell suppression assays; in vivo AML infiltration mouse models\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — systematic mutagenesis and chimeric protein dissection with in vivo validation\",\n      \"pmids\": [\"31700117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Humanized anti-LILRB4 antibody h128-3 blocks the LILRB4/APOE interaction, reverses T cell suppression, inhibits AML cell tissue infiltration, and mediates ADCC and ADCP, confirming APOE as the functional extracellular ligand triggering LILRB4 signaling in AML.\",\n      \"method\": \"Patient-derived xenograft mice; syngeneic immunocompetent AML mice; antibody blocking experiments; T cell functional assays; ADCC/ADCP assays; chemotherapy combination\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vivo models with mechanistic antibody blockade confirming APOE-LILRB4 axis\",\n      \"pmids\": [\"31213474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LILRB4 deficiency in macrophages promotes atherosclerosis development via decreased Shp1 phosphorylation, which enhances NF-κB-mediated inflammatory responses; bone marrow transplantation confirms the effect is macrophage-intrinsic.\",\n      \"method\": \"LILRB4-/-ApoE-/- double knockout mice; high-fat diet atherosclerosis model; bone marrow transplantation; Shp1 phosphorylation assay; NF-κB activity measurement\",\n      \"journal\": \"Clinical science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with bone marrow transplant and mechanistic signaling assays\",\n      \"pmids\": [\"28743735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Fibronectin is a functional ligand of ILT3/LILRB4 in the tumor microenvironment; fibronectin-ILT3 interaction polarizes myeloid cells toward a suppressive state, and this is reversed by an ILT3-specific blocking antibody, defining a 'stromal checkpoint' mechanism.\",\n      \"method\": \"Ligand screening approach; myeloid cell polarization assays; ex vivo human tumor explant treatment with anti-ILT3; functional phenotyping\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — screening plus functional cell-based validation in primary human tissue\",\n      \"pmids\": [\"34426457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Fibronectin (specifically the N-terminal 30 kDa domain, FN30) is identified as a physiological ligand for both human LILRB4 and murine gp49B with sub-micromolar affinity; blockade of B4-FN binding ameliorates autoimmune disease in lupus-prone BXSB/Yaa mice.\",\n      \"method\": \"Bio-layer interferometry; recombinant FN30-Fc fusion protein; BXSB/Yaa mouse autoimmune model; antibody blockade experiments\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biophysical affinity measurement plus in vivo genetic disease model\",\n      \"pmids\": [\"34089617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LILRB4 on tumor-associated macrophages suppresses anti-tumor immunity; LILRB4 knockout or antibody blockade reduces tumor burden, increases effector-to-Treg ratio, and shifts TAM phenotype toward less suppressive; LILRB4 (gp49B in mice) signals through ITIMs on macrophages.\",\n      \"method\": \"LILRB4-/- mice; anti-LILRB4 antibody treatment; tumor challenge models; flow cytometry of tumor infiltrates; TAM phenotyping\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO plus antibody blockade with defined cellular phenotypic readouts\",\n      \"pmids\": [\"33974041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ILT3 (LILRB4) expressed on CLL B cells inhibits Akt kinase activation upon BCR stimulation by mediating dynamic coalescence of ILT3, BCRs, and SHIP1 (phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1) into inhibitory clusters at the cell surface; ILT3 expression in CLL is driven by Deltex1.\",\n      \"method\": \"Flow cytometry; confocal imaging of inhibitory clusters; Akt phosphorylation assay; BCR stimulation assay; Deltex1 manipulation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway dissection with imaging and biochemical assays\",\n      \"pmids\": [\"28931525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Fibronectin on target cells attenuates NK cell natural cytotoxicity via LILRB4/gp49B; gp49B-deficient NK cells show augmented Syk tyrosine phosphorylation and increased killing of fibronectin-rich tumor cells, indicating LILRB4 delivers an inhibitory signal upon trans-engagement with fibronectin on target cells.