{"gene":"LILRB2","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1998,"finding":"LIR-2 (LILRB2) binds MHC class I molecules and, upon phosphorylation of its cytoplasmic tail, recruits the tyrosine phosphatase SHP-1. Coligation of LIR-2 with FcγRI (CD64) on monocytes inhibits tyrosine phosphorylation of the Fc receptor γ-chain and Syk, and blocks intracellular calcium mobilization, demonstrating that LILRB2 is an inhibitory receptor that down-modulates Fc receptor-mediated activation signals.","method":"Phosphorylation assays, SHP-1 binding assay, calcium mobilization assay, coligation experiments in primary monocytes","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct biochemical assays (phosphorylation, phosphatase recruitment, Ca2+ flux) with functional coligation readout in primary monocytes; single lab but multiple orthogonal methods","pmids":["9842885"],"is_preprint":false},{"year":2002,"finding":"The CD8+CD28− T suppressor cell interaction with dendritic cells up-regulates ILT4 (LILRB2) on monocytes/DCs, rendering these APCs tolerogenic with reduced costimulatory molecule expression and ability to induce antigen-specific T cell unresponsiveness in CD4+ T helper cells.","method":"Co-culture functional assays, flow cytometry, mixed lymphocyte reactions","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent functional assays including in vitro co-cultures and correlation with in vivo transplant tolerance; replicated in subsequent work by multiple labs","pmids":["11875462"],"is_preprint":false},{"year":2002,"finding":"Crystal structure of LIR-2 (LILRB2) D1D2 at 1.8 Å reveals that while the overall fold resembles LIR-1 (LILRB1) and KIR, the ligand-binding D1 domain differs from LIR-1 in the 44–57 helix region (shortened 3₁₀ helix) and the UL18-binding 76–84 loop is displaced 11 Å, explaining the >1000-fold lower affinity of LILRB2 for HCMV UL18 relative to LILRB1.","method":"X-ray crystallography (molecular replacement, 1.8 Å resolution)","journal":"BMC structural biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution crystal structure with direct structural comparison; single lab but Tier 1 method","pmids":["12390682"],"is_preprint":false},{"year":2003,"finding":"Surface plasmon resonance shows that ILT4 (LILRB2) binds a broad range of classical HLA-A, -B, -C alleles as well as the non-classical HLA-G, with binding to HLA-G 3–4 fold higher affinity than to classical MHCIs; ILT4 binds all these MHCIs with 2–3 fold lower affinity than ILT2. ILT2 and ILT4 compete with CD8 for MHCI binding.","method":"Surface plasmon resonance (SPR) with soluble receptor and multiple MHCI ligands; CD8 competition assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous biophysical SPR measurements across multiple MHCI alleles; replicated and extended in subsequent structural and binding studies","pmids":["12853576"],"is_preprint":false},{"year":2000,"finding":"HLA-F tetramers bind monocytes and B cells via direct interaction with ILT4 (LILRB2) and ILT2; transfection of ILT4 confers HLA-F tetramer staining on non-binding cells, and SPR confirms direct molecular interaction between HLA-F and ILT4.","method":"Tetramer staining, transfection, surface plasmon resonance","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct SPR binding plus transfection gain-of-function; multiple orthogonal methods in one study","pmids":["11169396"],"is_preprint":false},{"year":2006,"finding":"Crystal structure at 2.5 Å of the LILRB2/HLA-G complex shows that LILRB2 dominantly contacts the hydrophobic site on the HLA-G α3 domain; NMR binding studies confirm that LILRB2 (unlike LILRB1) can recognize the β2m-free form of HLA-B27, establishing distinct β2m-dependent binding specificities between LILRB family members.","method":"X-ray crystallography (2.5 Å co-crystal structure), NMR binding studies, SPR with β2m-free MHCIs","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — co-crystal structure plus NMR and SPR validation; multiple orthogonal methods; highly cited and subsequently replicated","pmids":["17056715"],"is_preprint":false},{"year":2008,"finding":"Ligation of ILT4 (LILRB2) by HLA-G1 on DCs results in recruitment of SHP-1 and SHP-2 phosphatases. SHP-2 and the downstream IL-6–STAT3 signaling pathway are required for ILT4-mediated arrest of DC maturation, reducing MHC class II, CD80, and CD86 expression. HLA-G5 dimer (but not monomer) and HLA-G1 tetramer both induce strong ILT4-mediated signaling.","method":"Co-immunoprecipitation of SHP-1/SHP-2, STAT3 activation assays, ILT4-transgenic mouse DCs, allograft survival experiments, signaling pathway inhibition","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — co-IP of phosphatases, in vivo transgenic model, pathway inhibition, multiple orthogonal methods in one study","pmids":["18550825"],"is_preprint":false},{"year":2013,"finding":"Murine PirB and its human ortholog LilrB2 (LILRB2) are receptors for soluble Aβ oligomers with nanomolar affinity. The first two extracellular Ig domains of PirB/LilrB2 mediate Aβ binding. Aβ oligomer binding triggers enhanced cofilin signaling (cofilin dephosphorylation). In mice, the deleterious effect of Aβ oligomers on hippocampal long-term potentiation required PirB, and PirB contributed to memory deficits and loss of synaptic plasticity in juvenile visual cortex in transgenic AD mice.","method":"Binding assays (nanomolar Kd), domain deletion mapping, cofilin phosphorylation assays, LTP electrophysiology in PirB KO mice, transgenic AD mouse behavioral and plasticity assays","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods: direct binding with affinity measurement, genetic KO with LTP and behavioral readouts, biochemical cofilin signaling; highly cited landmark study","pmids":["24052308"],"is_preprint":false},{"year":2013,"finding":"ILT4 (LILRB2) is expressed on primary human neutrophils, and its expression is induced during neutrophil differentiation. HLA-G (preferred ILT4 ligand) engagement of ILT4 inhibits phagocytosis; ILT4 co-localizes with CD32a (FcγRIIa) in lipid rafts and its engagement impairs reactive oxygen species production through CD32a. Inflammatory degranulation triggers rapid translocation of an intracellular ILT4 pool to the cell surface, amplifying HLA-G-mediated inhibition of phagocytosis.","method":"Flow cytometry, functional phagocytosis and ROS assays, lipid raft fractionation, co-localization microscopy, degranulation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple functional assays plus subcellular localization; co-localization in lipid rafts with FcγRIIa and direct functional consequence demonstrated","pmids":["24133137"],"is_preprint":false},{"year":2014,"finding":"A novel motif in the first and fourth Ig domains of LILRB2 is necessary for binding and activation by Angptl2. Angptl2 expressed in mammalian cells forms high-molecular-weight multimers, and ligand multimerization is required for LILRB2 activation and downstream signaling. Angptl2 binding to LILRB2 is distinct from and does not completely overlap with HLA-G binding.","method":"Domain mutagenesis, co-immunoprecipitation, gel filtration for multimerization, functional signaling assays, ex vivo HSC expansion assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis identifying binding motif plus multimerization biochemistry and functional rescue; multiple orthogonal methods in one study","pmids":["24899623"],"is_preprint":false},{"year":2018,"finding":"LILRB2 antagonism in tumor-associated myeloid cells inhibits receptor-mediated activation of SHP1/2 phosphatases and AKT/STAT6 signaling (in the presence of M-CSF and IL-4). Transcriptome analysis shows LILRB2 antagonism alters genes in cytoskeleton remodeling, lipid/cholesterol metabolism, and endosomal sorting, shifting myeloid differentiation from alternatively activated (M2) toward inflammatory (M1) phenotype.","method":"Anti-LILRB2 antibody antagonism, SHP1/2 phosphorylation assays, AKT/STAT6 activation assays, transcriptome (RNA-seq), in vivo tumor models with T cell checkpoint inhibitor combination","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple biochemical pathway assays plus transcriptomics plus in vivo tumor models; multiple orthogonal methods","pmids":["30352428"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of LilrB2 D1D2 complexed to small molecules mimicking phenylalanine identifies two hydrophobic pockets on LilrB2 that accommodate Aβ KLVFFA (residues 16–21) phenylalanine side chains. Mutagenesis confirmed these pockets as the KLVFFA binding site. Small molecule inhibitors designed to occupy these pockets block Aβ–LilrB2 interactions in vitro and on cell surfaces, and reduce Aβ cytotoxicity.","method":"X-ray crystallography of LilrB2 D1D2 with small molecule ligands, site-directed mutagenesis, Rosetta docking, in vitro binding inhibition assay, cell surface binding assay, cytotoxicity assay","journal":"Nature chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus cell-based functional validation; multiple orthogonal methods in one rigorous study","pmids":["30297750"],"is_preprint":false},{"year":2018,"finding":"Human Semaphorin-4A (hSema4A) binds ILT-4 (LILRB2) on activated CD4+ T cells. This interaction co-stimulates CD4+ T cell proliferation and drives Th2 differentiation, identifying LILRB2 as a co-stimulatory receptor for hSema4A on T cells (distinct from the Th1-driving murine Sema4A/Tim-2 axis).","method":"Two independent receptor cloning strategies, co-immunoprecipitation, T cell proliferation and Th subset differentiation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two independent cloning strategies plus functional T cell assays confirming ILT4 as hSema4A receptor; multiple methods in one study","pmids":["29467366"],"is_preprint":false},{"year":2019,"finding":"Crystal structure of the four Ig-like domain LILRB2 and four-domain LILRB1 in complex with HLA-G1 shows limited inter-domain flexibility. D1D2 mediates HLA-I binding while D3D4 acts as a structural scaffold. The geometry of LILRB1/2 complexes with dimeric HLA-G1 suggests dimeric receptor accessibility transduces stronger inhibitory signals.","method":"X-ray crystallography of full four-domain LILRB2 and LILRB1–HLA-G1 complex","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution crystal structures of full-length ectodomain with ligand; single lab but Tier 1 method","pmids":["31273318"],"is_preprint":false},{"year":2010,"finding":"Induction of Tr1 regulatory T cells by tolerogenic DC-10 requires an IL-10-dependent ILT4/HLA-G signaling pathway. Blocking ILT4 or HLA-G prevented Tr1 cell differentiation, placing ILT4–HLA-G engagement as a required upstream signal in IL-10-driven Tr1 induction.","method":"Blocking antibody experiments, co-culture assays, flow cytometry for Tr1 cell markers, cytokine measurements","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blockade with antibodies plus defined cellular readout; single lab, multiple orthogonal assays","pmids":["20448110"],"is_preprint":false},{"year":2021,"finding":"LILRB2 (ILT4) on myeloid cells recruits SHP1/2 as its canonical downstream effectors. When co-ligated with TREM2 by shared ligands (Aβ oligomers or phosphatidylserine), LILRB2 suppresses TREM2 signaling in microglia, reducing phagocytosis, migration, and cytokine responses. An antagonistic anti-LILRB2 antibody (Ab29) relieves this inhibition in human iPSC-derived microglia and increases microglial plaque phagocytosis in 5XFAD mice.","method":"iPSC-derived human microglia functional assays (phagocytosis, migration, cytokines), TREM2 signaling (Western blot), antagonistic antibody (Ab29), stereotaxic microglia transplantation into 5XFAD mice, immunofluorescence","journal":"Molecular neurodegeneration","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including human iPSC microglia, signaling biochemistry, and in vivo mouse model; single lab but comprehensive mechanistic dissection","pmids":["35717259"],"is_preprint":false},{"year":2015,"finding":"LILRB2 is expressed on non-small cell lung cancer (NSCLC) cells. ANGPTL2 binds LILRB2 to support lung cancer cell growth; LILRB2 knockdown reduces proliferation, colony formation, and migration. The SHP2/CaMK1/CREB signaling axis mediates ANGPTL2/LILRB2-driven lung cancer cell proliferation.","method":"LILRB2 knockdown in NSCLC cell lines, proliferation/colony/migration assays, signaling pathway analysis (SHP2/CaMK1/CREB Western blot)","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple cellular readouts plus pathway analysis; single lab, replicated downstream finding with endometrial cancer paper","pmids":["26056041"],"is_preprint":false},{"year":2018,"finding":"LILRB2 in endometrial cancer cells activates SHP2/CaMK1/CREB signaling pathways to support cancer cell expansion and migration. LILRB2 knockdown decreases proliferation and colony formation in vitro and reduces xenograft tumor growth in vivo.","method":"LILRB2 knockdown in endometrial cancer cell lines, proliferation/colony/migration assays, in vivo xenograft, Western blot for SHP2/CaMK1/CREB","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in vitro and in vivo with defined signaling pathway; single lab","pmids":["30343889"],"is_preprint":false},{"year":2021,"finding":"P. falciparum RIFIN proteins on infected erythrocytes are novel ligands for LILRB2. Domain mapping shows that domains 3 (D3) of LILRB2 mediates RIFIN binding, whereas domains 1 and 2 (D1D2) mediate binding to HLA class I, indicating distinct binding sites for pathogen vs. host ligands on the same receptor.","method":"RIFIN expression library screening, direct binding assays, LILRB2 domain-deletion mapping","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic domain-deletion mapping with a newly developed expression library; single lab, multiple domains tested","pmids":["33647792"],"is_preprint":false},{"year":2022,"finding":"ANGPTL8 interacts with LILRB2 to activate ERK signaling in hepatic stellate cells (HSCs), promoting expression of fibrosis-related genes and accelerating liver fibrosis in HFD-induced NAFLD. Co-IP confirmed the ANGPTL8–LILRB2 physical interaction; liver-specific ANGPTL8 knockout or PirB ectodomain protein (sequestering ANGPTL8) reduced fibrosis in mice.","method":"Co-immunoprecipitation (ANGPTL8–LILRB2), ANGPTL8 KO mice and bone marrow chimeras, AAV8 liver restoration, RNA-seq, ERK signaling Western blot","journal":"Journal of advanced research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — co-IP confirming physical interaction plus in vivo genetic models and signaling biochemistry; multiple orthogonal methods","pmids":["36031141"],"is_preprint":false},{"year":2021,"finding":"Tumor cell-derived ILT4 (LILRB2/PIR-B) activates MAPK ERK1/2 signaling to increase fatty acid synthesis and lipid accumulation in tumor cells, which in turn induces senescence in naïve/effector T cells. This mechanism was established by gain- and loss-of-function in vitro and validated in breast cancer and melanoma mouse models.","method":"ILT4/PIR-B gain- and loss-of-function, MAPK ERK1/2 Western blot, lipid droplet staining, T cell senescence assays, in vivo mouse tumor models","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined signaling pathway (ERK1/2-fatty acid synthesis-T cell senescence) supported by in vitro and in vivo data; single lab","pmids":["33653799"],"is_preprint":false},{"year":2021,"finding":"EGFR activation (via mutation or EGF-dependent phosphorylation) up-regulates ILT4 expression in NSCLC tumor cells through AKT and ERK1/2 phosphorylation. Tumor cell-expressed ILT4 induces TAM recruitment and M2-like polarization and directly inhibits T cell proliferation, cytotoxicity, and IFN-γ secretion.","method":"Western blotting, mRNA microarray, TCGA analysis, CCK8/apoptosis/CFSE assays, Transwell migration, ELISA, in vivo humanized NSG and C57BL/6 tumor models","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — signaling pathway validated by multiple methods in vitro plus in vivo models; single lab, comprehensive but complex study","pmids":["33537094"],"is_preprint":false},{"year":2023,"finding":"PirB/LILRB2 on macrophages acts as a receptor for ANGPTL8 to mediate macrophage migration to the liver during NASH. PirB-/- bone marrow chimeras abolish ANGPTL8-induced monocyte-derived macrophage (MDM) migration. The PirB ectodomain protein sequesters ANGPTL8 and ameliorates NASH. Direct LILRB2–ANGPTL8 binding promotes MDM migration and inflammatory activation in human peripheral blood monocytes.","method":"PirB knockout mice, bone marrow chimeras, AAV hepatocyte-specific rescue, in vitro migration assays with anti-LILRB2, direct binding and co-IP, human monocyte functional assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with BM chimera distinguishing cell-intrinsic effect, direct binding, and human monocyte validation; multiple orthogonal methods","pmids":["37481670"],"is_preprint":false},{"year":2024,"finding":"ILT4 in NSCLC tumor cells activates ERK1/2 signaling downstream of ANGPTL2 binding to increase secretion of VEGF-A and MMP-9, thereby promoting tumor angiogenesis in vitro and in vivo. ILT4 expression was positively correlated with microvessel density in patient samples.","method":"ILT4 knockdown/overexpression, ANGPTL2 stimulation, ERK1/2 Western blot, VEGF-A/MMP-9 ELISA, tube formation assay, in vivo tumor models with angiogenesis readout","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined signaling axis (ANGPTL2→ILT4→ERK1/2→VEGF-A/MMP-9) supported by in vitro and in vivo data; single lab","pmids":["38433526"],"is_preprint":false},{"year":2024,"finding":"ILT4 in triple-negative breast cancer cells activates AKT–mTOR signaling to up-regulate GLUT3 and PKM2, reprogramming tumor cell aerobic glycolysis and promoting proliferation, migration, invasion, and metastasis.","method":"ILT4 knockdown/overexpression in TNBC cell lines, AKT/mTOR pathway Western blot, GLUT3/PKM2 expression analysis, in vivo tumor growth and metastasis models","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined signaling pathway with in vitro and in vivo validation; single lab","pmids":["37622462"],"is_preprint":false},{"year":2024,"finding":"LILRB2 in breast cancer cells facilitates ubiquitination and proteasomal degradation of HLA-A by promoting the interaction between the E3 ubiquitin ligase MARCH9 and HLA-A, thereby reducing surface MHC-I and enabling CD8+ T cell evasion.","method":"Western blot, immunoprecipitation, histidine-tag pulldown ubiquitination assay, syngeneic mouse tumor model, flow cytometry","journal":"Cellular oncology (Dordrecht, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ubiquitination biochemistry plus MARCH9–HLA-A co-IP plus in vivo immune evasion model; single lab","pmids":["38656573"],"is_preprint":false},{"year":2024,"finding":"LILRB2 inhibition in NSCLC attenuates radiation-induced cellular senescence and the SASP by suppressing the JAK2/STAT3 signaling pathway, thereby increasing radiosensitivity. Radiation up-regulates LILRB2, which normally promotes senescence and tumor cell proliferation via JAK2/STAT3.","method":"Lentiviral LILRB2 silencing, irradiation assays, senescence markers (SA-β-gal, p21, p16), JAK2/STAT3 Western blot, in vivo tumor models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with pathway validation in vitro and in vivo; single lab","pmids":["38705566"],"is_preprint":false},{"year":2025,"finding":"SPI1 transcription factor transcriptionally activates LILRB2 expression in LPS-tolerant macrophages (confirmed by ChIP and dual-luciferase assays). LILRB2 physically interacts with TLR8 (co-IP) to suppress TLR8-mediated MyD88/NF-κB signaling and inhibit p65 nuclear translocation, establishing an immunosuppressive phenotype.","method":"Co-immunoprecipitation (LILRB2–TLR8 interaction), ChIP assay (SPI1 binding to LILRB2 promoter), dual-luciferase reporter assay, LILRB2 knockdown, NF-κB signaling Western blot, flow cytometry for macrophage polarization","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, and functional signaling assays; multiple orthogonal methods; single lab","pmids":["40551156"],"is_preprint":false},{"year":2025,"finding":"C4d (a cleavage product of complement C4) binds LilrB2/PirB with nanomolar affinity and colocalizes with LilrB2 at excitatory synapses in human cerebral cortex. In mice, C4d exposure reduces dendritic spine density on L5 pyramidal neurons in a PirB-dependent manner (PirB KO completely prevents spine loss), establishing C4d as a physiological LilrB2 ligand mediating synapse pruning.","method":"Direct binding assays (nanomolar Kd), co-localization by immunofluorescence, in vivo dendritic spine imaging in WT vs. PirB KO mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct binding affinity measurement plus in vivo genetic KO with quantitative spine readout; multiple orthogonal methods in one study","pmids":["40966293"],"is_preprint":false},{"year":2016,"finding":"HLA-G engagement of ILT4 on granulocytic MDSCs promotes MDSC accumulation (induction from PBMCs) and suppressive activity, induces STAT3 phosphorylation, and up-regulates IDO expression. Effects on MDSC accumulation were blocked by anti-ILT4 antibody, identifying ILT4→STAT3→IDO as a signaling axis in HLA-G-driven MDSC biology.","method":"Anti-ILT4 blocking antibody, sHLA-G stimulation, STAT3 phosphorylation Western blot/flow cytometry, IDO expression assay, MDSC induction and T cell suppression assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor blocking with downstream signaling readouts; single lab, multiple assays","pmids":["27859042"],"is_preprint":false},{"year":2021,"finding":"ANGPTL2 induces expression of inflammatory cytokines in human fibroblast-like synoviocytes (HFLS) via LILRB2, and pre-treatment with anti-LILRB2 antibody reduces this inflammatory gene expression and blocks ANGPTL2-induced phosphorylation of ERK, p38, JNK, NF-κB, and Akt.","method":"Real-time RT-PCR, Western blotting for MAPK/NF-κB/Akt phosphorylation, anti-LILRB2 antibody blocking in