{"gene":"LILRB3","run_date":"2026-04-28T18:30:27","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 to the TRAF2 complex, leading to NF-κB upregulation that enhances leukemic cell survival and inhibits T-cell-mediated anti-tumor activity. Hyperactivation of NF-κB induces a negative regulatory feedback loop via A20, which disrupts the LILRB3-TRAF2 interaction, allowing SHP-1/2-mediated inhibitory activity to become dominant.","method":"Co-immunoprecipitation, domain mapping, reporter assays, mutagenesis, in vitro and in vivo AML models, antagonistic antibody blockade","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, multiple orthogonal methods, in vivo validation, mechanistic pathway dissection in one study","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, triggering an SHP2-ROCK2 signaling pathway that generates mechanical force to extrude precancerous cells from the epithelial layer independently of NK cells or CD8+ T cells.","method":"Live-cell imaging, genetic knockdown/knockout, co-immunoprecipitation, epithelial cell competition assays, inhibitor studies","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway (SHP2-ROCK2) identified with multiple orthogonal methods and defined phenotypic readout","pmids":["34686865","34740904"],"is_preprint":false},{"year":2023,"finding":"APOE4, but not APOE2 or APOE3, specifically interacts with LILRB3; two immunoglobulin-like domains of the LILRB3 extracellular domain recognize a positively charged surface patch on the N-terminal domain of APOE4, forming a hetero-tetrameric complex of two APOE4 and two LILRB3 molecules. This interaction activates human microglia into a pro-inflammatory state in a LILRB3-dependent manner.","method":"Crystal structure determination, biochemical binding assays, cell activation assays with LILRB3 knockdown/knockout","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1 — atomic structure solved, biochemical validation, and functional cell assays in single study","pmids":["36588123"],"is_preprint":false},{"year":2016,"finding":"Specific allelic variants of LILRB3 (notably LILRB3*12) bind a ligand on necrotic glandular epithelial cells; immunoprecipitation identified cytokeratins 8, 18, and 19 as the LILRB3 ligand. Cytokeratin 8 knockdown abrogated LILRB3 ligand expression, and purified cytokeratin 8-associated proteins activated LILRB3*12 reporter cells.","method":"Immunoprecipitation of ligand from cell lysates, recombinant protein binding, reporter cell activation assay, siRNA knockdown, co-localization by immunofluorescence","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (IP, reporter assay, KD) in single lab","pmids":["26769854"],"is_preprint":false},{"year":2013,"finding":"LILRB3 mediates inhibitory signaling through immunoreceptor tyrosine-based inhibition motifs (ITIMs) in its cytoplasmic tail, while its paired activating receptor LILRA6 signals through association with FcRγ bearing an ITAM; both receptors share identical extracellular domains. LILRA6 copy number variation correlates with expression level on monocytes.","method":"mRNA expression analysis by fraction, genetic characterization, functional domain annotation","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 3 — functional domain characterization with expression correlation; mechanistic inference from receptor family properties","pmids":["24096970"],"is_preprint":false},{"year":2020,"finding":"LILRB3 is expressed on resting human neutrophils and is released from the surface upon activation; continuous ligation of LILRB3 inhibits IgA-mediated effector functions including reactive oxygen species production, phagocytic uptake, and microbial killing, identifying LILRB3 as a checkpoint controlling neutrophil antimicrobial activity.","method":"Immunoprecipitation followed by mass spectrometry, flow cytometry, ROS assay, phagocytosis assay, microbial killing assay, PLB-985 cell differentiation model","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional readouts with defined ligand-receptor engagement, single lab","pmids":["31915259"],"is_preprint":false},{"year":2020,"finding":"Agonistic ligation of LILRB3 on primary human monocytes induces phenotypic and functional changes leading to potent inhibition of immune responses, including significant reduction in T cell proliferation; agonizing LILRB3 in humanized mice induced tolerance and permitted efficient engraftment of allogeneic cells, establishing LILRB3 as a myeloid immune checkpoint.","method":"Monoclonal antibody panel generation, epitope mapping, primary monocyte functional assays, T cell proliferation assay, humanized mouse allograft model","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo mechanistic validation with defined agonistic antibodies, single lab","pmids":["32870822"],"is_preprint":false},{"year":2024,"finding":"Galectin-4 and galectin-7 induce activation