{"gene":"LILRB3","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2021,"finding":"LILRB3 intracellular domain is constitutively associated with the adaptor protein TRAF2. Upon LILRB3 activation in AML cells, cFLIP is recruited and NF-κB is upregulated, enhancing leukemic cell survival and inhibiting T-cell anti-tumor activity. Hyperactivation of NF-κB triggers a negative feedback loop via A20, which disrupts the LILRB3-TRAF2 interaction, causing SHP-1/2-mediated inhibitory activity of LILRB3 to become dominant.","method":"Co-immunoprecipitation, signaling pathway analysis, NF-κB reporter assays, antagonizing antibody blockade, in vivo AML progression models","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifying TRAF2 and cFLIP associations, functional signaling readouts (NF-κB, SHP-1/2), and in vivo validation in a single focused study with multiple orthogonal methods","pmids":["35122056"],"is_preprint":false},{"year":2021,"finding":"LILRB3 expressed on non-transformed epithelial cells recognizes MHC class I that is highly expressed on transformed cells. This MHC class I–LILRB3 interaction triggers an SHP2-ROCK2 signaling pathway that generates a mechanical force to extrude transformed (precancerous) cells from the epithelial layer, leading to their apoptosis and clearance independently of NK or CD8+ T cell activity.","method":"Live imaging of cell competition, loss-of-function (LILRB3 knockdown), co-immunoprecipitation, epistasis analysis with SHP2 and ROCK2 inhibitors/knockdowns, in vitro epithelial extrusion assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding established between MHC class I and LILRB3, downstream SHP2-ROCK2 pathway confirmed by epistasis/knockdown, multiple orthogonal methods in a single focused study","pmids":["34686865","34740904"],"is_preprint":false},{"year":2020,"finding":"LILRB3 ligation on primary human monocytes by an agonistic monoclonal antibody induces phenotypic and functional changes leading to potent inhibition of immune responses in vitro, including significant reduction in T cell proliferation. Agonizing LILRB3 in humanized mice induced tolerance and permitted efficient engraftment of allogeneic cells, establishing LILRB3 as an immunosuppressive myeloid checkpoint receptor.","method":"Monoclonal antibody panel, primary human monocyte stimulation assays, T cell proliferation assay, humanized mouse allograft engraftment model","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Moderate — agonistic antibody functional assay in primary cells plus in vivo humanized mouse model with defined cellular phenotype, multiple orthogonal methods","pmids":["32870822"],"is_preprint":false},{"year":2023,"finding":"APOE4, but not APOE2, specifically binds LilrB3. Two discrete immunoglobulin-like domains of the LilrB3 extracellular domain recognize a positively charged surface patch on the N-terminal domain of APOE4. The crystal structure reveals a hetero-tetrameric complex (two APOE4 molecules engaging two LilrB3 molecules), bringing intracellular signaling motifs into close proximity. APOE4, but not APOE2, activates human microglia (HMC3) into a pro-inflammatory state in a LilrB3-dependent manner.","method":"X-ray crystallography (atomic structure of APOE4–LilrB3 complex), biochemical binding assays, LilrB3 knockdown in microglia, functional inflammatory assays","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic-resolution crystal structure plus biochemical binding validation and functional cellular assays with LilrB3-knockdown controls, single lab","pmids":["36588123"],"is_preprint":false},{"year":2016,"finding":"Specific allelic variants of LILRB3 (notably LILRB3*12) bind a ligand on necrotic glandular epithelial cells that is associated with cytokeratin 8. Immunoprecipitation of the ligand from epithelial cell lysates using recombinant LILRB3*12 identified cytokeratins 8, 18, and 19. Knockdown of cytokeratin 8 in epithelial cells abrogated LILRB3 ligand expression. Purified cytokeratin 8-associated proteins activated LILRB3*12 reporter cells.","method":"Recombinant receptor binding assay, immunoprecipitation, cytokeratin 8 knockdown, LILRB3 reporter cell activation assay, co-localization by immunofluorescence","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (IP, knockdown, reporter activation, co-localization) in a single lab identifying cytokeratin 8/18/19 as allele-specific LILRB3 ligands","pmids":["26769854"],"is_preprint":false},{"year":2020,"finding":"LILRB3 (but not LILRA6) is expressed on the surface of resting human neutrophils and is released from the surface upon neutrophil activation. Continuous ligation of LILRB3 inhibits key IgA-mediated effector functions including reactive oxygen species production, phagocytic uptake, and microbial killing, establishing LILRB3 as an inhibitory checkpoint on neutrophil activation.","method":"Immunoprecipitation followed by mass spectrometry (detecting LILRB3 in neutrophil lysates), flow cytometry, PLB-985 differentiation model, functional assays (ROS, phagocytosis, microbial killing) with continuous LILRB3 ligation","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry confirmation of protein expression, functional assays with defined ligand, cell-line model validation, single lab","pmids":["31915259"],"is_preprint":false},{"year":2024,"finding":"Galectin-4 