HFLS","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor blocking with multiple downstream signaling readouts; single lab, in vitro cell line system","pmids":["33538932"],"is_preprint":false},{"year":2024,"finding":"ILT4 inhibits myeloid cells via both cis- (same-cell) and trans-engagement (cell-cell contact) with MHC-I ligands, whereas ILT2 only inhibits via trans-engagement. Dual ILT2/ILT4 blockade is required for optimal myeloid cell activation in 3D tumor spheroid models, and combined blockade enhances cytolytic T cell activity and generates immune niches in humanized mouse and human tumor explant systems.","method":"3D spheroid tumor model, myeloid cell functional assays (CXCL9/CCL5 secretion, CD86/CD163 expression), humanized mouse tumor models, human tumor explant histoculture, cis vs. trans engagement experiments","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple model systems (3D spheroid, humanized mice, human explants) distinguishing cis vs. trans engagement; single lab but orthogonal systems","pmids":["38393969"],"is_preprint":false},{"year":2004,"finding":"IL-10 up-regulates cell-surface LIR-2 (LILRB2) on maturing human DCs. LPS-stimulated LIR-2-transfected DCs inhibit autologous and allogeneic T cell proliferation. A novel soluble form of LIR-2 was detected in DC culture supernatants; IL-10 inhibits soluble LIR-2 production, and recombinant soluble LIR-2 restores T cell proliferation inhibited by LPS+IL-10-treated DCs.","method":"Retroviral expression cloning, flow cytometry, MLR assays, detection of soluble LIR-2 by ELISA/Western, recombinant soluble LIR-2 reconstitution","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — retroviral overexpression, functional T cell assays, and soluble form characterization; single lab, multiple methods","pmids":["14971032"],"is_preprint":false}],"current_model":"LILRB2 is an ITIM-bearing inhibitory receptor expressed on myeloid cells (monocytes, DCs, macrophages, neutrophils, MDSCs) and on certain tumor and neuronal cells that, upon ligand engagement, recruits SHP-1 and SHP-2 phosphatases to suppress activating signals; it binds classical and non-classical MHC-I molecules (with highest affinity for HLA-G via its α3 domain, as resolved by co-crystal structures), as well as diverse ligands including Aβ oligomers, C4d complement fragment, ANGPTLs (2 and 8), Semaphorin-4A, HLA-F, and P. falciparum RIFIN—each with distinct domain requirements—and signals through context-dependent downstream effectors (SHP2/CaMK1/CREB, ERK1/2, AKT/mTOR, IL-6/STAT3, JAK2/STAT3) to regulate DC tolerogenicity, myeloid cell polarization, neutrophil function, microglial phagocytosis via TREM2 co-ligation, tumor cell metabolism and immune evasion, and synaptic plasticity/pruning in the brain."},"narrative":{"mechanistic_narrative":"LILRB2 (ILT4/LIR-2; murine ortholog PirB) is an ITIM-bearing inhibitory receptor of myeloid cells that, upon ligand engagement and cytoplasmic-tail phosphorylation, recruits the tyrosine phosphatases SHP-1 and SHP-2 to dampen activating signals, as first established by its coligation with FcγRI to block γ-chain/Syk phosphorylation and calcium flux in monocytes [PMID:9842885, PMID:18550825]. Its ectodomain binds a broad spectrum of classical (HLA-A, -B, -C) and non-classical MHC-I molecules with highest affinity for HLA-G, and co-crystal structures show that the membrane-distal D1D2 domains dominantly contact the hydrophobic α3 site of HLA-G while D3D4 act as a structural scaffold; LILRB2 uniquely recognizes β2m-free MHC-I forms [PMID:12853576, PMID:17056715, PMID:31273318]. This receptor enforces immune tolerance: ligation by HLA-G arrests dendritic-cell maturation through an SHP-2/IL-6/STAT3 axis, drives tolerogenic APC programs and Tr1/T-suppressor responses, and promotes MDSC accumulation and IDO expression via STAT3 [PMID:18550825, PMID:11875462, PMID:20448110, PMID:27859042]. Beyond MHC-I, LILRB2 engages structurally distinct ligands through separable binding sites — Aβ oligomers and C4d at synapses, ANGPTL2/ANGPTL8 via a motif in D1 and D4, Semaphorin-4A on T cells, and P. falciparum RIFIN via D3 — coupling to context-dependent effectors [PMID:24052308, PMID:40966293, PMID:24899623, PMID:29467366, PMID:33647792]. In the brain, Aβ-oligomer binding to PirB/LILRB2 enhances cofilin signaling and mediates loss of synaptic plasticity, while C4d engagement drives PirB-dependent dendritic spine pruning, and LILRB2 suppresses TREM2-mediated microglial phagocytosis upon co-ligation by shared ligands [PMID:24052308, PMID:40966293, PMID:35717259]. In tumors and inflammatory tissue, LILRB2/ANGPTL signaling activates SHP2/CaMK1/CREB, ERK1/2, AKT/mTOR, and JAK2/STAT3 cascades to promote myeloid M2 polarization, tumor proliferation, glycolytic reprogramming, angiogenesis, senescence, and immune evasion — the latter in part by promoting MARCH9-dependent ubiquitination of HLA-A [PMID:30352428, PMID:26056041, PMID:37622462, PMID:38433526, PMID:38705566, PMID:38656573].","teleology":[{"year":1998,"claim":"Established LILRB2 as a bona fide inhibitory receptor: it was unknown whether MHC-I binding had a signaling consequence, and coligation experiments showed it recruits SHP-1 and shuts down activating Fc-receptor signaling.","evidence":"Phosphorylation, SHP-1 binding, and calcium-flux assays with FcγRI coligation in primary monocytes","pmids":["9842885"],"confidence":"High","gaps":["Did not define which MHC-I alleles bind with what affinity","SHP-2 contribution not yet distinguished from SHP-1"]},{"year":2002,"claim":"Connected LILRB2 to immune tolerance by showing T-suppressor/DC interactions up-regulate it on APCs to render them tolerogenic, framing it as an effector of antigen-specific unresponsiveness.","evidence":"Co-culture, MLR, and flow cytometry with CD8+CD28- suppressor cells and DCs","pmids":["11875462"],"confidence":"High","gaps":["Ligand driving tolerogenic signaling not pinpointed","Downstream signaling pathway in DCs undefined"]},{"year":2002,"claim":"Defined the structural basis for LILRB2 ligand discrimination, explaining its >1000-fold lower affinity for HCMV UL18 versus LILRB1 through D1 helix and loop differences.","evidence":"1.8 Å X-ray crystal structure of LILRB2 D1D2 with comparison to LIR-1/KIR","pmids":["12390682"],"confidence":"High","gaps":["No bound MHC-I in this structure","Functional consequence of fold differences not tested"]},{"year":2000,"claim":"Identified HLA-F as a direct LILRB2 ligand, broadening the receptor's MHC-I repertoire beyond classical molecules.","evidence":"HLA-F tetramer staining, ILT4 transfection gain-of-function, and SPR","pmids":["11169396"],"confidence":"High","gaps":["Signaling output of HLA-F engagement not measured","Physiological context of HLA-F/ILT4 axis unclear"]},{"year":2003,"claim":"Quantified LILRB2's MHC-I binding hierarchy, showing broad classical HLA binding with preferential HLA-G affinity and competition with CD8.","evidence":"Surface plasmon resonance across multiple HLA alleles plus CD8 competition assay","pmids":["12853576"],"confidence":"High","gaps":["Affinities are with soluble monomeric reagents, not cell-surface avidity","Functional threshold for inhibition not defined"]},{"year":2006,"claim":"Pinpointed the HLA-G α3 hydrophobic site as the dominant LILRB2 contact and showed LILRB2 (unlike LILRB1) recognizes β2m-free MHC-I, defining intra-family specificity.","evidence":"2.5 Å LILRB2/HLA-G co-crystal structure, NMR, and SPR with β2m-free MHC-I","pmids":["17056715"],"confidence":"High","gaps":["Biological role of β2m-free MHC-I recognition not established","Avidity contribution of dimeric/tetrameric HLA-G not yet resolved structurally"]},{"year":2019,"claim":"Resolved how the full four-domain ectodomain functions, showing D1D2 binds HLA-I while D3D4 act as a rigid scaffold and dimeric HLA-G geometry transduces stronger inhibition.","evidence":"X-ray crystallography of full four-domain LILRB2 and LILRB1 in complex with HLA-G1","pmids":["31273318"],"confidence":"High","gaps":["In-cell clustering/oligomerization not directly imaged","Quantitative link between geometry and ITIM phosphorylation unmeasured"]},{"year":2008,"claim":"Defined the tolerogenic signaling mechanism, showing HLA-G ligation recruits SHP-1/SHP-2 and engages an SHP-2/IL-6/STAT3 pathway required to arrest DC maturation.","evidence":"Co-IP of phosphatases, STAT3 assays, ILT4-transgenic mouse DCs, allograft survival, pathway inhibition","pmids":["18550825"],"confidence":"High","gaps":["How an inhibitory receptor activates STAT3 mechanistically not fully reconciled","Generalizability beyond DCs untested at the time"]},{"year":2010,"claim":"Placed ILT4/HLA-G engagement upstream of IL-10-driven regulatory T-cell induction, extending the tolerance circuit to Tr1 differentiation.","evidence":"Blocking antibodies, DC-10 co-culture, flow cytometry, cytokine measurement","pmids":["20448110"],"confidence":"Medium","gaps":["Antibody blockade only; no genetic loss-of-function","Direct receptor signaling steps in Tr1 induction undefined"]},{"year":2013,"claim":"Discovered a neuronal function: PirB/LILRB2 is a high-affinity Aβ-oligomer receptor whose engagement enhances cofilin signaling and mediates synaptic plasticity loss.","evidence":"Nanomolar binding, domain mapping, cofilin assays, LTP electrophysiology in PirB KO and AD transgenic mice","pmids":["24052308"],"confidence":"High","gaps":["Phosphatase coupling for cofilin pathway not fully mapped","Translation from murine PirB to human LILRB2 in brain incomplete"]},{"year":2013,"claim":"Showed ILT4 regulates neutrophil effector functions, inhibiting phagocytosis and ROS through lipid-raft association with FcγRIIa, with a mobilizable intracellular receptor pool.","evidence":"Phagocytosis/ROS assays, lipid-raft fractionation, co-localization microscopy, degranulation assays in primary neutrophils","pmids":["24133137"],"confidence":"High","gaps":["Molecular basis of FcγRIIa co-localization unresolved","Trafficking machinery for the intracellular pool unidentified"]},{"year":2014,"claim":"Identified ANGPTL2 as a non-MHC ligand requiring multimerization and a distinct D1/D4 motif, demonstrating ligand-class-specific binding modes on LILRB2.","evidence":"Domain mutagenesis, co-IP, gel filtration, signaling and HSC expansion assays","pmids":["24899623"],"confidence":"High","gaps":["Stoichiometry of multimeric ANGPTL2/receptor clusters undefined","Whether ANGPTL2 triggers inhibitory or activating output context-dependent"]},{"year":2018,"claim":"Added Semaphorin-4A as a co-stimulatory ligand on T cells, showing LILRB2 is not exclusively inhibitory but can drive Th2-skewed CD4 T-cell proliferation.","evidence":"Two receptor-cloning strategies, co-IP, T-cell proliferation and Th differentiation assays","pmids":["29467366"],"confidence":"High","gaps":["Signaling effectors for the co-stimulatory output unmapped","How an ITIM receptor produces a stimulatory T-cell signal unexplained"]},{"year":2018,"claim":"Defined LILRB2 antagonism as a myeloid