of LILRB3 on immunosuppressive myeloid cells (MDSCs); LILRB3 blockade with antagonistic antibody inhibits MDSC activity and impedes tumor development in myeloid-specific LILRB3 transgenic mice in a T cell-dependent manner.","method":"Ligand-receptor binding assays, antagonistic antibody blockade, LILRB3 myeloid transgenic mouse tumor model, T cell depletion experiments","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 — ligand identification plus in vivo epistasis via transgenic model, single lab","pmids":["38113030"],"is_preprint":false},{"year":2025,"finding":"A cluster of four missense SNPs (LILRB3-4SNPs) in the LILRB3 gene at amino acids 617-618, proximal to the SHP1/2-binding ITIM motif, is associated with kidney transplant failure in African Americans and is linked to enhanced monocyte inflammation and ferroptosis, suggesting these variants impair LILRB3 inhibitory signaling.","method":"Whole-blood RNA sequencing, SNP genotyping, multiomics analysis of blood and biopsies, Biobank association studies","journal":"Nature medicine","confidence":"Medium","confidence_rationale":"Tier 3 — mechanistic inference from SNP location near ITIM; functional consequence inferred from multiomics without direct in vitro validation of signaling","pmids":["40065170"],"is_preprint":false},{"year":2024,"finding":"miR-103a-2-5p directly targets the 3'-UTR of LILRB3 mRNA (validated by dual luciferase reporter assay), reducing LILRB3 protein levels and thereby inhibiting AML cell proliferation, promoting apoptosis via suppression of the Nrf2/HO-1 axis and increase of intracellular ROS, and reducing CD8+ T cell apoptosis.","method":"Dual luciferase reporter assay, qRT-PCR, CCK8, colony formation, flow cytometry, AML mouse model with cationic liposome delivery","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3'-UTR targeting validated by reporter assay plus downstream pathway analysis and in vivo model","pmids":["38486250"],"is_preprint":false},{"year":2023,"finding":"LILRB3 blockade with antagonistic antibodies upregulates myeloid lineage differentiation transcription factors (PU.1, C/EBP family, IRF) and decreases phosphorylation of AKT, cyclin D1, and retinoblastoma protein; agonist antibody activation of LILRB3 upregulates cholesterol metabolism pathways that promote leukemia cell survival.","method":"Antagonistic and agonistic antibody treatment, transcriptomic analysis, Western blotting for signaling intermediates, in vitro and in vivo AML models, CAR T cell assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple downstream pathway analyses with complementary gain- and loss-of-function approaches","pmids":["38098451"],"is_preprint":false}],"current_model":"LILRB3 is an inhibitory myeloid immune checkpoint receptor whose cytoplasmic ITIMs recruit SHP-1/2 phosphatases; its intracellular domain constitutively associates with TRAF2, and upon activation recruits cFLIP to drive NF-κB-mediated cell survival (with A20-dependent feedback restoring SHP-1/2 dominance); its extracellular immunoglobulin-like domains bind ligands including MHC class I (triggering SHP2-ROCK2-mediated epithelial cell extrusion), cytokeratins 8/18/19 on necrotic epithelial cells (in an allele-specific manner), APOE4 (forming a heterotetrameric complex that activates microglial inflammation), and galectins-4/7 (activating immunosuppressive myeloid cells), while ligation on monocytes potently suppresses T cell responses and on neutrophils inhibits IgA-mediated antimicrobial effector functions."},"narrative":{"teleology":[{"year":2013,"claim":"Establishing the signaling architecture: LILRB3 was shown to signal through cytoplasmic ITIMs while sharing identical extracellular domains with its paired activating receptor LILRA6, defining LILRB3 as an inhibitory counterpart in a paired receptor system on monocytes.","evidence":"mRNA expression analysis, genetic characterization, and functional domain annotation","pmids":["24096970"],"confidence":"Medium","gaps":["No direct demonstration of SHP-1/2 recruitment to LILRB3 ITIMs in this study","Endogenous ligand unknown at this point","Downstream signaling consequences not measured"]},{"year":2016,"claim":"Identification of the first endogenous ligand: allele-specific variants of LILRB3 were found to bind cytokeratins 8/18/19 exposed on necrotic glandular epithelial cells, revealing that LILRB3 senses damage-associated signals in an allele-dependent manner.","evidence":"Immunoprecipitation from cell lysates, reporter cell activation assay, siRNA knockdown of cytokeratin 8","pmids":["26769854"],"confidence":"Medium","gaps":["Binding restricted to LILRB3*12 allele — generalizability to other alleles unclear","Structural basis of allele-specific recognition unresolved","Downstream signaling pathway upon cytokeratin engagement not characterized"]},{"year":2020,"claim":"Functional demonstration