\",\n      \"method\": \"Flow cytometry; gp49B-deficient NK cells; NK cell cytotoxicity assays against FN-rich and FN-poor target cells; FN30-KO target cells; Syk phosphorylation biochemical assay\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic KO with biochemical and functional assays confirming mechanism\",\n      \"pmids\": [\"37083755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LILRB4/gp49B and integrin co-tether fibronectin on macrophages in a triplet configuration (B4/gp49B-FN-integrin); gp49B deficiency augments FN-induced Syk phosphorylation, indicating LILRB4 suppresses integrin-mediated pro-inflammatory signaling at focal adhesion sites.\",\n      \"method\": \"FN pull-down/co-IP showing gp49B and integrin β1 in same complex; confocal fluorescent imaging; Syk phosphorylation in gp49B-deficient macrophages; RAW264.7 and THP-1 cell adhesion assays\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — co-IP, imaging, and biochemical phosphorylation analysis with KO cells\",\n      \"pmids\": [\"35689642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Fibronectin-LILRB4/gp49B interaction negatively regulates RANKL-induced osteoclastogenesis by increasing SHP-1 phosphorylation and TRAF6-SHP-1 association, suppressing downstream TAK1, NF-κB, and MAPK phosphorylation; gp49B-deficient mice show increased osteoclast formation and trabecular bone loss.\",\n      \"method\": \"gp49B knockout mice; micro-CT; osteoclast differentiation assays; SHP-1 co-IP with TRAF6; TAK1/NF-κB/MAPK phosphorylation western blot; FN30 fragment treatment\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo KO phenotype with biochemical pathway dissection and co-IP\",\n      \"pmids\": [\"36331874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LILRB4 signaling in decidual MDSCs operates through SHP-2/STAT6 pathway; T. gondii-induced downregulation of LILRB4 reduces p-SHP2 and p-STAT6, decreasing Arg-1 and IL-10 expression; SHP-2 was found to directly bind STAT6, which then binds the Arg-1 and IL-10 promoters.\",\n      \"method\": \"LILRB4-/- pregnant mouse model; anti-LILRB4 neutralizing antibody on human primary dMDSCs; SHP-2/STAT6 co-IP; chromatin promoter binding assay; western blot for p-SHP2, p-STAT6, Arg-1, IL-10\",\n      \"journal\": \"Parasites & vectors\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO and in vitro antibody blockade with mechanistic co-IP, single lab\",\n      \"pmids\": [\"37461040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Galectin-8 (Gal-8) is a high-affinity functional ligand of LILRB4 in solid tumors; Gal-8 ligation induces M-MDSC polarization 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.\",\n      \"method\": \"Ligand screening; binding affinity assays; STAT3 and NF-κB activity assays; MDSC induction assays; LILRB4 KO mouse tumor models; competitive binding analysis\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — new ligand identified with multiple functional assays and in vivo KO validation\",\n      \"pmids\": [\"38232701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LILRB4 on multiple myeloma cells promotes osteoclast differentiation and bone lesion by inducing secretion of RELT cytokine via a p-SHP2/NF-κB signaling pathway; LILRB4 KO abrogates osteoclastogenesis and bone damage; exogenous RELT rescues the phenotype in LILRB4-KO cells.\",\n      \"method\": \"LILRB4-WT and KO conditioned media osteoclast assays; xenograft/syngeneic/PDX models with micro-CT; cytokine array; RNA-seq; luciferase reporter; Co-IP; western blot; RELT rescue experiment\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal assays including co-IP, rescue experiments, and in vivo models\",\n      \"pmids\": [\"38951916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Microglia LILRB4 limits CD8+ T cell infiltration into ischemic brain by a CCL2-mediated mechanism and via arginase-1 activity; conditional LILRB4 KO in microglia increases CD8+ T cell recruitment and worsens infarct, while LILRB4 overexpression is neuroprotective after stroke.