checkpoint strategy, showing blockade inhibits SHP1/2 and AKT/STAT6 and repolarizes macrophages from M2 toward inflammatory M1.","evidence":"Anti-LILRB2 antibody, phosphatase/AKT/STAT6 assays, RNA-seq, in vivo tumor models with checkpoint inhibitor combination","pmids":["30352428"],"confidence":"High","gaps":["Endogenous tumor ligand driving the signal not identified","Which downstream gene programs are directly versus indirectly affected unresolved"]},{"year":2018,"claim":"Provided structural and chemical proof of the Aβ binding site, mapping two hydrophobic pockets accommodating the KLVFFA motif and validating druggability with inhibitors that block Aβ–LilrB2 binding.","evidence":"Crystallography of D1D2 with small molecules, mutagenesis, Rosetta docking, cell-surface binding and cytotoxicity assays","pmids":["30297750"],"confidence":"High","gaps":["In vivo efficacy of inhibitors not demonstrated here","Selectivity against other LILRB family members untested"]},{"year":2021,"claim":"Established LILRB2 as a negative regulator of microglial TREM2 signaling, showing co-ligation by shared ligands suppresses phagocytosis and that antagonism restores plaque clearance.","evidence":"iPSC-derived human microglia assays, TREM2 signaling Western blot, antagonist antibody, microglia transplantation into 5XFAD mice","pmids":["35717259"],"confidence":"High","gaps":["Physical mechanism of LILRB2–TREM2 cross-regulation unresolved","Whether direct receptor–receptor contact occurs not shown"]},{"year":2021,"claim":"Distinguished cis- versus trans-engagement, showing ILT4 (unlike ILT2) inhibits via both modes and that dual ILT2/ILT4 blockade is needed for optimal myeloid activation.","evidence":"3D tumor spheroids, humanized mouse and human tumor explant models, cis/trans engagement experiments","pmids":["38393969"],"confidence":"Medium","gaps":["Molecular basis enabling cis engagement uncharacterized","Single-lab model systems; in vivo human relevance still indirect"]},{"year":2021,"claim":"Mapped tumor-cell-intrinsic LILRB2 signaling to ERK1/2-driven lipid metabolism that induces T-cell senescence, identifying a metabolic immune-evasion mechanism.","evidence":"Gain/loss-of-function, ERK1/2 Western blot, lipid droplet staining, T-cell senescence assays, breast cancer and melanoma mouse models","pmids":["33653799"],"confidence":"Medium","gaps":["Ligand driving tumor-intrinsic ERK activation unclear","Single lab; mechanism linking lipid accumulation to T-cell senescence indirect"]},{"year":2021,"claim":"Linked EGFR oncogenic signaling to ILT4 up-regulation, connecting tumor genetics to a myeloid checkpoint that recruits TAMs and suppresses T cells.","evidence":"Western blot, microarray, TCGA, functional T-cell and migration assays, humanized and syngeneic tumor models","pmids":["33537094"],"confidence":"Medium","gaps":["Direct transcriptional mechanism of ILT4 induction not fully resolved","Single lab; complex multi-arm study"]},{"year":2021,"claim":"Showed ANGPTL2/LILRB2 drives inflammatory cytokine production in synoviocytes via broad MAPK/NF-κB/Akt activation, extending the axis to joint inflammation.","evidence":"RT-PCR, MAPK/NF-κB/Akt Western blot, anti-LILRB2 blockade in fibroblast-like synoviocytes","pmids":["33538932"],"confidence":"Medium","gaps":["Direct binding in this system not biochemically confirmed","Single in vitro cell-line system"]},{"year":2015,"claim":"Demonstrated tumor-cell-intrinsic LILRB2 oncogenic signaling, with ANGPTL2 engagement driving proliferation through an SHP2/CaMK1/CREB axis in NSCLC.","evidence":"LILRB2 knockdown in NSCLC lines, proliferation/colony/migration assays, SHP2/CaMK1/CREB Western blot","pmids":["26056041"],"confidence":"Medium","gaps":["No in vivo validation in this study","Single lab"]},{"year":2018,"claim":"Reinforced the SHP2/CaMK1/CREB oncogenic axis in a second tumor type (endometrial cancer) with in vivo validation.","evidence":"LILRB2 knockdown, proliferation/colony/migration assays, xenografts, SHP2/CaMK1/CREB Western blot","pmids":["30343889"],"confidence":"Medium","gaps":["Ligand source in vivo undefined","Single lab"]},{"year":2016,"claim":"Identified an ILT4→STAT3→IDO axis by which HLA-G expands and arms granulocytic MDSCs, extending the receptor's immunosuppressive role to MDSC biology.","evidence":"Anti-ILT4 blockade, sHLA-G stimulation, STAT3 and IDO assays, MDSC induction and suppression assays","pmids":["27859042"],"confidence":"Medium","gaps":["Direct receptor proximal signaling steps to STAT3 unmapped","Single lab, blockade-based"]},{"year":2022,"claim":"Established ANGPTL8 as a LILRB2 ligand activating ERK in hepatic stellate cells to drive liver fibrosis, linking the receptor to metabolic liver disease.","evidence":"Co-IP, ANGPTL8 KO mice and BM chimeras, AAV8 restoration, RNA-seq, ERK Western blot","pmids":["36031141"],"confidence":"High","gaps":["Binding domain on LILRB2 for ANGPTL8 not mapped","Cell-type-specific effector wiring incompletely resolved"]},{"year":2023,"claim":"Showed PirB/LILRB2 on macrophages is an ANGPTL8 receptor mediating monocyte-derived macrophage recruitment to the liver in NASH, with ectodomain decoy as a therapeutic strategy.","evidence":"PirB KO mice, BM chimeras, AAV hepatocyte rescue, migration assays, direct binding/co-IP, human monocyte assays","pmids":["37481670"],"confidence":"High","gaps":["Proximal signaling driving migration not fully defined","Relationship to ITIM/SHP inhibitory output unclear"]},{"year":2024,"claim":"Extended tumor-intrinsic ERK1/2 signaling to angiogenesis, showing ANGPTL2/ILT4 increases VEGF-A/MMP-9 secretion correlating with microvessel density.","evidence":"ILT4 knockdown/overexpression, ANGPTL2 stimulation, ERK Western blot, ELISA, tube-formation, in vivo angiogenesis readout","pmids":["38433526"],"confidence":"Medium","gaps":["Single lab","Direct versus paracrine angiogenic contribution not separated"]},{"year":2024,"claim":"Linked ILT4 to glycolytic reprogramming via AKT-mTOR-driven GLUT3/PKM2 upregulation, promoting TNBC proliferation and metastasis.","evidence":"ILT4 knockdown/overexpression, AKT/mTOR Western blot, GLUT3/PKM2 analysis, in vivo growth and metastasis models","pmids":["37622462"],"confidence":"Medium","gaps":["Ligand triggering AKT/mTOR axis undefined","Single lab"]},{"year":2024,"claim":"Uncovered a direct MHC-I downregulation mechanism in which LILRB2 promotes MARCH9-mediated ubiquitination and degradation of HLA-A, enabling CD8 T-cell evasion.","evidence":"Western blot, IP, His-tag pulldown ubiquitination, syngeneic tumor model, flow cytometry","pmids":["38656573"],"confidence":"Medium","gaps":["How LILRB2 promotes MARCH9–HLA-A interaction mechanistically unclear","Single lab"]},{"year":2024,"claim":"Connected radiation-induced LILRB2 to JAK2/STAT3-driven senescence and SASP, identifying it as a radiosensitization target.","evidence":"Lentiviral silencing, irradiation, senescence markers, JAK2/STAT3 Western blot, in vivo tumor models","pmids":["38705566"],"confidence":"Medium","gaps":["Mechanism of radiation-induced LILRB2 upregulation undefined","Single lab"]},{"year":2025,"claim":"Defined a transcriptional and signaling circuit in LPS-tolerant macrophages where SPI1 activates LILRB2, which physically engages TLR8 to suppress MyD88/NF-κB signaling.","evidence":"Co-IP (LILRB2-TLR8), ChIP and dual-luciferase (SPI1), knockdown, NF-κB Western blot, polarization flow cytometry","pmids":["40551156"],"confidence":"Medium","gaps":["Whether LILRB2-TLR8 inhibition requires SHP recruitment untested","Single lab"]},{"year":2025,"claim":"Identified C4d as a physiological neuronal LilrB2 ligand mediating PirB-dependent synaptic pruning, integrating complement and the receptor in synapse elimination.","evidence":"Nanomolar binding, synaptic co-localization, in vivo dendritic spine imaging in WT vs PirB KO mice","pmids":["40966293"],"confidence":"High","gaps":["Downstream signaling from C4d engagement to spine loss unmapped","Human LILRB2 dependence inferred from murine PirB"]},{"year":null,"claim":"How a single ITIM-bearing receptor reconciles inhibitory (SHP1/2) output with activating signaling (ERK, AKT/mTOR, STAT3, co-stimulation) across cell types and ligand classes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking ligand class/geometry to inhibitory versus activating output","Binding sites for several ligands (ANGPTL8, C4d) not mapped onto the structure","Endogenous tumor ligands driving cell-intrinsic signaling largely unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[3,4,5,18]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,6,9,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,6,15]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[9,12,28]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,8,13]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,6,10,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,6,16,24,26]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[7,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,16,19,22,25]}],"complexes":[],"partners":["HLA-G","HLA-F","PTPN6","PTPN11","ANGPTL2","ANGPTL8","TREM2","TLR8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N423","full_name":"Leukocyte immunoglobulin-like receptor subfamily B member 2","aliases":["CD85 antigen-like family member D","Immunoglobulin-like transcript 4","ILT-4","Monocyte/macrophage immunoglobulin-like receptor 10","MIR-10"],"length_aa":597,"mass_kda":65.0,"function":"Receptor for class I MHC antigens. Recognizes a broad spectrum of HLA-A, HLA-B, HLA-C, HLA-G and HLA-F alleles (PubMed:11169396, PubMed:12853576, PubMed:16455647, PubMed:20448110, PubMed:27859042). Involved in the down-regulation of the immune response and the development of tolerance. Recognizes HLA-G in complex with B2M/beta-2 microglobulin and a nonamer self-peptide (peptide-bound HLA-G-B2M) triggering differentiation of type 1 regulatory T cells and myeloid-derived suppressor cells, both of which actively maintain maternal-fetal tolerance (PubMed:16455647, PubMed:20448110, PubMed:27859042). Competes with CD8A for binding to class I MHC antigens. Inhibits FCGR1A-mediated phosphorylation of cellular proteins and mobilization of intracellular calcium ions (PubMed:11875462, PubMed:12853576, PubMed:9548455, PubMed:9842885)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8N423/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LILRB2","classification":"Not Classified","n_dependent_lines":22,"n_total_lines":1208,"dependency_fraction":0.018211920529801324},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LILRB2","total_profiled":1310},"omim":[{"mim_id":"609336","title":"ANGIOPOIETIN-LIKE 6; ANGPTL6","url":"https://www.omim.org/entry/609336"},{"mim_id":"607666","title":"ANGIOPOIETIN-LIKE 5; ANGPTL5","url":"https://www.omim.org/entry/607666"},{"mim_id":"605910","title":"ANGIOPOIETIN-LIKE 4; ANGPTL4","url":"https://www.omim.org/entry/605910"},{"mim_id":"605001","title":"ANGIOPOIETIN-LIKE 2; ANGPTL2","url":"https://www.omim.org/entry/605001"},{"mim_id":"604821","title":"LEUKOCYTE IMMUNOGLOBULIN-LIKE RECEPTOR, SUBFAMILY B, MEMBER 4; LILRB4","url":"https://www.omim.org/entry/604821"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":33.1},{"tissue":"lung","ntpm":14.3},{"tissue":"lymphoid tissue","ntpm":48.8}],"url":"https://www.proteinatlas.org/search/LILRB2"},"hgnc":{"alias_symbol":["LIR-2","ILT4","MIR-10","LIR2","CD85d","MIR10"],"prev_symbol":[]},"alphafold":{"accession":"Q8N423","domains":[{"cath_id":"2.60.40.10","chopping":"31-118","consensus_level":"high","plddt":90.9162,"start":31,"end":118},{"cath_id":"2.60.40.10","chopping":"123-217","consensus_level":"high","plddt":85.7702,"start":123,"end":217},{"cath_id":"2.60.40.10","chopping":"224-318","consensus_level":"high","plddt":92.2532,"start":224,"end":318},{"cath_id":"2.60.40.10","chopping":"323-420","consensus_level":"high","plddt":94.1399,"start":323,"end":420}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N423","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N423-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N423-F1-predicted_aligned_error_v6.png","plddt_mean":75.