as a myeloid immune checkpoint: LILRB3 ligation on monocytes suppressed T cell proliferation and enabled allograft tolerance in humanized mice, while on neutrophils it inhibited IgA-mediated antimicrobial effector functions, establishing its broad immunosuppressive role across myeloid lineages.","evidence":"Agonistic monoclonal antibodies on primary monocytes and neutrophils, T cell proliferation assays, ROS/phagocytosis/killing assays, humanized mouse allograft model","pmids":["32870822","31915259"],"confidence":"Medium","gaps":["Endogenous ligand driving these checkpoint functions in vivo not identified","Relative contribution of SHP-1 versus SHP-2 to different effector outputs not dissected","Mechanism of LILRB3 shedding from activated neutrophils not characterized"]},{"year":2021,"claim":"Discovery of a dual intracellular signaling switch: LILRB3 constitutively associates with TRAF2, and activation recruits cFLIP to drive NF-κB-mediated leukemic cell survival; hyperactivated NF-κB induces A20, which disrupts the TRAF2 interaction and restores SHP-1/2-dominated inhibitory signaling, revealing an intrinsic toggle between pro-survival and inhibitory pathways.","evidence":"Reciprocal co-immunoprecipitation, domain mapping, NF-κB reporter assays, mutagenesis, in vivo AML models, antagonistic antibody blockade","pmids":["35122056"],"confidence":"High","gaps":["Structural basis of TRAF2 binding to LILRB3 intracellular domain not resolved","Whether A20 feedback operates in non-leukemic myeloid cells unknown","Threshold of NF-κB activation required to trigger the switch not quantified"]},{"year":2021,"claim":"Revealing a cell-autonomous tumor surveillance mechanism: non-transformed epithelial cells expressing LILRB3 recognize MHC class I upregulated on transformed neighbors and activate SHP2-ROCK2 signaling to mechanically extrude precancerous cells, independent of adaptive immunity.","evidence":"Live-cell imaging, genetic knockdown/knockout, co-immunoprecipitation, epithelial cell competition assays, pharmacological inhibitors","pmids":["34686865","34740904"],"confidence":"High","gaps":["How LILRB3 distinguishes normal from elevated MHC-I levels to trigger extrusion not defined","Whether this mechanism operates in vivo in human tissues not shown","Contribution of other LILRB family members to cell competition not excluded"]},{"year":2023,"claim":"Structural elucidation of isoform-specific APOE4 recognition: crystal structures revealed that two LILRB3 molecules form a heterotetrameric complex with two APOE4 molecules via a positively charged patch on the APOE4 N-terminal domain, and this interaction activates pro-inflammatory microglia, linking LILRB3 to neuroinflammation.","evidence":"X-ray crystallography, biochemical binding assays, microglial activation assays with LILRB3 knockdown/knockout","pmids":["36588123"],"confidence":"High","gaps":["Whether LILRB3-APOE4 interaction drives neurodegeneration in Alzheimer's disease models not tested","Signaling pathway downstream of LILRB3 activation in microglia (SHP vs. NF-κB) not resolved","Whether APOE4-LILRB3 engagement occurs in vivo in human brain not demonstrated"]},{"year":2023,"claim":"Mapping downstream transcriptional and metabolic consequences: LILRB3 blockade in AML cells upregulated myeloid differentiation transcription factors (PU.1, C/EBP, IRF) and suppressed AKT/cyclin D1/Rb phosphorylation, while agonist activation induced cholesterol metabolism pathways promoting leukemia survival.","evidence":"Antagonistic and agonistic antibody treatment, transcriptomic profiling, Western blotting, in vivo AML models, CAR T cell co-culture assays","pmids":["38098451"],"confidence":"Medium","gaps":["Whether cholesterol metabolic reprogramming is a direct LILRB3 signaling output or secondary effect unknown","Whether differentiation induction by LILRB3 blockade generalizes beyond AML not tested","Direct transcription factor regulation versus indirect pathway effects not distinguished"]},{"year":2024,"claim":"Identification of galectins as tumor-associated LILRB3 ligands: galectin-4 and galectin-7 were found to activate LILRB3 on immunosuppressive myeloid cells (MDSCs), and LILRB3 blockade impeded tumor growth in a T cell-dependent manner in myeloid-specific transgenic mice.","evidence":"Ligand-receptor binding assays, antagonistic antibody blockade, LILRB3 myeloid transgenic mouse tumor model, T cell depletion experiments","pmids":["38113030"],"confidence":"Medium","gaps":["Binding site of galectins on LILRB3 extracellular domain not structurally resolved","Glycan dependence of galectin-LILRB3 interaction not tested","Relative importance of galectin-4 vs. galectin-7 in tumor microenvironment not distinguished"]},{"year":2024,"claim":"Post-transcriptional regulation of LILRB3 identified: miR-103a-2-5p directly targets the LILRB3 3′-UTR, reducing LILRB3 protein