and galectin-7 are ligands that induce activation of LILRB3 on immunosuppressive myeloid cells (MDSCs). Blockade of LILRB3 signaling by an antagonistic antibody inhibited immunosuppressive myeloid cell activity and impeded tumor development in myeloid-specific LILRB3 transgenic mice through a T cell-dependent mechanism.","method":"Ligand-receptor binding assays identifying galectin-4 and galectin-7 as LILRB3 ligands, LILRB3 transgenic mouse tumor model, antibody blockade, T cell depletion epistasis","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — identification of novel ligands with functional readout in transgenic in vivo model plus T cell epistasis, single lab","pmids":["38113030"],"is_preprint":false},{"year":2013,"finding":"LILRB3 and LILRA6 share identical extracellular domains. LILRB3 mediates inhibitory signaling via immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic tail, whereas LILRA6 signals through association with the activating adaptor FcRγ (which bears an ITAM). LILRA6 expression level on monocytes correlates with copy number of the LILRA6 gene.","method":"mRNA expression analysis across PBMC fractions, copy number variation analysis, receptor domain characterization","journal":"Immunogenetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — domain characterization and expression correlation without direct functional reconstitution of ITIM signaling; single lab, primarily genetic/expression analysis","pmids":["24096970"],"is_preprint":false},{"year":2025,"finding":"A cluster of four consecutive missense SNPs (LILRB3-4SNPs) in LILRB3 at amino acids 617–618, proximal to a SHP1/2 phosphatase-binding ITIM, is strongly associated with kidney transplant failure in African Americans. Multiomics analysis of blood and biopsies showed that recipients with LILRB3-4SNPs exhibited enhanced inflammation and monocyte ferroptosis, suggesting these mutations functionally impair ITIM-mediated SHP1/2 signaling.","method":"Blood RNA sequencing, genomic SNP association analysis, multiomics (transcriptomics + biopsy proteomics), APOL1 epistasis analysis","journal":"Nature medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic association with multiomics correlates; no direct in vitro or biochemical demonstration that the SNPs disrupt SHP1/2 binding or ITIM function","pmids":["40065170"],"is_preprint":false},{"year":2023,"finding":"LILRB3 blockade with antagonist antibodies upregulates myeloid lineage differentiation transcription factors (PU.1, C/EBP family, IRF) and decreases phosphorylation of AKT, cyclin D1, and retinoblastoma protein in AML cells, inhibiting leukemia cell proliferation. Conversely, LILRB3 agonism enhances leukemia survival through upregulation of cholesterol metabolism pathways.","method":"Antibody blockade/agonism, western blot (phosphorylation), transcriptomic analysis, in vitro and in vivo CAR T cell assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined downstream signaling changes (AKT, cyclin D1, Rb phosphorylation) with antibody manipulation plus transcriptomic pathway identification, single lab, multiple methods","pmids":["38098451"],"is_preprint":false},{"year":2024,"finding":"miR-103a-2-5p directly targets the 3'-UTR of LILRB3 mRNA (confirmed by dual luciferase reporter assay), suppressing LILRB3 expression and thereby inhibiting AML cell growth, reducing CD8+ T cell apoptosis, suppressing the Nrf2/HO-1 axis, and reducing the GSH/ROS ratio leading to increased intracellular ROS and AML cell apoptosis.","method":"Dual luciferase reporter assay (direct 3'-UTR targeting), qPCR, western blot, flow cytometry (apoptosis, cell cycle), in vivo mouse AML model with CLP-delivered miRNA","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'-UTR interaction confirmed by reporter assay, downstream pathway (Nrf2/HO-1) and immune consequence validated in vitro and in vivo, single lab","pmids":["38486250"],"is_preprint":false}],"current_model":"LILRB3 is an ITIM-bearing inhibitory receptor expressed predominantly on myeloid cells (monocytes, neutrophils, macrophages) and on non-immune epithelial cells, whose extracellular domain binds multiple ligands including MHC class I (on transformed cells), APOE4 (isoform-specific), galectins-4/7, and cytokeratin 8-associated complexes on necrotic epithelial cells; ligand engagement recruits SHP-1/2 via ITIMs to suppress innate immune effector functions, while in AML cells LILRB3 additionally signals through a TRAF2–cFLIP–NF-κB activating axis to promote leukemic survival, with A20-mediated feedback shifting the balance back to ITIM/SHP-1/2 inhibitory dominance, and in epithelial cell competition LILRB3 couples MHC class I recognition to an SHP2–ROCK2 mechanical extrusion pathway."