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LILRB2","jax_strain_url":"https://www.jax.org/strain/search?query=LILRB2"},"sequence":{"accession":"Q8N423","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N423.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N423/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N423"}},"corpus_meta":[{"pmid":"11875462","id":"PMC_11875462","title":"Tolerization 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Coligation of LIR-2 with FcγRI (CD64) on monocytes inhibits tyrosine phosphorylation of the Fc receptor γ-chain and Syk, and blocks intracellular calcium mobilization, demonstrating that LILRB2 is an inhibitory receptor that down-modulates Fc receptor-mediated activation signals.\",\n      \"method\": \"Phosphorylation assays, SHP-1 binding assay, calcium mobilization assay, coligation experiments in primary monocytes\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct biochemical assays (phosphorylation, phosphatase recruitment, Ca2+ flux) with functional coligation readout in primary monocytes; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"9842885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The CD8+CD28− T suppressor cell interaction with dendritic cells up-regulates ILT4 (LILRB2) on monocytes/DCs, rendering these APCs tolerogenic with reduced costimulatory molecule expression and ability to induce antigen-specific T cell unresponsiveness in CD4+ T helper cells.\",\n      \"method\": \"Co-culture functional assays, flow cytometry, mixed lymphocyte reactions\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent functional assays including in vitro co-cultures and correlation with in vivo transplant tolerance; replicated in subsequent work by multiple labs\",\n      \"pmids\": [\"11875462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal structure of LIR-2 (LILRB2) D1D2 at 1.8 Å reveals that while the overall fold resembles LIR-1 (LILRB1) and KIR, the ligand-binding D1 domain differs from LIR-1 in the 44–57 helix region (shortened 3₁₀ helix) and the UL18-binding 76–84 loop is displaced 11 Å, explaining the >1000-fold lower affinity of LILRB2 for HCMV UL18 relative to LILRB1.\",\n      \"method\": \"X-ray crystallography (molecular replacement, 1.8 Å resolution)\",\n      \"journal\": \"BMC structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution crystal structure with direct structural comparison; single lab but Tier 1 method\",\n      \"pmids\": [\"12390682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Surface plasmon resonance shows that ILT4 (LILRB2) binds a broad range of classical HLA-A, -B, -C alleles as well as the non-classical HLA-G, with binding to HLA-G 3–4 fold higher affinity than to classical MHCIs; ILT4 binds all these MHCIs with 2–3 fold lower affinity than ILT2. ILT2 and ILT4 compete with CD8 for MHCI binding.\",\n      \"method\": \"Surface plasmon resonance (SPR) with soluble receptor and multiple MHCI ligands; CD8 competition assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — rigorous biophysical SPR measurements across multiple MHCI alleles; replicated and extended in subsequent structural and binding studies\",\n      \"pmids\": [\"12853576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"HLA-F tetramers bind monocytes and B cells via direct interaction with ILT4 (LILRB2) and ILT2; transfection of ILT4 confers HLA-F tetramer staining on non-binding cells, and SPR confirms direct molecular interaction between HLA-F and ILT4.\",\n      \"method\": \"Tetramer staining, transfection, surface plasmon resonance\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct SPR binding plus transfection gain-of-function; multiple orthogonal methods in one study\",\n      \"pmids\": [\"11169396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure at 2.5 Å of the LILRB2/HLA-G complex shows that LILRB2 dominantly contacts the hydrophobic site on the HLA-G α3 domain; NMR binding studies confirm that LILRB2 (unlike LILRB1) can recognize the β2m-free form of HLA-B27, establishing distinct β2m-dependent binding specificities between LILRB family members.\",\n      \"method\": \"X-ray crystallography (2.5 Å co-crystal structure), NMR binding studies, SPR with β2m-free MHCIs\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — co-crystal structure plus NMR and SPR validation; multiple orthogonal methods; highly cited and subsequently replicated\",\n      \"pmids\": [\"17056715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Ligation of ILT4 (LILRB2) by HLA-G1 on DCs results in recruitment of SHP-1 and SHP-2 phosphatases. SHP-2 and the downstream IL-6–STAT3 signaling pathway are required for ILT4-mediated arrest of DC maturation, reducing MHC class II, CD80, and CD86 expression. HLA-G5 dimer (but not monomer) and HLA-G1 tetramer both induce strong ILT4-mediated signaling.\",\n      \"method\": \"Co-immunoprecipitation of SHP-1/SHP-2, STAT3 activation assays, ILT4-transgenic mouse DCs, allograft survival experiments, signaling pathway inhibition\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — co-IP of phosphatases, in vivo transgenic model, pathway inhibition, multiple orthogonal methods in one study\",\n      \"pmids\": [\"18550825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Murine PirB and its human ortholog LilrB2 (LILRB2) are receptors for soluble Aβ oligomers with nanomolar affinity. The first two extracellular Ig domains of PirB/LilrB2 mediate Aβ binding. Aβ oligomer binding triggers enhanced cofilin signaling (cofilin dephosphorylation). In mice, the deleterious effect of Aβ oligomers on hippocampal long-term potentiation required PirB, and PirB contributed to memory deficits and loss of synaptic plasticity in juvenile visual cortex in transgenic AD mice.\",\n      \"method\": \"Binding assays (nanomolar Kd), domain deletion mapping, cofilin phosphorylation assays, LTP electrophysiology in PirB KO mice, transgenic AD mouse behavioral and plasticity assays\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods: direct binding with affinity measurement, genetic KO with LTP and behavioral readouts, biochemical cofilin signaling; highly cited landmark study\",\n      \"pmids\": [\"24052308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ILT4 (LILRB2) is expressed on primary human neutrophils, and its expression is induced during neutrophil differentiation. HLA-G (preferred ILT4 ligand) engagement of ILT4 inhibits phagocytosis; ILT4 co-localizes with CD32a (FcγRIIa) in lipid rafts and its engagement impairs reactive oxygen species production through CD32a. Inflammatory degranulation triggers rapid translocation of an intracellular ILT4 pool to the cell surface, amplifying HLA-G-mediated inhibition of phagocytosis.\",\n      \"method\": \"Flow cytometry, functional phagocytosis and ROS assays, lipid raft fractionation, co-localization microscopy, degranulation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays plus subcellular localization; co-localization in lipid rafts with FcγRIIa and direct functional consequence demonstrated\",\n      \"pmids\": [\"24133137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A novel motif in the first and fourth Ig domains of LILRB2 is necessary for binding and activation by Angptl2. Angptl2 expressed in mammalian cells forms high-molecular-weight multimers, and ligand multimerization is required for LILRB2 activation and downstream signaling. Angptl2 binding to LILRB2 is distinct from and does not completely overlap with HLA-G binding.\",\n      \"method\": \"Domain mutagenesis, co-immunoprecipitation, gel filtration for multimerization, functional signaling assays, ex vivo HSC expansion assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis identifying binding motif plus multimerization biochemistry and functional rescue; multiple orthogonal methods in one study\",\n      \"pmids\": [\"24899623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LILRB2 antagonism in tumor-associated myeloid cells inhibits receptor-mediated activation of SHP1/2 phosphatases and AKT/STAT6 signaling (in the presence of M-CSF and IL-4). Transcriptome analysis shows LILRB2 antagonism alters genes in cytoskeleton remodeling, lipid/cholesterol metabolism, and endosomal sorting, shifting myeloid differentiation from alternatively activated (M2) toward inflammatory (M1) phenotype.\",\n      \"method\": \"Anti-LILRB2 antibody antagonism, SHP1/2 phosphorylation assays, AKT/STAT6 activation assays, transcriptome (RNA-seq), in vivo tumor models with T cell checkpoint inhibitor combination\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical pathway assays plus transcriptomics plus in vivo tumor models; multiple orthogonal methods\",\n      \"pmids\": [\"30352428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of LilrB2 D1D2 complexed to small molecules mimicking phenylalanine identifies two hydrophobic pockets on LilrB2 that accommodate Aβ KLVFFA (residues 16–21) phenylalanine side chains. Mutagenesis confirmed these pockets as the KLVFFA binding site. Small molecule inhibitors designed to occupy these pockets block Aβ–LilrB2 interactions in vitro and on cell surfaces, and reduce Aβ cytotoxicity.\",\n      \"method\": \"X-ray crystallography of LilrB2 D1D2 with small molecule ligands, site-directed mutagenesis, Rosetta docking, in vitro binding inhibition assay, cell surface binding assay, cytotoxicity assay\",\n      \"journal\": \"Nature chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus cell-based functional validation; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"30297750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Human Semaphorin-4A (hSema4A) binds ILT-4 (LILRB2) on activated CD4+ T cells. This interaction co-stimulates CD4+ T cell proliferation and drives Th2 differentiation, identifying LILRB2 as a co-stimulatory receptor for hSema4A on T cells (distinct from the Th1-driving murine Sema4A/Tim-2 axis).