and thereby inhibiting AML proliferation and promoting apoptosis via increased ROS and suppressed Nrf2/HO-1, while rescuing CD8+ T cell viability.","evidence":"Dual luciferase reporter assay, qRT-PCR, colony formation, flow cytometry, AML mouse model with liposomal miRNA delivery","pmids":["38486250"],"confidence":"Medium","gaps":["Whether Nrf2/HO-1 axis is directly regulated by LILRB3 signaling or an indirect consequence of LILRB3 loss not resolved","Specificity of miR-103a-2-5p for LILRB3 versus other targets not controlled","In vivo pharmacokinetics and off-target effects of liposomal miRNA delivery not characterized"]},{"year":2025,"claim":"Genetic variants near the ITIM link LILRB3 to transplant outcome: a cluster of four missense SNPs proximal to the SHP-1/2-binding ITIM motif was associated with kidney transplant failure in African Americans, correlated with enhanced monocyte inflammation and ferroptosis.","evidence":"Whole-blood RNA sequencing, SNP genotyping, multiomics analysis of blood and biopsies, Biobank association studies","pmids":["40065170"],"confidence":"Medium","gaps":["Direct demonstration that these SNPs impair ITIM phosphorylation or SHP recruitment not performed","Causal relationship between LILRB3 variants and ferroptosis not mechanistically validated","Whether these variants affect other LILRB3 functions (e.g., TRAF2 binding) not tested"]},{"year":null,"claim":"Major open question: how LILRB3 integrates signals from its diverse extracellular ligands (MHC-I, APOE4, cytokeratins, galectins) to select between ITIM/SHP-mediated inhibition and TRAF2/NF-κB-mediated survival in different myeloid cell contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model of how ligand identity determines intracellular pathway choice","Structural basis for simultaneous or competitive ligand engagement across domains not known","In vivo relevance of LILRB3-APOE4 axis in Alzheimer's disease not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,4,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5,6,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,4,5,6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,5,6,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,7,9,10]}],"complexes":[],"partners":["TRAF2","SHP1","SHP2","APOE4","ROCK2","CFLAR","LGALS4","LGALS7"],"other_free_text":[]},"mechanistic_narrative":"LILRB3 is an inhibitory immunoreceptor expressed on myeloid cells that integrates multiple extracellular ligand inputs to control immune activation, cell survival, and tissue surveillance. Its cytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs) recruit SHP-1/SHP-2 phosphatases to suppress myeloid effector functions — including IgA-mediated neutrophil antimicrobial responses and monocyte-driven T cell proliferation — establishing it as a myeloid immune checkpoint [PMID:31915259, PMID:32870822, PMID:24096970]. The intracellular domain also constitutively associates with TRAF2; upon activation, cFLIP recruitment drives NF-κB-dependent survival signaling in AML cells, with A20-mediated feedback restoring SHP-1/2 dominance, while LILRB3 blockade promotes myeloid differentiation and suppresses AKT/cyclin D1 signaling [PMID:35122056, PMID:38098451]. The extracellular immunoglobulin-like domains recognize diverse ligands — MHC class I (triggering SHP2-ROCK2-dependent epithelial cell extrusion of transformed cells), APOE4 (forming a heterotetrameric complex that activates microglial inflammation), cytokeratins 8/18/19 on necrotic epithelial cells, and galectins-4/7 on immunosuppressive myeloid cells — linking LILRB3 to cancer immunosurveillance, neuroinflammation, and tumor immune evasion [PMID:34686865, PMID:36588123, PMID:26769854, PMID:38113030]."},"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":86,"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":68,"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":53,"is_preprint":false},{"pmid":"32870822","id":"PMC_32870822","title":"LILRB3 (ILT5) is a myeloid cell 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33526815","citation_count":5,"is_preprint":false},{"pmid":"36449053","id":"PMC_36449053","title":"Distinct frequency patterns of LILRB3 and LILRA6 allelic variants in Europeans.","date":"2022","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/36449053","citation_count":4,"is_preprint":false},{"pmid":"40054016","id":"PMC_40054016","title":"JoGo-LILR caller: Unveiling and navigating the complex diversity of LILRB3-LILRA6 copy number haplotype structures with whole-genome sequencing.","date":"2025","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40054016","citation_count":3,"is_preprint":false},{"pmid":"34740904","id":"PMC_34740904","title":"Transformed Cell Exclusion Occurs through MHC Class I/LILRB3 Interactions.","date":"2021","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/34740904","citation_count":1,"is_preprint":false},{"pmid":"41937130","id":"PMC_41937130","title":"LILRB3 