},"narrative":{"mechanistic_narrative":"LILRB3 is an ITIM-bearing inhibitory receptor of myeloid cells that functions as an immunosuppressive checkpoint, dampening innate effector responses upon ligand engagement [PMID:32870822, PMID:31915259]. On primary monocytes its ligation drives potent suppression of T cell proliferation and, in humanized mice, induces tolerance permitting allogeneic engraftment [PMID:32870822]; on resting neutrophils, continuous LILRB3 ligation inhibits IgA-mediated ROS production, phagocytosis, and microbial killing [PMID:31915259]. The extracellular domain engages a structurally diverse ligand repertoire: MHC class I [PMID:34686865, PMID:34740904], an APOE4-specific surface patch resolved at atomic resolution as a 2:2 hetero-tetrameric APOE4–LILRB3 complex [PMID:36588123], galectin-4 and galectin-7 on immunosuppressive myeloid cells [PMID:38113030], and a cytokeratin 8–associated complex on necrotic glandular epithelium recognized in an allele-specific manner [PMID:26769854]. Receptor signaling bifurcates by context: epithelial recognition of MHC class I on transformed cells couples to an SHP2–ROCK2 mechanical pathway that extrudes precancerous cells independently of NK or CD8+ T cells [PMID:34686865, PMID:34740904], whereas in AML the intracellular domain constitutively associates with TRAF2 and, upon activation, recruits cFLIP to upregulate NF-κB and promote leukemic survival, with A20-mediated feedback disrupting the LILRB3–TRAF2 interaction to restore SHP-1/2 inhibitory dominance [PMID:35122056]. In AML cells, blockade derepresses myeloid differentiation factors (PU.1, C/EBP, IRF) and reduces AKT, cyclin D1, and Rb phosphorylation, while agonism sustains survival via cholesterol metabolism [PMID:38098451]; APOE4 engagement likewise activates microglia into a pro-inflammatory state in a LILRB3-dependent manner [PMID:36588123]. A cluster of four missense SNPs proximal to a SHP1/2-binding ITIM associates with kidney transplant failure in African Americans, linking impaired LILRB3 inhibitory signaling to inflammation and monocyte ferroptosis [PMID:40065170].","teleology":[{"year":2013,"claim":"Established that LILRB3 and the near-identical LILRA6 are functionally opposite paired receptors, with LILRB3 signaling via cytoplasmic ITIMs while its sister receptor signals through an activating FcRgamma/ITAM module.","evidence":"mRNA expression profiling across PBMC fractions, copy number analysis, and receptor domain characterization","pmids":["24096970"],"confidence":"Low","gaps":["No direct functional reconstitution of ITIM-driven inhibitory signaling","Ligand identity not addressed","Primarily genetic/expression correlation"]},{"year":2016,"claim":"Identified the first defined LILRB3 ligand as a cytokeratin 8-associated complex on necrotic epithelial cells, recognized in an allele-specific manner, addressing what LILRB3 senses on damaged tissue.","evidence":"Recombinant receptor pulldown, cytokeratin 8 knockdown, and LILRB3*12 reporter cell activation with co-localization","pmids":["26769854"],"confidence":"Medium","gaps":["Allele-specificity limits generalization to all LILRB3 variants","Downstream signaling consequence not mapped","Physiological context of necrotic-cell sensing not defined"]},{"year":2020,"claim":"Defined LILRB3 as an immunosuppressive myeloid checkpoint by showing agonistic ligation of monocytes suppresses T cell responses and induces transplant tolerance in vivo.","evidence":"Agonistic monoclonal antibody assays on primary human monocytes, T cell proliferation readout, and humanized mouse allograft engraftment","pmids":["32870822"],"confidence":"High","gaps":["Natural ligand driving the tolerogenic response not identified","Intracellular signaling intermediates not dissected"]},{"year":2020,"claim":"Extended the inhibitory checkpoint role to neutrophils, showing LILRB3 ligation restrains IgA-mediated effector functions and that surface receptor is shed upon activation.","evidence":"IP-mass spectrometry, flow cytometry, PLB-985 differentiation model, and functional ROS/phagocytosis/killing assays under continuous ligation","pmids":["31915259"],"confidence":"Medium","gaps":["Mechanism of activation-induced surface release unknown","Endogenous neutrophil ligand not defined"]},{"year":2021,"claim":"Revealed a context-dependent activating signaling axis in AML, distinct from canonical ITIM inhibition, explaining how LILRB3 promotes leukemic survival and the feedback that restores inhibition.","evidence":"Reciprocal Co-IP identifying TRAF2/cFLIP, NF-kB reporter assays, antagonist antibody blockade, and in vivo AML models","pmids":["35122056"],"confidence":"High","gaps":["Ligand triggering the AML TRAF2-NF-kB axis not identified","Switch determinants between activating and inhibitory modes incompletely defined"]},{"year":2021,"claim":"Demonstrated a non-immune role in epithelial cell competition, where LILRB3 recognition of MHC class I on transformed cells drives mechanical extrusion via SHP2-ROCK2 independently of cytotoxic lymphocytes.","evidence":"Live cell-competition imaging, LILRB3 knockdown, Co-IP, and SHP2/ROCK2 inhibitor and knockdown epistasis in epithelial extrusion assays","pmids":["34686865","34740904"],"confidence":"High","gaps":["How an inhibitory receptor couples to a force-generating ROCK2 pathway mechanistically unresolved","Generality across epithelial tissues not established"]},{"year":2023,"claim":"Provided atomic-resolution structural and functional evidence for isoform-specific APOE4 binding, defining a 2:2 receptor clustering geometry and linking LILRB3 to microglial pro-inflammatory activation.","evidence":"X-ray crystallography of the APOE4-LILRB3 complex, biochemical binding assays, and LILRB3 knockdown in HMC3 microglia with inflammatory readouts","pmids":["36588123"],"confidence":"High","gaps":["Downstream signaling from APOE4-induced