\",\n      \"method\": \"Two independent receptor cloning strategies, co-immunoprecipitation, T cell proliferation and Th subset differentiation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent cloning strategies plus functional T cell assays confirming ILT4 as hSema4A receptor; multiple methods in one study\",\n      \"pmids\": [\"29467366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of the four Ig-like domain LILRB2 and four-domain LILRB1 in complex with HLA-G1 shows limited inter-domain flexibility. D1D2 mediates HLA-I binding while D3D4 acts as a structural scaffold. The geometry of LILRB1/2 complexes with dimeric HLA-G1 suggests dimeric receptor accessibility transduces stronger inhibitory signals.\",\n      \"method\": \"X-ray crystallography of full four-domain LILRB2 and LILRB1–HLA-G1 complex\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution crystal structures of full-length ectodomain with ligand; single lab but Tier 1 method\",\n      \"pmids\": [\"31273318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Induction of Tr1 regulatory T cells by tolerogenic DC-10 requires an IL-10-dependent ILT4/HLA-G signaling pathway. Blocking ILT4 or HLA-G prevented Tr1 cell differentiation, placing ILT4–HLA-G engagement as a required upstream signal in IL-10-driven Tr1 induction.\",\n      \"method\": \"Blocking antibody experiments, co-culture assays, flow cytometry for Tr1 cell markers, cytokine measurements\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blockade with antibodies plus defined cellular readout; single lab, multiple orthogonal assays\",\n      \"pmids\": [\"20448110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LILRB2 (ILT4) on myeloid cells recruits SHP1/2 as its canonical downstream effectors. When co-ligated with TREM2 by shared ligands (Aβ oligomers or phosphatidylserine), LILRB2 suppresses TREM2 signaling in microglia, reducing phagocytosis, migration, and cytokine responses. An antagonistic anti-LILRB2 antibody (Ab29) relieves this inhibition in human iPSC-derived microglia and increases microglial plaque phagocytosis in 5XFAD mice.\",\n      \"method\": \"iPSC-derived human microglia functional assays (phagocytosis, migration, cytokines), TREM2 signaling (Western blot), antagonistic antibody (Ab29), stereotaxic microglia transplantation into 5XFAD mice, immunofluorescence\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including human iPSC microglia, signaling biochemistry, and in vivo mouse model; single lab but comprehensive mechanistic dissection\",\n      \"pmids\": [\"35717259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LILRB2 is expressed on non-small cell lung cancer (NSCLC) cells. ANGPTL2 binds LILRB2 to support lung cancer cell growth; LILRB2 knockdown reduces proliferation, colony formation, and migration. The SHP2/CaMK1/CREB signaling axis mediates ANGPTL2/LILRB2-driven lung cancer cell proliferation.\",\n      \"method\": \"LILRB2 knockdown in NSCLC cell lines, proliferation/colony/migration assays, signaling pathway analysis (SHP2/CaMK1/CREB Western blot)\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple cellular readouts plus pathway analysis; single lab, replicated downstream finding with endometrial cancer paper\",\n      \"pmids\": [\"26056041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LILRB2 in endometrial cancer cells activates SHP2/CaMK1/CREB signaling pathways to support cancer cell expansion and migration. LILRB2 knockdown decreases proliferation and colony formation in vitro and reduces xenograft tumor growth in vivo.\",\n      \"method\": \"LILRB2 knockdown in endometrial cancer cell lines, proliferation/colony/migration assays, in vivo xenograft, Western blot for SHP2/CaMK1/CREB\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in vitro and in vivo with defined signaling pathway; single lab\",\n      \"pmids\": [\"30343889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"P. falciparum RIFIN proteins on infected erythrocytes are novel ligands for LILRB2. Domain mapping shows that domains 3 (D3) of LILRB2 mediates RIFIN binding, whereas domains 1 and 2 (D1D2) mediate binding to HLA class I, indicating distinct binding sites for pathogen vs. host ligands on the same receptor.\",\n      \"method\": \"RIFIN expression library screening, direct binding assays, LILRB2 domain-deletion mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic domain-deletion mapping with a newly developed expression library; single lab, multiple domains tested\",\n      \"pmids\": [\"33647792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ANGPTL8 interacts with LILRB2 to activate ERK signaling in hepatic stellate cells (HSCs), promoting expression of fibrosis-related genes and accelerating liver fibrosis in HFD-induced NAFLD. Co-IP confirmed the ANGPTL8–LILRB2 physical interaction; liver-specific ANGPTL8 knockout or PirB ectodomain protein (sequestering ANGPTL8) reduced fibrosis in mice.\",\n      \"method\": \"Co-immunoprecipitation (ANGPTL8–LILRB2), ANGPTL8 KO mice and bone marrow chimeras, AAV8 liver restoration, RNA-seq, ERK signaling Western blot\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — co-IP confirming physical interaction plus in vivo genetic models and signaling biochemistry; multiple orthogonal methods\",\n      \"pmids\": [\"36031141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tumor cell-derived ILT4 (LILRB2/PIR-B) activates MAPK ERK1/2 signaling to increase fatty acid synthesis and lipid accumulation in tumor cells, which in turn induces senescence in naïve/effector T cells. This mechanism was established by gain- and loss-of-function in vitro and validated in breast cancer and melanoma mouse models.\",\n      \"method\": \"ILT4/PIR-B gain- and loss-of-function, MAPK ERK1/2 Western blot, lipid droplet staining, T cell senescence assays, in vivo mouse tumor models\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined signaling pathway (ERK1/2-fatty acid synthesis-T cell senescence) supported by in vitro and in vivo data; single lab\",\n      \"pmids\": [\"33653799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EGFR activation (via mutation or EGF-dependent phosphorylation) up-regulates ILT4 expression in NSCLC tumor cells through AKT and ERK1/2 phosphorylation. Tumor cell-expressed ILT4 induces TAM recruitment and M2-like polarization and directly inhibits T cell proliferation, cytotoxicity, and IFN-γ secretion.\",\n      \"method\": \"Western blotting, mRNA microarray, TCGA analysis, CCK8/apoptosis/CFSE assays, Transwell migration, ELISA, in vivo humanized NSG and C57BL/6 tumor models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — signaling pathway validated by multiple methods in vitro plus in vivo models; single lab, comprehensive but complex study\",\n      \"pmids\": [\"33537094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PirB/LILRB2 on macrophages acts as a receptor for ANGPTL8 to mediate macrophage migration to the liver during NASH. PirB-/- bone marrow chimeras abolish ANGPTL8-induced monocyte-derived macrophage (MDM) migration. The PirB ectodomain protein sequesters ANGPTL8 and ameliorates NASH. Direct LILRB2–ANGPTL8 binding promotes MDM migration and inflammatory activation in human peripheral blood monocytes.\",\n      \"method\": \"PirB knockout mice, bone marrow chimeras, AAV hepatocyte-specific rescue, in vitro migration assays with anti-LILRB2, direct binding and co-IP, human monocyte functional assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with BM chimera distinguishing cell-intrinsic effect, direct binding, and human monocyte validation; multiple orthogonal methods\",\n      \"pmids\": [\"37481670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ILT4 in NSCLC tumor cells activates ERK1/2 signaling downstream of ANGPTL2 binding to increase secretion of VEGF-A and MMP-9, thereby promoting tumor angiogenesis in vitro and in vivo. ILT4 expression was positively correlated with microvessel density in patient samples.\",\n      \"method\": \"ILT4 knockdown/overexpression, ANGPTL2 stimulation, ERK1/2 Western blot, VEGF-A/MMP-9 ELISA, tube formation assay, in vivo tumor models with angiogenesis readout\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined signaling axis (ANGPTL2→ILT4→ERK1/2→VEGF-A/MMP-9) supported by in vitro and in vivo data; single lab\",\n      \"pmids\": [\"38433526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ILT4 in triple-negative breast cancer cells activates AKT–mTOR signaling to up-regulate GLUT3 and PKM2, reprogramming tumor cell aerobic glycolysis and promoting proliferation, migration, invasion, and metastasis.\",\n      \"method\": \"ILT4 knockdown/overexpression in TNBC cell lines, AKT/mTOR pathway Western blot, GLUT3/PKM2 expression analysis, in vivo tumor growth and metastasis models\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined signaling pathway with in vitro and in vivo validation; single lab\",\n      \"pmids\": [\"37622462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LILRB2 in breast cancer cells facilitates ubiquitination and proteasomal degradation of HLA-A by promoting the interaction between the E3 ubiquitin ligase MARCH9 and HLA-A, thereby reducing surface MHC-I and enabling CD8+ T cell evasion.\",\n      \"method\": \"Western blot, immunoprecipitation, histidine-tag pulldown ubiquitination assay, syngeneic mouse tumor model, flow cytometry\",\n      \"journal\": \"Cellular oncology (Dordrecht, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ubiquitination biochemistry plus MARCH9–HLA-A co-IP plus in vivo immune evasion model; single lab\",\n      \"pmids\": [\"38656573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LILRB2 inhibition in NSCLC attenuates radiation-induced cellular senescence and the SASP by suppressing the JAK2/STAT3 signaling pathway, thereby increasing radiosensitivity. Radiation up-regulates LILRB2, which normally promotes senescence and tumor cell proliferation via JAK2/STAT3.\",\n      \"method\": \"Lentiviral LILRB2 silencing, irradiation assays, senescence markers (SA-β-gal, p21, p16), JAK2/STAT3 Western blot, in vivo tumor models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with pathway validation in vitro and in vivo; single lab\",\n      \"pmids\": [\"38705566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SPI1 transcription factor transcriptionally activates LILRB2 expression in LPS-tolerant macrophages (confirmed by ChIP and dual-luciferase assays). LILRB2 physically interacts with TLR8 (co-IP) to suppress TLR8-mediated MyD88/NF-κB signaling and inhibit p65 nuclear translocation, establishing an immunosuppressive phenotype.