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":11063,"output_tokens":2867,"usd":0.038097},"stage2":{"model":"claude-opus-4-6","input_tokens":6208,"output_tokens":3325,"usd":0.171247},"total_usd":0.209344,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","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 to the TRAF2 complex, leading to NF-κB upregulation that enhances leukemic cell survival and inhibits T-cell-mediated anti-tumor activity. Hyperactivation of NF-κB induces a negative regulatory feedback loop via A20, which disrupts the LILRB3-TRAF2 interaction, allowing SHP-1/2-mediated inhibitory activity to become dominant.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, reporter assays, mutagenesis, in vitro and in vivo AML models, antagonistic antibody blockade\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, multiple orthogonal methods, in vivo validation, mechanistic pathway dissection in one study\",\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, triggering an SHP2-ROCK2 signaling pathway that generates mechanical force to extrude precancerous cells from the epithelial layer independently of NK cells or CD8+ T cells.\",\n      \"method\": \"Live-cell imaging, genetic knockdown/knockout, co-immunoprecipitation, epithelial cell competition assays, inhibitor studies\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway (SHP2-ROCK2) identified with multiple orthogonal methods and defined phenotypic readout\",\n      \"pmids\": [\"34686865\", \"34740904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"APOE4, but not APOE2 or APOE3, specifically interacts with LILRB3; two immunoglobulin-like domains of the LILRB3 extracellular domain recognize a positively charged surface patch on the N-terminal domain of APOE4, forming a hetero-tetrameric complex of two APOE4 and two LILRB3 molecules. This interaction activates human microglia into a pro-inflammatory state in a LILRB3-dependent manner.\",\n      \"method\": \"Crystal structure determination, biochemical binding assays, cell activation assays with LILRB3 knockdown/knockout\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic structure solved, biochemical validation, and functional cell assays in single study\",\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; immunoprecipitation identified cytokeratins 8, 18, and 19 as the LILRB3 ligand. Cytokeratin 8 knockdown abrogated LILRB3 ligand expression, and purified cytokeratin 8-associated proteins activated LILRB3*12 reporter cells.\",\n      \"method\": \"Immunoprecipitation of ligand from cell lysates, recombinant protein binding, reporter cell activation assay, siRNA knockdown, co-localization by immunofluorescence\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (IP, reporter assay, KD) in single lab\",\n      \"pmids\": [\"26769854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LILRB3 mediates inhibitory signaling through immunoreceptor tyrosine-based inhibition motifs (ITIMs) in its cytoplasmic tail, while its paired activating receptor LILRA6 signals through association with FcRγ bearing an ITAM; both receptors share identical extracellular domains. LILRA6 copy number variation correlates with expression level on monocytes.\",\n      \"method\": \"mRNA expression analysis by fraction, genetic characterization, functional domain annotation\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional domain characterization with expression correlation; mechanistic inference from receptor family properties\",\n      \"pmids\": [\"24096970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LILRB3 is expressed on resting human neutrophils and is released from the surface upon activation; continuous ligation of LILRB3 inhibits IgA-mediated effector functions including reactive oxygen species production, phagocytic uptake, and microbial killing, identifying LILRB3 as a checkpoint controlling neutrophil antimicrobial activity.\",\n      \"method\": \"Immunoprecipitation followed by mass spectrometry, flow cytometry, ROS assay, phagocytosis assay, microbial killing assay, PLB-985 cell differentiation model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional readouts with defined ligand-receptor engagement, single lab\",\n      \"pmids\": [\"31915259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Agonistic ligation of LILRB3 on primary human monocytes induces phenotypic and functional changes leading to potent inhibition of immune responses, including significant reduction in T cell proliferation; agonizing LILRB3 in humanized mice induced tolerance and permitted efficient engraftment of allogeneic cells, establishing LILRB3 as a myeloid immune checkpoint.