clustering not biochemically mapped","Relevance to neurodegenerative disease in vivo not tested"]},{"year":2023,"claim":"Mapped downstream effectors of LILRB3 in AML, showing blockade derepresses myeloid differentiation and proliferation signaling while agonism sustains survival via cholesterol metabolism.","evidence":"Antibody blockade/agonism, western blot of AKT/cyclin D1/Rb phosphorylation, transcriptomics, and CAR T cell assays in vitro and in vivo","pmids":["38098451"],"confidence":"Medium","gaps":["Direct biochemical link between receptor and AKT/cyclin D1 axis not established","Single lab"]},{"year":2024,"claim":"Identified galectin-4 and galectin-7 as activating ligands on immunosuppressive myeloid cells, linking ligand engagement to tumor-promoting immunosuppression that is T cell-dependent.","evidence":"Ligand-receptor binding assays, myeloid-specific LILRB3 transgenic tumor model, antagonist antibody blockade, and T cell depletion epistasis","pmids":["38113030"],"confidence":"Medium","gaps":["Intracellular signaling triggered by galectins not dissected","Single lab"]},{"year":2024,"claim":"Established post-transcriptional regulation of LILRB3, with miR-103a-2-5p directly suppressing its expression and thereby reducing AML growth through the Nrf2/HO-1 redox axis.","evidence":"Dual luciferase 3'-UTR reporter, qPCR, western blot, apoptosis flow cytometry, and in vivo AML model with delivered miRNA","pmids":["38486250"],"confidence":"Medium","gaps":["Whether endogenous miR-103a-2-5p regulates LILRB3 physiologically not established","Connection between receptor level and Nrf2/HO-1 axis is correlative"]},{"year":2025,"claim":"Linked LILRB3 ITIM-proximal genetic variation to disease, associating a four-SNP cluster with kidney transplant failure and implicating impaired inhibitory signaling in inflammation and monocyte ferroptosis.","evidence":"Genomic SNP association, blood RNA-seq, biopsy multiomics, and APOL1 epistasis analysis","pmids":["40065170"],"confidence":"Low","gaps":["No direct biochemical demonstration that the SNPs disrupt SHP1/2 binding or ITIM function","Causality versus association not resolved","Mechanistic link to ferroptosis correlative"]},{"year":null,"claim":"It remains unresolved how a single ITIM-bearing receptor switches between SHP-1/2 inhibition, TRAF2-NF-kB activation, and SHP2-ROCK2 mechanical signaling depending on ligand and cell type.","evidence":"No timeline study reconstitutes the determinants selecting among the alternative signaling outputs","pmids":[],"confidence":"Low","gaps":["Ligand-specific signaling bias not defined","Stoichiometry/clustering rules linking ligand geometry to output unknown","No unified structural model across ligands"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2,3,5,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,5]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,5,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,8]}],"complexes":[],"partners":["TRAF2","SHP1","SHP2","ROCK2","APOE4","CFLIP","A20"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75022","full_name":"Leukocyte immunoglobulin-like receptor subfamily B member 3","aliases":["CD85 antigen-like family member A","Immunoglobulin-like transcript 5","ILT-5","Monocyte inhibitory receptor HL9"],"length_aa":631,"mass_kda":69.4,"function":"May act as receptor for class I MHC antigens. Becomes activated upon coligation of LILRB3 and immune receptors, such as FCGR2B and the B-cell receptor. Down-regulates antigen-induced B-cell activation by recruiting phosphatases to its immunoreceptor tyrosine-based inhibitor motifs (ITIM)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O75022/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LILRB3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1088,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LILRB3","total_profiled":1310},"omim":[{"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"},{"mim_id":"604811","title":"LEUKOCYTE IMMUNOGLOBULIN-LIKE RECEPTOR, SUBFAMILY B, MEMBER 1; LILRB1","url":"https://www.omim.org/entry/604811"},{"mim_id":"167414","title":"PAIRED BOX GENE 5; PAX5","url":"https://www.omim.org/entry/167414"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lung","ntpm":18.8},{"tissue":"lymphoid tissue","ntpm":37.9}],"url":"https://www.proteinatlas.org/search/LILRB3"},"hgnc":{"alias_symbol":["LIR-3","HL9","ILT5","LIR3","CD85a","PIRB","PIR-B"],"prev_symbol":[]},"alphafold":{"accession":"O75022","domains":[{"cath_id":"2.60.40.10","chopping":"31-118","consensus_level":"high","plddt":88.2056,"start":31,"end":118},{"cath_id":"2.60.40.10","chopping":"123-219","consensus_level":"high","plddt":89.5203,"start":123,"end":219},{"cath_id":"2.60.40.10","chopping":"221-318","consensus_level":"high","plddt":92.2096,"start":221,"end":318},{"cath_id":"2.60.40.10","chopping":"323-420","consensus_level":"high","plddt":93.7067,"start":323,"end":420}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75022","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75022-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75022-F1-predicted_aligned_error_v6.png","plddt_mean":74.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LILRB3","jax_strain_url":"https://www.jax.org/strain/search?query=LILRB3"},"sequence":{"accession":"O75022","fasta_url":"https://rest.uniprot.org/uniprotkb/O75022.