\",\n      \"method\": \"Microglia-specific LILRB4 conditional KO and overexpression transgenic mice (Cre-loxP); tMCAO stroke model; scRNA-seq; spatial transcriptomics; flow cytometry; immunofluorescence; T cell migration assays with CCL2 inhibition and recombinant arginase-1\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO and OE with mechanistic pathway identification via scRNA-seq and functional rescue\",\n      \"pmids\": [\"39217343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IKZF1 transactivates LILRB4 expression in multiple myeloma, activating downstream STAT3-PFKFB1 signaling to support MM cell proliferation; LILRB4 knockdown delays MM growth in vitro and in vivo.\",\n      \"method\": \"IKZF1 transcriptional regulation assays; STAT3 and PFKFB1 pathway analysis; LILRB4 knockdown; in vitro proliferation and in vivo xenograft models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptional regulation with signaling pathway dissection, single lab\",\n      \"pmids\": [\"39025844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Secretogranin 2 (SCG2), a granin-family secretory protein, binds LILRB4 on monocytic cells; tumor-derived SCG2 promotes tumor growth in myeloid-specific LILRB4 transgenic mice in a T cell-dependent manner; SCG2-LILRB4 interaction triggers SHP recruitment and SHP-independent STAT3 activation; SCG2 deficiency impairs immunosuppressive monocytic cell infiltration.\",\n      \"method\": \"Myeloid-specific LILRB4 transgenic mouse model; SCG2 deficient mice; binding assays; T cell depletion; LILRB4 blockade; SHP co-IP; STAT3 phosphorylation assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — new ligand discovery with genetic mouse models and mechanistic pathway assays\",\n      \"pmids\": [\"40707822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ILT3 (LILRB4) promotes the immunosuppressive function of monocytic MDSCs; anti-ILT3 antibody treatment impairs MDSC suppressor phenotype acquisition and reduces T cell suppression capacity; combined with anti-PD1, ILT3 blockade enhances T cell IFN-γ secretion.\",\n      \"method\": \"Co-culture MDSC generation with SK-MEL-5 cancer cells; anti-ILT3 antibody treatment; CD8+ T cell proliferation and IFN-γ secretion assays; flow cytometry phenotyping\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional antibody blockade with defined cellular phenotype, single lab\",\n      \"pmids\": [\"33372059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ILT3 overexpression in NSCLC cells recruits SHP2 and SHIP1 and activates ERK1/2 signaling to mediate EMT and tumor cell motility; additionally upregulates VEGF-A for angiogenesis; interaction with ApoE ligand upregulated by ILT3 itself contributes to these effects.\",\n      \"method\": \"ILT3 overexpression in NSCLC lines; SHP2/SHIP1 co-immunoprecipitation; ERK1/2 phosphorylation assay; EMT markers; VEGF-A ELISA; murine metastasis models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP and signaling assays with in vivo metastasis model, single lab\",\n      \"pmids\": [\"33152402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Soluble ILT3-Fc (containing only the extracellular Ig-like domain) induces CD8+ T suppressor cell differentiation associated with significant upregulation of BCL6 (a transcriptional repressor of IL-2, IFN-γ, IL-5, and granzyme B), SOCS1, and DUSP10, defining the gene signature of ILT3-Fc-induced Ts cells.\",\n      \"method\": \"Soluble ILT3-Fc treatment of human T cells; gene expression profiling; BCL6, SOCS1, DUSP10 functional validation; humanized NOD/SCID transplant model\",\n      \"journal\": \"International reviews of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gene profiling with functional validation in humanized mouse model, single lab\",\n      \"pmids\": [\"20132030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LILRB4/gp49B (murine ortholog) promotes M2 polarization of MDSCs and tumor metastasis; gp49B deficiency inhibited monocytic MDSC tumor infiltration and impaired Treg activation, cancer cell migration promotion, and tumor angiogenesis; gp49B knockout increased plasma exosomal miR-1 family miRNAs with anti-tumor activity.\",\n      \"method\": \"gp49B-/- mouse tumor metastasis models; M-MDSC characterization; Treg activation assays; plasma exosome miRNA profiling; cancer cell migration assay\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple functional phenotypic readouts, single lab\",\n      \"pmids\": [\"35402083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LILRB4 deficiency in decidual macrophages strengthens M1 activation and weakens M2 tolerance functions; T. gondii infection downregulates LILRB4 on decidual macrophages, shifting arginine metabolic enzyme expression (iNOS vs. Arg-1) and cytokine profiles, contributing to abnormal pregnancy outcomes.