\",\n      \"method\": \"Co-immunoprecipitation (LILRB2–TLR8 interaction), ChIP assay (SPI1 binding to LILRB2 promoter), dual-luciferase reporter assay, LILRB2 knockdown, NF-κB signaling Western blot, flow cytometry for macrophage polarization\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, and functional signaling assays; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"40551156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"C4d (a cleavage product of complement C4) binds LilrB2/PirB with nanomolar affinity and colocalizes with LilrB2 at excitatory synapses in human cerebral cortex. In mice, C4d exposure reduces dendritic spine density on L5 pyramidal neurons in a PirB-dependent manner (PirB KO completely prevents spine loss), establishing C4d as a physiological LilrB2 ligand mediating synapse pruning.\",\n      \"method\": \"Direct binding assays (nanomolar Kd), co-localization by immunofluorescence, in vivo dendritic spine imaging in WT vs. PirB KO mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding affinity measurement plus in vivo genetic KO with quantitative spine readout; multiple orthogonal methods in one study\",\n      \"pmids\": [\"40966293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HLA-G engagement of ILT4 on granulocytic MDSCs promotes MDSC accumulation (induction from PBMCs) and suppressive activity, induces STAT3 phosphorylation, and up-regulates IDO expression. Effects on MDSC accumulation were blocked by anti-ILT4 antibody, identifying ILT4→STAT3→IDO as a signaling axis in HLA-G-driven MDSC biology.\",\n      \"method\": \"Anti-ILT4 blocking antibody, sHLA-G stimulation, STAT3 phosphorylation Western blot/flow cytometry, IDO expression assay, MDSC induction and T cell suppression assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor blocking with downstream signaling readouts; single lab, multiple assays\",\n      \"pmids\": [\"27859042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANGPTL2 induces expression of inflammatory cytokines in human fibroblast-like synoviocytes (HFLS) via LILRB2, and pre-treatment with anti-LILRB2 antibody reduces this inflammatory gene expression and blocks ANGPTL2-induced phosphorylation of ERK, p38, JNK, NF-κB, and Akt.\",\n      \"method\": \"Real-time RT-PCR, Western blotting for MAPK/NF-κB/Akt phosphorylation, anti-LILRB2 antibody blocking in HFLS\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor blocking with multiple downstream signaling readouts; single lab, in vitro cell line system\",\n      \"pmids\": [\"33538932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ILT4 inhibits myeloid cells via both cis- (same-cell) and trans-engagement (cell-cell contact) with MHC-I ligands, whereas ILT2 only inhibits via trans-engagement. Dual ILT2/ILT4 blockade is required for optimal myeloid cell activation in 3D tumor spheroid models, and combined blockade enhances cytolytic T cell activity and generates immune niches in humanized mouse and human tumor explant systems.\",\n      \"method\": \"3D spheroid tumor model, myeloid cell functional assays (CXCL9/CCL5 secretion, CD86/CD163 expression), humanized mouse tumor models, human tumor explant histoculture, cis vs. trans engagement experiments\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple model systems (3D spheroid, humanized mice, human explants) distinguishing cis vs. trans engagement; single lab but orthogonal systems\",\n      \"pmids\": [\"38393969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-10 up-regulates cell-surface LIR-2 (LILRB2) on maturing human DCs. LPS-stimulated LIR-2-transfected DCs inhibit autologous and allogeneic T cell proliferation. A novel soluble form of LIR-2 was detected in DC culture supernatants; IL-10 inhibits soluble LIR-2 production, and recombinant soluble LIR-2 restores T cell proliferation inhibited by LPS+IL-10-treated DCs.\",\n      \"method\": \"Retroviral expression cloning, flow cytometry, MLR assays, detection of soluble LIR-2 by ELISA/Western, recombinant soluble LIR-2 reconstitution\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — retroviral overexpression, functional T cell assays, and soluble form characterization; single lab, multiple methods\",\n      \"pmids\": [\"14971032\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LILRB2 is an ITIM-bearing inhibitory receptor expressed on myeloid cells (monocytes, DCs, macrophages, neutrophils, MDSCs) and on certain tumor and neuronal cells that, upon ligand engagement, recruits SHP-1 and SHP-2 phosphatases to suppress activating signals; it binds classical and non-classical MHC-I molecules (with highest affinity for HLA-G via its α3 domain, as resolved by co-crystal structures), as well as diverse ligands including Aβ oligomers, C4d complement fragment, ANGPTLs (2 and 8), Semaphorin-4A, HLA-F, and P. falciparum RIFIN—each with distinct domain requirements—and signals through context-dependent downstream effectors (SHP2/CaMK1/CREB, ERK1/2, AKT/mTOR, IL-6/STAT3, JAK2/STAT3) to regulate DC tolerogenicity, myeloid cell polarization, neutrophil function, microglial phagocytosis via TREM2 co-ligation, tumor cell metabolism and immune evasion, and synaptic plasticity/pruning in the brain.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LILRB2 (ILT4/LIR-2; murine ortholog PirB) is an ITIM-bearing inhibitory receptor of myeloid cells that, upon ligand engagement and cytoplasmic-tail phosphorylation, recruits the tyrosine phosphatases SHP-1 and SHP-2 to dampen activating signals, as first established by its coligation with FcγRI to block γ-chain/Syk phosphorylation and calcium flux in monocytes [#0, #6]. Its ectodomain binds a broad spectrum of classical (HLA-A, -B, -C) and non-classical MHC-I molecules with highest affinity for HLA-G, and co-crystal structures show that the membrane-distal D1D2 domains dominantly contact the hydrophobic α3 site of HLA-G while D3D4 act as a structural scaffold; LILRB2 uniquely recognizes β2m-free MHC-I forms [#3, #5, #13]. This receptor enforces immune tolerance: ligation by HLA-G arrests dendritic-cell maturation through an SHP-2/IL-6/STAT3 axis, drives tolerogenic APC programs and Tr1/T-suppressor responses, and promotes MDSC accumulation and IDO expression via STAT3 [#6, #1, #14, #29]. Beyond MHC-I, LILRB2 engages structurally distinct ligands through separable binding sites — Aβ oligomers and C4d at synapses, ANGPTL2/ANGPTL8 via a motif in D1 and D4, Semaphorin-4A on T cells, and P. falciparum RIFIN via D3 — coupling to context-dependent effectors [#7, #28, #9, #12, #18]. In the brain, Aβ-oligomer binding to PirB/LILRB2 enhances cofilin signaling and mediates loss of synaptic plasticity, while C4d engagement drives PirB-dependent dendritic spine pruning, and LILRB2 suppresses TREM2-mediated microglial phagocytosis upon co-ligation by shared ligands [#7, #28, #15]. In tumors and inflammatory tissue, LILRB2/ANGPTL signaling activates SHP2/CaMK1/CREB, ERK1/2, AKT/mTOR, and JAK2/STAT3 cascades to promote myeloid M2 polarization, tumor proliferation, glycolytic reprogramming, angiogenesis, senescence, and immune evasion — the latter in part by promoting MARCH9-dependent ubiquitination of HLA-A [#10, #16, #24, #23, #26, #25].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established LILRB2 as a bona fide inhibitory receptor: it was unknown whether MHC-I binding had a signaling consequence, and coligation experiments showed it recruits SHP-1 and shuts down activating Fc-receptor signaling.\",\n      \"evidence\": \"Phosphorylation, SHP-1 binding, and calcium-flux assays with FcγRI coligation in primary monocytes\",\n      \"pmids\": [\"9842885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which MHC-I alleles bind with what affinity\", \"SHP-2 contribution not yet distinguished from SHP-1\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected LILRB2 to immune tolerance by showing T-suppressor/DC interactions up-regulate it on APCs to render them tolerogenic, framing it as an effector of antigen-specific unresponsiveness.\",\n      \"evidence\": \"Co-culture, MLR, and flow cytometry with CD8+CD28- suppressor cells and DCs\",\n      \"pmids\": [\"11875462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand driving tolerogenic signaling not pinpointed\", \"Downstream signaling pathway in DCs undefined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the structural basis for LILRB2 ligand discrimination, explaining its >1000-fold lower affinity for HCMV UL18 versus LILRB1 through D1 helix and loop differences.\",\n      \"evidence\": \"1.8 Å X-ray crystal structure of LILRB2 D1D2 with comparison to LIR-1/KIR\",\n      \"pmids\": [\"12390682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No bound MHC-I in this structure\", \"Functional consequence of fold differences not tested\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified HLA-F as a direct LILRB2 ligand, broadening the receptor's MHC-I repertoire beyond classical molecules.\",\n      \"evidence\": \"HLA-F tetramer staining, ILT4 transfection gain-of-function, and SPR\",\n      \"pmids\": [\"11169396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling output of HLA-F engagement not measured\", \"Physiological context of HLA-F/ILT4 axis unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Quantified LILRB2's MHC-I binding hierarchy, showing broad classical HLA binding with preferential HLA-G affinity and competition with CD8.\",\n      \"evidence\": \"Surface plasmon resonance across multiple HLA alleles plus CD8 competition assay\",\n      \"pmids\": [\"12853576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinities are with soluble monomeric reagents, not cell-surface avidity\", \"Functional threshold for inhibition not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Pinpointed the HLA-G α3 hydrophobic site as the dominant LILRB2 contact and showed LILRB2 (unlike LILRB1) recognizes β2m-free MHC-I, defining intra-family specificity.\",\n      \"evidence\": \"2.5 Å LILRB2/HLA-G co-crystal structure, NMR, and SPR with β2m-free MHC-I\",\n      \"pmids\": [\"17056715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biological role of β2m-free MHC-I recognition not established\", \"Avidity contribution of dimeric/tetrameric HLA-G not yet resolved structurally\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved how the full four-domain ectodomain functions, showing D1D2 binds HLA-I while D3D4 act as a rigid scaffold and dimeric HLA-G geometry transduces stronger inhibition.\",\n      \"evidence\": \"X-ray crystallography of full four-domain LILRB2 and LILRB1 in complex with HLA-G1\",\n      \"pmids\": [\"31273318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell clustering/oligomerization not directly imaged\", \"Quantitative link between geometry and ITIM phosphorylation unmeasured\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the tolerogenic signaling mechanism, showing HLA-G ligation recruits SHP-1/SHP-2 and engages an SHP-2/IL-6/STAT3 pathway required to arrest DC maturation.\",\n      \"evidence\": \"Co-IP of phosphatases, STAT3 assays, ILT4-transgenic mouse DCs, allograft survival, pathway inhibition\",\n      \"pmids\": [\"18550825\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How an inhibitory receptor activates STAT3 mechanistically not fully reconciled\", \"Generalizability beyond DCs untested at the time\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed ILT4/HLA-G engagement upstream of IL-10-driven regulatory T-cell induction, extending the tolerance circuit to Tr1 differentiation.