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75022/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75022"}},"corpus_meta":[{"pmid":"25604533","id":"PMC_25604533","title":"Identification of Susceptibility Loci in IL6, RPS9/LILRB3, and an Intergenic Locus on Chromosome 21q22 in Takayasu Arteritis in a Genome-Wide Association Study.","date":"2015","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/25604533","citation_count":87,"is_preprint":false},{"pmid":"15779891","id":"PMC_15779891","title":"Structural and functional modeling of human lysozyme reveals a unique nonapeptide, HL9, with anti-HIV activity.","date":"2005","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15779891","citation_count":69,"is_preprint":false},{"pmid":"35122056","id":"PMC_35122056","title":"LILRB3 supports acute myeloid leukemia development and regulates T-cell antitumor immune responses through the TRAF2-cFLIP-NF-κB signaling axis.","date":"2021","source":"Nature cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35122056","citation_count":54,"is_preprint":false},{"pmid":"32870822","id":"PMC_32870822","title":"LILRB3 (ILT5) is a myeloid cell 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inhibition reverses immunosuppression in glioma: a nanoparticle-based therapeutic strategy.","date":"2026","source":"Journal of nanobiotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/41937130","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11842,"output_tokens":3376,"usd":0.043083,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10901,"output_tokens":4054,"usd":0.077927,"stage2_stop_reason":"end_turn"},"total_usd":0.12101,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"LILRB3 intracellular domain is constitutively associated with the adaptor protein TRAF2. Upon LILRB3 activation in AML cells, cFLIP is recruited and NF-κB is upregulated, enhancing leukemic cell survival and inhibiting T-cell anti-tumor activity. Hyperactivation of NF-κB triggers a negative feedback loop via A20, which disrupts the LILRB3-TRAF2 interaction, causing SHP-1/2-mediated inhibitory activity of LILRB3 to become dominant.\",\n      \"method\": \"Co-immunoprecipitation, signaling pathway analysis, NF-κB reporter assays, antagonizing antibody blockade, in vivo AML progression models\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying TRAF2 and cFLIP associations, functional signaling readouts (NF-κB, SHP-1/2), and in vivo validation in a single focused study with multiple orthogonal methods\",\n      \"pmids\": [\"35122056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LILRB3 expressed on non-transformed epithelial cells recognizes MHC class I that is highly expressed on transformed cells. This MHC class I–LILRB3 interaction triggers an SHP2-ROCK2 signaling pathway that generates a mechanical force to extrude transformed (precancerous) cells from the epithelial layer, leading to their apoptosis and clearance independently of NK or CD8+ T cell activity.\",\n      \"method\": \"Live imaging of cell competition, loss-of-function (LILRB3 knockdown), co-immunoprecipitation, epistasis analysis with SHP2 and ROCK2 inhibitors/knockdowns, in vitro epithelial extrusion assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding established between MHC class I and LILRB3, downstream SHP2-ROCK2 pathway confirmed by epistasis/knockdown, multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"34686865\", \"34740904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LILRB3 ligation on primary human monocytes by an agonistic monoclonal antibody induces phenotypic and functional changes leading to potent inhibition of immune responses in vitro, including significant reduction in T cell proliferation. Agonizing LILRB3 in humanized mice induced tolerance and permitted efficient engraftment of allogeneic cells, establishing LILRB3 as an immunosuppressive myeloid checkpoint receptor.\",\n      \"method\": \"Monoclonal antibody panel, primary human monocyte stimulation assays, T cell proliferation assay, humanized mouse allograft engraftment model\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — agonistic antibody functional assay in primary cells plus in vivo humanized mouse model with defined cellular phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"32870822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"APOE4, but not APOE2, specifically binds LilrB3. Two discrete immunoglobulin-like domains of the LilrB3 extracellular domain recognize a positively charged surface patch on the N-terminal domain of APOE4. The crystal structure reveals a hetero-tetrameric complex (two APOE4 molecules engaging two LilrB3 molecules), bringing intracellular signaling motifs into close proximity. APOE4, but not APOE2, activates human microglia (HMC3) into a pro-inflammatory state in a LilrB3-dependent manner.