\",\n      \"method\": \"Monoclonal antibody panel generation, epitope mapping, primary monocyte functional assays, T cell proliferation assay, humanized mouse allograft model\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo mechanistic validation with defined agonistic antibodies, single lab\",\n      \"pmids\": [\"32870822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Galectin-4 and galectin-7 induce activation of LILRB3 on immunosuppressive myeloid cells (MDSCs); LILRB3 blockade with antagonistic antibody inhibits MDSC activity and impedes tumor development in myeloid-specific LILRB3 transgenic mice in a T cell-dependent manner.\",\n      \"method\": \"Ligand-receptor binding assays, antagonistic antibody blockade, LILRB3 myeloid transgenic mouse tumor model, T cell depletion experiments\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ligand identification plus in vivo epistasis via transgenic model, single lab\",\n      \"pmids\": [\"38113030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A cluster of four missense SNPs (LILRB3-4SNPs) in the LILRB3 gene at amino acids 617-618, proximal to the SHP1/2-binding ITIM motif, is associated with kidney transplant failure in African Americans and is linked to enhanced monocyte inflammation and ferroptosis, suggesting these variants impair LILRB3 inhibitory signaling.\",\n      \"method\": \"Whole-blood RNA sequencing, SNP genotyping, multiomics analysis of blood and biopsies, Biobank association studies\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic inference from SNP location near ITIM; functional consequence inferred from multiomics without direct in vitro validation of signaling\",\n      \"pmids\": [\"40065170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"miR-103a-2-5p directly targets the 3'-UTR of LILRB3 mRNA (validated by dual luciferase reporter assay), reducing LILRB3 protein levels and thereby inhibiting AML cell proliferation, promoting apoptosis via suppression of the Nrf2/HO-1 axis and increase of intracellular ROS, and reducing CD8+ T cell apoptosis.\",\n      \"method\": \"Dual luciferase reporter assay, qRT-PCR, CCK8, colony formation, flow cytometry, AML mouse model with cationic liposome delivery\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3'-UTR targeting validated by reporter assay plus downstream pathway analysis and in vivo model\",\n      \"pmids\": [\"38486250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LILRB3 blockade with antagonistic antibodies upregulates myeloid lineage differentiation transcription factors (PU.1, C/EBP family, IRF) and decreases phosphorylation of AKT, cyclin D1, and retinoblastoma protein; agonist antibody activation of LILRB3 upregulates cholesterol metabolism pathways that promote leukemia cell survival.\",\n      \"method\": \"Antagonistic and agonistic antibody treatment, transcriptomic analysis, Western blotting for signaling intermediates, in vitro and in vivo AML models, CAR T cell assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple downstream pathway analyses with complementary gain- and loss-of-function approaches\",\n      \"pmids\": [\"38098451\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LILRB3 is an inhibitory myeloid immune checkpoint receptor whose cytoplasmic ITIMs recruit SHP-1/2 phosphatases; its intracellular domain constitutively associates with TRAF2, and upon activation recruits cFLIP to drive NF-κB-mediated cell survival (with A20-dependent feedback restoring SHP-1/2 dominance); its extracellular immunoglobulin-like domains bind ligands including MHC class I (triggering SHP2-ROCK2-mediated epithelial cell extrusion), cytokeratins 8/18/19 on necrotic epithelial cells (in an allele-specific manner), APOE4 (forming a heterotetrameric complex that activates microglial inflammation), and galectins-4/7 (activating immunosuppressive myeloid cells), while ligation on monocytes potently suppresses T cell responses and on neutrophils inhibits IgA-mediated antimicrobial effector functions.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LILRB3 is an inhibitory immunoreceptor expressed on myeloid cells that integrates multiple extracellular ligand inputs to control immune activation, cell survival, and tissue surveillance. Its cytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs) recruit SHP-1/SHP-2 phosphatases to suppress myeloid effector functions — including IgA-mediated neutrophil antimicrobial responses and monocyte-driven T cell proliferation — establishing it as a myeloid immune checkpoint [PMID:31915259, PMID:32870822, PMID:24096970]. The intracellular domain also constitutively associates with TRAF2; upon activation, cFLIP recruitment drives NF-κB-dependent survival signaling in AML cells, with A20-mediated feedback restoring SHP-1/2 dominance, while LILRB3 blockade promotes myeloid differentiation and suppresses AKT/cyclin D1 signaling [PMID:35122056, PMID:38098451]. The extracellular immunoglobulin-like domains recognize diverse ligands — MHC class I (triggering SHP2-ROCK2-dependent epithelial cell extrusion of transformed cells), APOE4 (forming a heterotetrameric complex that activates microglial inflammation), cytokeratins 8/18/19 on necrotic epithelial cells, and galectins-4/7 on immunosuppressive myeloid cells — linking LILRB3 to cancer immunosurveillance, neuroinflammation, and tumor immune evasion [PMID:34686865, PMID:36588123, PMID:26769854, PMID:38113030].