\",\n      \"method\": \"LILRB4-/- pregnant mouse model; T. gondii infection; anti-LILRB4 neutralizing antibody on human primary decidual macrophages; M1/M2 surface molecule quantification; arginine metabolic enzyme measurement; cytokine profiling\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO and in vitro antibody blockade with defined functional readouts\",\n      \"pmids\": [\"28883820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LILRB4 promotes inflammation and pyroptosis in myocardial ischemia-reperfusion injury by activating SHP-2 phosphorylation, which upregulates TXNIP/NLRP3/Caspase-1/GSDMD signaling; LILRB4 KO mice show diminished inflammatory cytokines and reduced pyroptotic protein expression after I/R.\",\n      \"method\": \"LILRB4-/- mice; adenoviral overexpression/knockdown in H9C2 cardiomyocytes; I/R and H/R models; SHP2 inhibitor PHPS1; western blot for p-SHP2, TXNIP, NLRP3, Caspase-1, GSDMD; ELISA for cytokines\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO and pharmacological inhibition with mechanistic signaling pathway dissection, single lab\",\n      \"pmids\": [\"40550372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Homoharringtonine (HHT) suppresses LILRB4 expression by promoting FTO (m6A demethylase) degradation, increasing global RNA m6A levels, which reduces expression of downstream targets MLL1 and LILRB4, thereby enhancing CD8+ T cell cytotoxicity against monocytic AML cells.\",\n      \"method\": \"RNA-seq; functional assays; m6A quantification; FTO degradation assay; MLL1 and LILRB4 mRNA/protein measurement; in vitro cytotoxicity assays; AML xenograft mouse models\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway (FTO/m6A/LILRB4) with in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"40590394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NK cells require LILRB4/gp49B for proper function during neurotropic Zika virus infection; LILRB4 KO mice show increased neurological disease severity with reduced viral clearance, associated with altered NK cell maturation, diminished glucose consumption, reduced IFN-γ and granzyme B production, and impaired cytotoxicity.\",\n      \"method\": \"LILRB4 KO mice; neonatal ZIKV infection model; NK cell functional assays (granzyme B, IFN-γ, cytotoxicity); NK cell metabolic assay (glucose consumption); phenotypic characterization of NK maturation stages\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple NK cell functional readouts, single lab\",\n      \"pmids\": [\"35132958\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LILRB4 is an ITIM-containing inhibitory receptor expressed primarily on myeloid cells that signals through recruitment of SHP-1/SHP-2 phosphatases to dephosphorylate and suppress activation kinases (Lck, Syk, LAT, Erk) and downstream transcription factors (NF-κB, MAPK); its extracellular domain binds multiple ligands including APOE, fibronectin (FN30 domain), galectin-8, CD166/ALCAM, and secretogranin 2, each triggering distinct downstream pathways (SHP-2/uPAR/ARG1 in AML; SHP-2/STAT3 with SCG2; STAT3/NF-κB with galectin-8; TRAF6/TAK1/NF-κB/MAPK in osteoclasts; SHP-2/TXNIP/NLRP3 in cardiomyocytes), and in AML cells specifically, ITIM tyrosines Y412 and Y442 mediate T cell suppression while all three ITIMs (Y360, Y412, Y442) are required for tissue infiltration, collectively establishing LILRB4 as a context-dependent immune checkpoint that suppresses myeloid and NK cell activation, promotes tolerogenic APC function, and supports tumor immune evasion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LILRB4 (ILT3) is an ITIM-bearing inhibitory immunoreceptor on myeloid cells that functions as a context-dependent immune checkpoint, dampening innate and adaptive immune activation through phosphatase-mediated suppression of activating kinase cascades. Upon engagement by extracellular ligands — APOE in AML [PMID:30333625], fibronectin (FN30 domain) in the tumor microenvironment and at focal adhesions [PMID:34089617, PMID:35689642], galectin-8 in solid tumors [PMID:38232701], CD166/ALCAM on activated T cells [PMID:29263213], and secretogranin 