\",\n      \"method\": \"X-ray crystallography (atomic structure of APOE4–LilrB3 complex), biochemical binding assays, LilrB3 knockdown in microglia, functional inflammatory assays\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution crystal structure plus biochemical binding validation and functional cellular assays with LilrB3-knockdown controls, single lab\",\n      \"pmids\": [\"36588123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Specific allelic variants of LILRB3 (notably LILRB3*12) bind a ligand on necrotic glandular epithelial cells that is associated with cytokeratin 8. Immunoprecipitation of the ligand from epithelial cell lysates using recombinant LILRB3*12 identified cytokeratins 8, 18, and 19. Knockdown of cytokeratin 8 in epithelial cells abrogated LILRB3 ligand expression. Purified cytokeratin 8-associated proteins activated LILRB3*12 reporter cells.\",\n      \"method\": \"Recombinant receptor binding assay, immunoprecipitation, cytokeratin 8 knockdown, LILRB3 reporter cell activation assay, co-localization by immunofluorescence\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (IP, knockdown, reporter activation, co-localization) in a single lab identifying cytokeratin 8/18/19 as allele-specific LILRB3 ligands\",\n      \"pmids\": [\"26769854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LILRB3 (but not LILRA6) is expressed on the surface of resting human neutrophils and is released from the surface upon neutrophil activation. Continuous ligation of LILRB3 inhibits key IgA-mediated effector functions including reactive oxygen species production, phagocytic uptake, and microbial killing, establishing LILRB3 as an inhibitory checkpoint on neutrophil activation.\",\n      \"method\": \"Immunoprecipitation followed by mass spectrometry (detecting LILRB3 in neutrophil lysates), flow cytometry, PLB-985 differentiation model, functional assays (ROS, phagocytosis, microbial killing) with continuous LILRB3 ligation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry confirmation of protein expression, functional assays with defined ligand, cell-line model validation, single lab\",\n      \"pmids\": [\"31915259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Galectin-4 and galectin-7 are ligands that induce activation of LILRB3 on immunosuppressive myeloid cells (MDSCs). Blockade of LILRB3 signaling by an antagonistic antibody inhibited immunosuppressive myeloid cell activity and impeded tumor development in myeloid-specific LILRB3 transgenic mice through a T cell-dependent mechanism.\",\n      \"method\": \"Ligand-receptor binding assays identifying galectin-4 and galectin-7 as LILRB3 ligands, LILRB3 transgenic mouse tumor model, antibody blockade, T cell depletion epistasis\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identification of novel ligands with functional readout in transgenic in vivo model plus T cell epistasis, single lab\",\n      \"pmids\": [\"38113030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LILRB3 and LILRA6 share identical extracellular domains. LILRB3 mediates inhibitory signaling via immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic tail, whereas LILRA6 signals through association with the activating adaptor FcRγ (which bears an ITAM). LILRA6 expression level on monocytes correlates with copy number of the LILRA6 gene.\",\n      \"method\": \"mRNA expression analysis across PBMC fractions, copy number variation analysis, receptor domain characterization\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — domain characterization and expression correlation without direct functional reconstitution of ITIM signaling; single lab, primarily genetic/expression analysis\",\n      \"pmids\": [\"24096970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A cluster of four consecutive missense SNPs (LILRB3-4SNPs) in LILRB3 at amino acids 617–618, proximal to a SHP1/2 phosphatase-binding ITIM, is strongly associated with kidney transplant failure in African Americans. Multiomics analysis of blood and biopsies showed that recipients with LILRB3-4SNPs exhibited enhanced inflammation and monocyte ferroptosis, suggesting these mutations functionally impair ITIM-mediated SHP1/2 signaling.\",\n      \"method\": \"Blood RNA sequencing, genomic SNP association analysis, multiomics (transcriptomics + biopsy proteomics), APOL1 epistasis analysis\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic association with multiomics correlates; no direct in vitro or biochemical demonstration that the SNPs disrupt SHP1/2 binding or ITIM function\",\n      \"pmids\": [\"40065170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LILRB3 blockade with antagonist antibodies upregulates myeloid lineage differentiation transcription factors (PU.1, C/EBP family, IRF) and decreases phosphorylation of AKT, cyclin D1, and retinoblastoma protein in AML cells, inhibiting leukemia cell proliferation. Conversely, LILRB3 agonism enhances leukemia survival through upregulation of cholesterol metabolism pathways.\",\n      \"method\": \"Antibody blockade/agonism, western blot (phosphorylation), transcriptomic analysis, in vitro and in vivo CAR T cell assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined downstream signaling changes (AKT, cyclin D1, Rb phosphorylation) with antibody manipulation plus transcriptomic pathway identification, single lab, multiple methods\",\n      \"pmids\": [\"38098451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"miR-103a-2-5p directly targets the 3'-UTR of LILRB3 mRNA (confirmed by dual luciferase reporter assay), suppressing LILRB3 expression and thereby inhibiting AML cell growth, reducing CD8+ T cell apoptosis, suppressing the Nrf2/HO-1 axis, and reducing the GSH/ROS ratio leading to increased intracellular ROS and AML cell apoptosis.