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing the signaling architecture: LILRB3 was shown to signal through cytoplasmic ITIMs while sharing identical extracellular domains with its paired activating receptor LILRA6, defining LILRB3 as an inhibitory counterpart in a paired receptor system on monocytes.\",\n      \"evidence\": \"mRNA expression analysis, genetic characterization, and functional domain annotation\",\n      \"pmids\": [\"24096970\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct demonstration of SHP-1/2 recruitment to LILRB3 ITIMs in this study\", \"Endogenous ligand unknown at this point\", \"Downstream signaling consequences not measured\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of the first endogenous ligand: allele-specific variants of LILRB3 were found to bind cytokeratins 8/18/19 exposed on necrotic glandular epithelial cells, revealing that LILRB3 senses damage-associated signals in an allele-dependent manner.\",\n      \"evidence\": \"Immunoprecipitation from cell lysates, reporter cell activation assay, siRNA knockdown of cytokeratin 8\",\n      \"pmids\": [\"26769854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding restricted to LILRB3*12 allele — generalizability to other alleles unclear\", \"Structural basis of allele-specific recognition unresolved\", \"Downstream signaling pathway upon cytokeratin engagement not characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Functional demonstration as a myeloid immune checkpoint: LILRB3 ligation on monocytes suppressed T cell proliferation and enabled allograft tolerance in humanized mice, while on neutrophils it inhibited IgA-mediated antimicrobial effector functions, establishing its broad immunosuppressive role across myeloid lineages.\",\n      \"evidence\": \"Agonistic monoclonal antibodies on primary monocytes and neutrophils, T cell proliferation assays, ROS/phagocytosis/killing assays, humanized mouse allograft model\",\n      \"pmids\": [\"32870822\", \"31915259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous ligand driving these checkpoint functions in vivo not identified\", \"Relative contribution of SHP-1 versus SHP-2 to different effector outputs not dissected\", \"Mechanism of LILRB3 shedding from activated neutrophils not characterized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery of a dual intracellular signaling switch: LILRB3 constitutively associates with TRAF2, and activation recruits cFLIP to drive NF-κB-mediated leukemic cell survival; hyperactivated NF-κB induces A20, which disrupts the TRAF2 interaction and restores SHP-1/2-dominated inhibitory signaling, revealing an intrinsic toggle between pro-survival and inhibitory pathways.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, domain mapping, NF-κB reporter assays, mutagenesis, in vivo AML models, antagonistic antibody blockade\",\n      \"pmids\": [\"35122056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TRAF2 binding to LILRB3 intracellular domain not resolved\", \"Whether A20 feedback operates in non-leukemic myeloid cells unknown\", \"Threshold of NF-κB activation required to trigger the switch not quantified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealing a cell-autonomous tumor surveillance mechanism: non-transformed epithelial cells expressing LILRB3 recognize MHC class I upregulated on transformed neighbors and activate SHP2-ROCK2 signaling to mechanically extrude precancerous cells, independent of adaptive immunity.\",\n      \"evidence\": \"Live-cell imaging, genetic knockdown/knockout, co-immunoprecipitation, epithelial cell competition assays, pharmacological inhibitors\",\n      \"pmids\": [\"34686865\", \"34740904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LILRB3 distinguishes normal from elevated MHC-I levels to trigger extrusion not defined\", \"Whether this mechanism operates in vivo in human tissues not shown\", \"Contribution of other LILRB family members to cell competition not excluded\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Structural elucidation of isoform-specific APOE4 recognition: crystal structures revealed that two LILRB3 molecules form a heterotetrameric complex with two APOE4 molecules via a positively charged patch on the APOE4 N-terminal domain, and this interaction activates pro-inflammatory microglia, linking LILRB3 to neuroinflammation.