2 from tumor cells [PMID:40707822] — LILRB4 recruits SHP-1 or SHP-2 to its cytoplasmic ITIMs (with Y412 and Y442 critical for T cell suppression and all three ITIMs required for tissue infiltration [PMID:31700117]), leading to dephosphorylation of Syk, Lck, LAT, and Erk [PMID:19833736] and suppression of downstream NF-κB, MAPK, and STAT pathways, which collectively promote tolerogenic APC and MDSC polarization, suppress T and NK cell effector function, and facilitate leukemia cell infiltration [PMID:9151699, PMID:33974041, PMID:37083755]. Beyond immune cells, LILRB4 inhibits TRAF6 ubiquitination via SHP-1 in hepatocytes to restrain NF-κB/MAPK-driven inflammation in NAFLD [PMID:29091299], negatively regulates osteoclastogenesis through SHP-1–TRAF6 association [PMID:36331874], and in cardiomyocytes activates SHP-2/TXNIP/NLRP3 pyroptotic signaling during ischemia–reperfusion injury [PMID:40550372].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing LILRB4 as an inhibitory receptor: co-ligation with activating receptors on APCs was shown to dampen calcium flux and tyrosine phosphorylation through SHP-1 recruitment to ITIMs, while also mediating antigen internalization — defining LILRB4's dual role in signal inhibition and antigen processing.\",\n      \"evidence\": \"Co-ligation assays on monocytes/DCs with calcium flux, phosphorylation, SHP-1 recruitment, and antigen presentation readouts\",\n      \"pmids\": [\"9151699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the natural extracellular ligand unknown\", \"Which specific ITIMs are functionally required not yet determined\", \"Whether SHP-1 is the sole effector phosphatase unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"LILRB4 upregulation on APCs was shown to be induced by CD8+CD28− T suppressor cells, rendering APCs tolerogenic and capable of inducing CD4+ T cell anergy — placing LILRB4 in a feedback circuit of peripheral tolerance.\",\n      \"evidence\": \"In vitro Ts–APC co-cultures with flow cytometry and MLR assays, replicated in transplant recipients\",\n      \"pmids\": [\"11875462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular signals from Ts cells that upregulate LILRB4 not identified\", \"Whether LILRB4 ITIM signaling is required for the tolerogenic phenotype not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Dissection of intracellular versus extracellular signaling revealed that membrane LILRB4 inhibits NF-κB and costimulatory molecule transcription via its ITIMs, yet a cytoplasmic-deletion mutant retains extracellular T cell–suppressive capacity — establishing a bidirectional signaling model.\",\n      \"evidence\": \"Cytoplasmic deletion mutants in KG1 cell line with T cell proliferation and NF-κB activity assays\",\n      \"pmids\": [\"17161342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Extracellular suppressive mechanism (reverse signaling or ligand decoy) not molecularly defined\", \"Single cell line system limits generalizability\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The scope of LILRB4's inhibitory mechanism was broadened beyond SHP-1: co-ligation with FcγRI showed dephosphorylation of Lck, Syk, LAT, and Erk, and pharmacological evidence implicated additional phosphatases, revealing a broader kinase-suppressive program than initially appreciated.\",\n      \"evidence\": \"Cross-linking on THP-1 and primary monocytes with phosphoprotein western blot and phosphatase inhibitor reversal\",\n      \"pmids\": [\"19833736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the non-SHP-1 phosphatase(s) not determined\", \"Whether identical substrates are targeted in all myeloid cell contexts unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Soluble ILT3-Fc was shown to induce CD8+ T suppressor cell differentiation marked by BCL6, SOCS1, and DUSP10 upregulation, providing the molecular gene signature downstream of extracellular LILRB4 engagement on T cells.\",\n      \"evidence\": \"Soluble ILT3-Fc treatment of human T cells with gene expression profiling and humanized mouse transplant model\",\n      \"pmids\": [\"20132030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"T cell receptor for soluble ILT3-Fc not identified\", \"Whether BCL6 is required for Ts induction not tested with loss-of-function\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The 1.7 Å crystal structure of the LILRB4 ectodomain revealed a distinctive obtuse interdomain angle and electrostatic surface incompatible with MHC class I binding, predicting non-MHC ligands and distinguishing LILRB4 from Group 1 LILRs.