\",\n      \"method\": \"Dual luciferase reporter assay (direct 3'-UTR targeting), qPCR, western blot, flow cytometry (apoptosis, cell cycle), in vivo mouse AML model with CLP-delivered miRNA\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'-UTR interaction confirmed by reporter assay, downstream pathway (Nrf2/HO-1) and immune consequence validated in vitro and in vivo, single lab\",\n      \"pmids\": [\"38486250\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LILRB3 is an ITIM-bearing inhibitory receptor expressed predominantly on myeloid cells (monocytes, neutrophils, macrophages) and on non-immune epithelial cells, whose extracellular domain binds multiple ligands including MHC class I (on transformed cells), APOE4 (isoform-specific), galectins-4/7, and cytokeratin 8-associated complexes on necrotic epithelial cells; ligand engagement recruits SHP-1/2 via ITIMs to suppress innate immune effector functions, while in AML cells LILRB3 additionally signals through a TRAF2–cFLIP–NF-κB activating axis to promote leukemic survival, with A20-mediated feedback shifting the balance back to ITIM/SHP-1/2 inhibitory dominance, and in epithelial cell competition LILRB3 couples MHC class I recognition to an SHP2–ROCK2 mechanical extrusion pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LILRB3 is an ITIM-bearing inhibitory receptor of myeloid cells that functions as an immunosuppressive checkpoint, dampening innate effector responses upon ligand engagement [#2, #5]. On primary monocytes its ligation drives potent suppression of T cell proliferation and, in humanized mice, induces tolerance permitting allogeneic engraftment [#2]; on resting neutrophils, continuous LILRB3 ligation inhibits IgA-mediated ROS production, phagocytosis, and microbial killing [#5]. The extracellular domain engages a structurally diverse ligand repertoire: MHC class I [#1], an APOE4-specific surface patch resolved at atomic resolution as a 2:2 hetero-tetrameric APOE4\\u2013LILRB3 complex [#3], galectin-4 and galectin-7 on immunosuppressive myeloid cells [#6], and a cytokeratin 8\\u2013associated complex on necrotic glandular epithelium recognized in an allele-specific manner [#4]. Receptor signaling bifurcates by context: epithelial recognition of MHC class I on transformed cells couples to an SHP2\\u2013ROCK2 mechanical pathway that extrudes precancerous cells independently of NK or CD8+ T cells [#1], whereas in AML the intracellular domain constitutively associates with TRAF2 and, upon activation, recruits cFLIP to upregulate NF-\\u03baB and promote leukemic survival, with A20-mediated feedback disrupting the LILRB3\\u2013TRAF2 interaction to restore SHP-1/2 inhibitory dominance [#0]. In AML cells, blockade derepresses myeloid differentiation factors (PU.1, C/EBP, IRF) and reduces AKT, cyclin D1, and Rb phosphorylation, while agonism sustains survival via cholesterol metabolism [#9]; APOE4 engagement likewise activates microglia into a pro-inflammatory state in a LILRB3-dependent manner [#3]. A cluster of four missense SNPs proximal to a SHP1/2-binding ITIM associates with kidney transplant failure in African Americans, linking impaired LILRB3 inhibitory signaling to inflammation and monocyte ferroptosis [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that LILRB3 and the near-identical LILRA6 are functionally opposite paired receptors, with LILRB3 signaling via cytoplasmic ITIMs while its sister receptor signals through an activating FcRgamma/ITAM module.\",\n      \"evidence\": \"mRNA expression profiling across PBMC fractions, copy number analysis, and receptor domain characterization\",\n      \"pmids\": [\"24096970\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct functional reconstitution of ITIM-driven inhibitory signaling\", \"Ligand identity not addressed\", \"Primarily genetic/expression correlation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the first defined LILRB3 ligand as a cytokeratin 8-associated complex on necrotic epithelial cells, recognized in an allele-specific manner, addressing what LILRB3 senses on damaged tissue.\",\n      \"evidence\": \"Recombinant receptor pulldown, cytokeratin 8 knockdown, and LILRB3*12 reporter cell activation with co-localization\",\n      \"pmids\": [\"26769854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Allele-specificity limits generalization to all LILRB3 variants\", \"Downstream signaling consequence not mapped\", \"Physiological context of necrotic-cell sensing not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined LILRB3 as an immunosuppressive myeloid checkpoint by showing agonistic ligation of monocytes suppresses T cell responses and induces transplant tolerance in vivo.\",\n      \"evidence\": \"Agonistic monoclonal antibody assays on primary human monocytes, T cell proliferation readout, and humanized mouse allograft engraftment\",\n      \"pmids\": [\"32870822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Natural ligand driving the tolerogenic response not identified\", \"Intracellular signaling intermediates not dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the inhibitory checkpoint role to neutrophils, showing LILRB3 ligation restrains IgA-mediated effector functions and that surface receptor is shed upon activation.