\",\n      \"evidence\": \"X-ray crystallography, biochemical binding assays, microglial activation assays with LILRB3 knockdown/knockout\",\n      \"pmids\": [\"36588123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LILRB3-APOE4 interaction drives neurodegeneration in Alzheimer's disease models not tested\", \"Signaling pathway downstream of LILRB3 activation in microglia (SHP vs. NF-κB) not resolved\", \"Whether APOE4-LILRB3 engagement occurs in vivo in human brain not demonstrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapping downstream transcriptional and metabolic consequences: LILRB3 blockade in AML cells upregulated myeloid differentiation transcription factors (PU.1, C/EBP, IRF) and suppressed AKT/cyclin D1/Rb phosphorylation, while agonist activation induced cholesterol metabolism pathways promoting leukemia survival.\",\n      \"evidence\": \"Antagonistic and agonistic antibody treatment, transcriptomic profiling, Western blotting, in vivo AML models, CAR T cell co-culture assays\",\n      \"pmids\": [\"38098451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether cholesterol metabolic reprogramming is a direct LILRB3 signaling output or secondary effect unknown\", \"Whether differentiation induction by LILRB3 blockade generalizes beyond AML not tested\", \"Direct transcription factor regulation versus indirect pathway effects not distinguished\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of galectins as tumor-associated LILRB3 ligands: galectin-4 and galectin-7 were found to activate LILRB3 on immunosuppressive myeloid cells (MDSCs), and LILRB3 blockade impeded tumor growth in a T cell-dependent manner in myeloid-specific transgenic mice.\",\n      \"evidence\": \"Ligand-receptor binding assays, antagonistic antibody blockade, LILRB3 myeloid transgenic mouse tumor model, T cell depletion experiments\",\n      \"pmids\": [\"38113030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site of galectins on LILRB3 extracellular domain not structurally resolved\", \"Glycan dependence of galectin-LILRB3 interaction not tested\", \"Relative importance of galectin-4 vs. galectin-7 in tumor microenvironment not distinguished\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Post-transcriptional regulation of LILRB3 identified: miR-103a-2-5p directly targets the LILRB3 3′-UTR, reducing LILRB3 protein and thereby inhibiting AML proliferation and promoting apoptosis via increased ROS and suppressed Nrf2/HO-1, while rescuing CD8+ T cell viability.\",\n      \"evidence\": \"Dual luciferase reporter assay, qRT-PCR, colony formation, flow cytometry, AML mouse model with liposomal miRNA delivery\",\n      \"pmids\": [\"38486250\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Nrf2/HO-1 axis is directly regulated by LILRB3 signaling or an indirect consequence of LILRB3 loss not resolved\", \"Specificity of miR-103a-2-5p for LILRB3 versus other targets not controlled\", \"In vivo pharmacokinetics and off-target effects of liposomal miRNA delivery not characterized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Genetic variants near the ITIM link LILRB3 to transplant outcome: a cluster of four missense SNPs proximal to the SHP-1/2-binding ITIM motif was associated with kidney transplant failure in African Americans, correlated with enhanced monocyte inflammation and ferroptosis.\",\n      \"evidence\": \"Whole-blood RNA sequencing, SNP genotyping, multiomics analysis of blood and biopsies, Biobank association studies\",\n      \"pmids\": [\"40065170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration that these SNPs impair ITIM phosphorylation or SHP recruitment not performed\", \"Causal relationship between LILRB3 variants and ferroptosis not mechanistically validated\", \"Whether these variants affect other LILRB3 functions (e.g., TRAF2 binding) not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open question: how LILRB3 integrates signals from its diverse extracellular ligands (MHC-I, APOE4, cytokeratins, galectins) to select between ITIM/SHP-mediated inhibition and TRAF2/NF-κB-mediated survival in different myeloid cell contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model of how ligand identity determines intracellular pathway choice\", \"Structural basis for simultaneous or competitive ligand engagement across domains not known\", \"In vivo relevance of LILRB3-APOE4 axis in Alzheimer's disease not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 4, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5, 6, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 5, 6, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 7, 9, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TRAF2\",\n      \"SHP1\",\n      \"SHP2\",\n      \"APOE4\",\n      \"ROCK2\",\n      \"CFLAR\",\n      \"LGALS4\",\n      \"LGALS7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}