\",\n      \"evidence\": \"X-ray crystallography at 1.7 Å resolution with structural comparison to MHC-binding LILRs\",\n      \"pmids\": [\"21454581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal with any ligand obtained\", \"Structural basis for ligand selectivity unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Multiple ligands and cell contexts for LILRB4 were identified in parallel: CD166/ALCAM on activated T cells was found by mass spectrometry and SPR [PMID:29263213]; in CLL, LILRB4 clustered with BCR and SHIP1 to inhibit Akt [PMID:28931525]; and in macrophages, LILRB4 deficiency enhanced NF-κB via reduced SHP-1 phosphorylation, promoting atherosclerosis [PMID:28743735].\",\n      \"evidence\": \"MS/SPR ligand identification with CD166 KO validation; confocal imaging of inhibitory clusters in CLL; double-KO mice with bone marrow transplant in atherosclerosis model\",\n      \"pmids\": [\"29263213\", \"28931525\", \"28743735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD166 engagement triggers the same ITIM-dependent pathway as other ligands not shown\", \"SHIP1 vs. SHP-1 preference in different cell types not systematically compared\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A full signaling axis was defined in AML: APOE as the extracellular ligand activates LILRB4, which recruits SHP-2 intracellularly to drive uPAR and ARG1 expression, supporting both T cell suppression and leukemia tissue infiltration; separately, in hepatocytes, LILRB4 recruits SHP-1 to block TRAF6 ubiquitination and NF-κB/MAPK signaling in NAFLD.\",\n      \"evidence\": \"LILRB4 KO and antibody blockade in AML mouse models with pathway analysis [PMID:30333625]; hepatocyte-specific KO/OE with co-IP of SHP1-TRAF6 [PMID:29091299]; decidual macrophage KO with M1/M2 polarization [PMID:28883820]\",\n      \"pmids\": [\"30333625\", \"29091299\", \"28883820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How APOE-triggered SHP-2 differs from SHP-1-mediated pathways mechanistically not resolved\", \"Whether SHP-2 vs. SHP-1 preference is cell-type or ligand determined unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Systematic ITIM mutagenesis resolved that Y412 and Y442 are essential for T cell suppression while all three ITIMs (Y360, Y412, Y442) are required for tissue infiltration; chimeric proteins showed these functions are specific to LILRB4's intracellular domain, not shared with LILRB1; humanized anti-LILRB4 antibody blocking APOE binding confirmed therapeutic tractability.\",\n      \"evidence\": \"Site-directed mutagenesis with chimeric constructs in vitro and in vivo [PMID:31700117]; anti-LILRB4 antibody in PDX and syngeneic models [PMID:31213474]\",\n      \"pmids\": [\"31700117\", \"31213474\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which phosphatases bind each individual ITIM not mapped\", \"Structural basis for ITIM functional specialization unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Fibronectin (specifically the N-terminal FN30 domain) was established as a major LILRB4 ligand with sub-micromolar affinity, defining a 'stromal checkpoint': FN-LILRB4 interaction polarizes myeloid cells toward immunosuppression in tumors, while blockade ameliorates autoimmune disease in lupus-prone mice; LILRB4 KO on TAMs shifted phenotype and improved anti-tumor immunity.\",\n      \"evidence\": \"Bio-layer interferometry for FN30 affinity [PMID:34089617]; anti-ILT3 blockade in human tumor explants [PMID:34426457]; LILRB4-KO tumor models with TAM phenotyping [PMID:33974041]\",\n      \"pmids\": [\"34089617\", \"34426457\", \"33974041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FN30 and APOE compete for the same binding site not determined\", \"Structural basis of FN30-LILRB4 interaction unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A ternary complex model was established: LILRB4/gp49B co-tethers fibronectin with integrins at focal adhesions, suppressing integrin-mediated Syk phosphorylation — providing a mechanism for how LILRB4 integrates extracellular matrix sensing with inhibitory signaling at adhesion sites.