\",\n      \"evidence\": \"IP-mass spectrometry, flow cytometry, PLB-985 differentiation model, and functional ROS/phagocytosis/killing assays under continuous ligation\",\n      \"pmids\": [\"31915259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of activation-induced surface release unknown\", \"Endogenous neutrophil ligand not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a context-dependent activating signaling axis in AML, distinct from canonical ITIM inhibition, explaining how LILRB3 promotes leukemic survival and the feedback that restores inhibition.\",\n      \"evidence\": \"Reciprocal Co-IP identifying TRAF2/cFLIP, NF-kB reporter assays, antagonist antibody blockade, and in vivo AML models\",\n      \"pmids\": [\"35122056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand triggering the AML TRAF2-NF-kB axis not identified\", \"Switch determinants between activating and inhibitory modes incompletely defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated a non-immune role in epithelial cell competition, where LILRB3 recognition of MHC class I on transformed cells drives mechanical extrusion via SHP2-ROCK2 independently of cytotoxic lymphocytes.\",\n      \"evidence\": \"Live cell-competition imaging, LILRB3 knockdown, Co-IP, and SHP2/ROCK2 inhibitor and knockdown epistasis in epithelial extrusion assays\",\n      \"pmids\": [\"34686865\", \"34740904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How an inhibitory receptor couples to a force-generating ROCK2 pathway mechanistically unresolved\", \"Generality across epithelial tissues not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided atomic-resolution structural and functional evidence for isoform-specific APOE4 binding, defining a 2:2 receptor clustering geometry and linking LILRB3 to microglial pro-inflammatory activation.\",\n      \"evidence\": \"X-ray crystallography of the APOE4-LILRB3 complex, biochemical binding assays, and LILRB3 knockdown in HMC3 microglia with inflammatory readouts\",\n      \"pmids\": [\"36588123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling from APOE4-induced clustering not biochemically mapped\", \"Relevance to neurodegenerative disease in vivo not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped downstream effectors of LILRB3 in AML, showing blockade derepresses myeloid differentiation and proliferation signaling while agonism sustains survival via cholesterol metabolism.\",\n      \"evidence\": \"Antibody blockade/agonism, western blot of AKT/cyclin D1/Rb phosphorylation, transcriptomics, and CAR T cell assays in vitro and in vivo\",\n      \"pmids\": [\"38098451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between receptor and AKT/cyclin D1 axis not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified galectin-4 and galectin-7 as activating ligands on immunosuppressive myeloid cells, linking ligand engagement to tumor-promoting immunosuppression that is T cell-dependent.\",\n      \"evidence\": \"Ligand-receptor binding assays, myeloid-specific LILRB3 transgenic tumor model, antagonist antibody blockade, and T cell depletion epistasis\",\n      \"pmids\": [\"38113030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular signaling triggered by galectins not dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established post-transcriptional regulation of LILRB3, with miR-103a-2-5p directly suppressing its expression and thereby reducing AML growth through the Nrf2/HO-1 redox axis.\",\n      \"evidence\": \"Dual luciferase 3'-UTR reporter, qPCR, western blot, apoptosis flow cytometry, and in vivo AML model with delivered miRNA\",\n      \"pmids\": [\"38486250\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether endogenous miR-103a-2-5p regulates LILRB3 physiologically not established\", \"Connection between receptor level and Nrf2/HO-1 axis is correlative\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked LILRB3 ITIM-proximal genetic variation to disease, associating a four-SNP cluster with kidney transplant failure and implicating impaired inhibitory signaling in inflammation and monocyte ferroptosis.\",\n      \"evidence\": \"Genomic SNP association, blood RNA-seq, biopsy multiomics, and APOL1 epistasis analysis\",\n      \"pmids\": [\"40065170\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical demonstration that the SNPs disrupt SHP1/2 binding or ITIM function\", \"Causality versus association not resolved\", \"Mechanistic link to ferroptosis correlative\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single ITIM-bearing receptor switches between SHP-1/2 inhibition, TRAF2-NF-kB activation, and SHP2-ROCK2 mechanical signaling depending on ligand and cell type.\",\n      \"evidence\": \"No timeline study reconstitutes the determinants selecting among the alternative signaling outputs\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Ligand-specific signaling bias not defined\", \"Stoichiometry/clustering rules linking ligand geometry to output unknown\", \"No unified structural model across ligands\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 5, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TRAF2\", \"SHP1\", \"SHP2\", \"ROCK2\", \"APOE4\", \"cFLIP\", \"A20\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}