\",\n      \"evidence\": \"Co-IP of gp49B/integrin β1/FN complex; confocal imaging; Syk phosphorylation in gp49B-deficient macrophages\",\n      \"pmids\": [\"35689642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of the ternary complex not characterized\", \"Whether integrin subtype specificity matters not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"LILRB4 was shown to regulate NK cell cytotoxicity and osteoclastogenesis via fibronectin engagement: gp49B-deficient NK cells had augmented Syk phosphorylation and superior killing of FN-rich targets, while in osteoclast precursors, FN-LILRB4 interaction recruited SHP-1 to TRAF6 to suppress TAK1/NF-κB/MAPK and limit RANKL-induced osteoclastogenesis.\",\n      \"evidence\": \"gp49B-KO NK cell cytotoxicity and Syk phosphorylation [PMID:37083755]; gp49B-KO mice with micro-CT and SHP-1–TRAF6 co-IP [PMID:36331874]; SHP-2/STAT6 co-IP in decidual MDSCs [PMID:37461040]\",\n      \"pmids\": [\"37083755\", \"36331874\", \"37461040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the same receptor engages SHP-1 in osteoclasts but SHP-2 in AML/MDSCs not explained\", \"Whether FN30 binding site overlaps with galectin-8 or APOE binding sites unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Galectin-8 was identified as a high-affinity LILRB4 ligand that binds noncompetitively with APOE, activates STAT3, and inhibits NF-κB to polarize MDSCs in solid tumors; separately, in myeloma, LILRB4 drives osteoclastogenesis via SHP-2/NF-κB-dependent RELT secretion, and IKZF1 was identified as a transcriptional activator of LILRB4 feeding into STAT3-PFKFB1 signaling.\",\n      \"evidence\": \"Ligand screening with competitive binding and LILRB4-KO tumor models [PMID:38232701]; myeloma xenograft/PDX with cytokine array and RELT rescue [PMID:38951916]; IKZF1 transcriptional assays [PMID:39025844]\",\n      \"pmids\": [\"38232701\", \"38951916\", \"39025844\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for noncompetitive APOE/Gal-8 binding not resolved\", \"Whether IKZF1-driven LILRB4 expression occurs in non-myeloma contexts unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Secretogranin 2 (SCG2) was discovered as a tumor-derived LILRB4 ligand that triggers SHP recruitment and SHP-independent STAT3 activation to promote immunosuppressive myeloid infiltration; separately, LILRB4 was found to promote pyroptosis in cardiomyocytes via SHP-2/TXNIP/NLRP3 during ischemia–reperfusion, and HHT was shown to suppress LILRB4 via FTO-mediated m6A regulation.\",\n      \"evidence\": \"Myeloid-specific LILRB4 transgenic and SCG2-KO mice with binding and signaling assays [PMID:40707822]; LILRB4-KO mice in I/R with SHP2 inhibitor [PMID:40550372]; FTO degradation and m6A assays in AML [PMID:40590394]\",\n      \"pmids\": [\"40707822\", \"40550372\", \"40590394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SCG2 binding site on LILRB4 relative to other ligands not mapped\", \"How LILRB4 switches from anti-inflammatory to pro-pyroptotic signaling in cardiomyocytes not explained\", \"Whether m6A regulation of LILRB4 is generalizable beyond AML unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis for multi-ligand binding at the ectodomain (APOE, FN30, galectin-8, CD166, SCG2); the molecular determinants that switch LILRB4 between SHP-1- and SHP-2-dependent pathways in different cell types; and whether the extracellular ITIM-independent suppressive activity involves reverse signaling through a T cell counter-receptor.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No co-crystal structure with any ligand\", \"SHP-1 vs. SHP-2 selectivity mechanism unknown\", \"Reverse signaling mechanism molecularly undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 3, 7, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 6, 13, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 4, 14, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 6, 8, 13, 15, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 6, 7, 14, 17, 19, 20]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [29]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 9, 19, 20, 22]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SHP-1\",\n      \"SHP-2\",\n      \"SHIP1\",\n      \"TRAF6\",\n      \"APOE\",\n      \"FN1\",\n      \"LGALS8\",\n      \"ALCAM\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}