\",\n      \"evidence\": \"Blocking antibodies, DC-10 co-culture, flow cytometry, cytokine measurement\",\n      \"pmids\": [\"20448110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Antibody blockade only; no genetic loss-of-function\", \"Direct receptor signaling steps in Tr1 induction undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovered a neuronal function: PirB/LILRB2 is a high-affinity Aβ-oligomer receptor whose engagement enhances cofilin signaling and mediates synaptic plasticity loss.\",\n      \"evidence\": \"Nanomolar binding, domain mapping, cofilin assays, LTP electrophysiology in PirB KO and AD transgenic mice\",\n      \"pmids\": [\"24052308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase coupling for cofilin pathway not fully mapped\", \"Translation from murine PirB to human LILRB2 in brain incomplete\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed ILT4 regulates neutrophil effector functions, inhibiting phagocytosis and ROS through lipid-raft association with FcγRIIa, with a mobilizable intracellular receptor pool.\",\n      \"evidence\": \"Phagocytosis/ROS assays, lipid-raft fractionation, co-localization microscopy, degranulation assays in primary neutrophils\",\n      \"pmids\": [\"24133137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of FcγRIIa co-localization unresolved\", \"Trafficking machinery for the intracellular pool unidentified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified ANGPTL2 as a non-MHC ligand requiring multimerization and a distinct D1/D4 motif, demonstrating ligand-class-specific binding modes on LILRB2.\",\n      \"evidence\": \"Domain mutagenesis, co-IP, gel filtration, signaling and HSC expansion assays\",\n      \"pmids\": [\"24899623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of multimeric ANGPTL2/receptor clusters undefined\", \"Whether ANGPTL2 triggers inhibitory or activating output context-dependent\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Added Semaphorin-4A as a co-stimulatory ligand on T cells, showing LILRB2 is not exclusively inhibitory but can drive Th2-skewed CD4 T-cell proliferation.\",\n      \"evidence\": \"Two receptor-cloning strategies, co-IP, T-cell proliferation and Th differentiation assays\",\n      \"pmids\": [\"29467366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling effectors for the co-stimulatory output unmapped\", \"How an ITIM receptor produces a stimulatory T-cell signal unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined LILRB2 antagonism as a myeloid checkpoint strategy, showing blockade inhibits SHP1/2 and AKT/STAT6 and repolarizes macrophages from M2 toward inflammatory M1.\",\n      \"evidence\": \"Anti-LILRB2 antibody, phosphatase/AKT/STAT6 assays, RNA-seq, in vivo tumor models with checkpoint inhibitor combination\",\n      \"pmids\": [\"30352428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous tumor ligand driving the signal not identified\", \"Which downstream gene programs are directly versus indirectly affected unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided structural and chemical proof of the Aβ binding site, mapping two hydrophobic pockets accommodating the KLVFFA motif and validating druggability with inhibitors that block Aβ–LilrB2 binding.\",\n      \"evidence\": \"Crystallography of D1D2 with small molecules, mutagenesis, Rosetta docking, cell-surface binding and cytotoxicity assays\",\n      \"pmids\": [\"30297750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo efficacy of inhibitors not demonstrated here\", \"Selectivity against other LILRB family members untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established LILRB2 as a negative regulator of microglial TREM2 signaling, showing co-ligation by shared ligands suppresses phagocytosis and that antagonism restores plaque clearance.\",\n      \"evidence\": \"iPSC-derived human microglia assays, TREM2 signaling Western blot, antagonist antibody, microglia transplantation into 5XFAD mice\",\n      \"pmids\": [\"35717259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physical mechanism of LILRB2–TREM2 cross-regulation unresolved\", \"Whether direct receptor–receptor contact occurs not shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Distinguished cis- versus trans-engagement, showing ILT4 (unlike ILT2) inhibits via both modes and that dual ILT2/ILT4 blockade is needed for optimal myeloid activation.\",\n      \"evidence\": \"3D tumor spheroids, humanized mouse and human tumor explant models, cis/trans engagement experiments\",\n      \"pmids\": [\"38393969\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis enabling cis engagement uncharacterized\", \"Single-lab model systems; in vivo human relevance still indirect\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped tumor-cell-intrinsic LILRB2 signaling to ERK1/2-driven lipid metabolism that induces T-cell senescence, identifying a metabolic immune-evasion mechanism.\",\n      \"evidence\": \"Gain/loss-of-function, ERK1/2 Western blot, lipid droplet staining, T-cell senescence assays, breast cancer and melanoma mouse models\",\n      \"pmids\": [\"33653799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand driving tumor-intrinsic ERK activation unclear\", \"Single lab; mechanism linking lipid accumulation to T-cell senescence indirect\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked EGFR oncogenic signaling to ILT4 up-regulation, connecting tumor genetics to a myeloid checkpoint that recruits TAMs and suppresses T cells.\",\n      \"evidence\": \"Western blot, microarray, TCGA, functional T-cell and migration assays, humanized and syngeneic tumor models\",\n      \"pmids\": [\"33537094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional mechanism of ILT4 induction not fully resolved\", \"Single lab; complex multi-arm study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed ANGPTL2/LILRB2 drives inflammatory cytokine production in synoviocytes via broad MAPK/NF-κB/Akt activation, extending the axis to joint inflammation.\",\n      \"evidence\": \"RT-PCR, MAPK/NF-κB/Akt Western blot, anti-LILRB2 blockade in fibroblast-like synoviocytes\",\n      \"pmids\": [\"33538932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding in this system not biochemically confirmed\", \"Single in vitro cell-line system\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated tumor-cell-intrinsic LILRB2 oncogenic signaling, with ANGPTL2 engagement driving proliferation through an SHP2/CaMK1/CREB axis in NSCLC.\",\n      \"evidence\": \"LILRB2 knockdown in NSCLC lines, proliferation/colony/migration assays, SHP2/CaMK1/CREB Western blot\",\n      \"pmids\": [\"26056041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo validation in this study\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Reinforced the SHP2/CaMK1/CREB oncogenic axis in a second tumor type (endometrial cancer) with in vivo validation.\",\n      \"evidence\": \"LILRB2 knockdown, proliferation/colony/migration assays, xenografts, SHP2/CaMK1/CREB Western blot\",\n      \"pmids\": [\"30343889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand source in vivo undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified an ILT4→STAT3→IDO axis by which HLA-G expands and arms granulocytic MDSCs, extending the receptor's immunosuppressive role to MDSC biology.\",\n      \"evidence\": \"Anti-ILT4 blockade, sHLA-G stimulation, STAT3 and IDO assays, MDSC induction and suppression assays\",\n      \"pmids\": [\"27859042\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor proximal signaling steps to STAT3 unmapped\", \"Single lab, blockade-based\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established ANGPTL8 as a LILRB2 ligand activating ERK in hepatic stellate cells to drive liver fibrosis, linking the receptor to metabolic liver disease.\",\n      \"evidence\": \"Co-IP, ANGPTL8 KO mice and BM chimeras, AAV8 restoration, RNA-seq, ERK Western blot\",\n      \"pmids\": [\"36031141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding domain on LILRB2 for ANGPTL8 not mapped\", \"Cell-type-specific effector wiring incompletely resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed PirB/LILRB2 on macrophages is an ANGPTL8 receptor mediating monocyte-derived macrophage recruitment to the liver in NASH, with ectodomain decoy as a therapeutic strategy.\",\n      \"evidence\": \"PirB KO mice, BM chimeras, AAV hepatocyte rescue, migration assays, direct binding/co-IP, human monocyte assays\",\n      \"pmids\": [\"37481670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Proximal signaling driving migration not fully defined\", \"Relationship to ITIM/SHP inhibitory output unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended tumor-intrinsic ERK1/2 signaling to angiogenesis, showing ANGPTL2/ILT4 increases VEGF-A/MMP-9 secretion correlating with microvessel density.\",\n      \"evidence\": \"ILT4 knockdown/overexpression, ANGPTL2 stimulation, ERK Western blot, ELISA, tube-formation, in vivo angiogenesis readout\",\n      \"pmids\": [\"38433526\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct versus paracrine angiogenic contribution not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked ILT4 to glycolytic reprogramming via AKT-mTOR-driven GLUT3/PKM2 upregulation, promoting TNBC proliferation and metastasis.\",\n      \"evidence\": \"ILT4 knockdown/overexpression, AKT/mTOR Western blot, GLUT3/PKM2 analysis, in vivo growth and metastasis models\",\n      \"pmids\": [\"37622462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand triggering AKT/mTOR axis undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovered a direct MHC-I downregulation mechanism in which LILRB2 promotes MARCH9-mediated ubiquitination and degradation of HLA-A, enabling CD8 T-cell evasion.\",\n      \"evidence\": \"Western blot, IP, His-tag pulldown ubiquitination, syngeneic tumor model, flow cytometry\",\n      \"pmids\": [\"38656573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How LILRB2 promotes MARCH9–HLA-A interaction mechanistically unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected radiation-induced LILRB2 to JAK2/STAT3-driven senescence and SASP, identifying it as a radiosensitization target.\",\n      \"evidence\": \"Lentiviral silencing, irradiation, senescence markers, JAK2/STAT3 Western blot, in vivo tumor models\",\n      \"pmids\": [\"38705566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of radiation-induced LILRB2 upregulation undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a transcriptional and signaling circuit in LPS-tolerant macrophages where SPI1 activates LILRB2, which physically engages TLR8 to suppress MyD88/NF-κB signaling.\",\n      \"evidence\": \"Co-IP (LILRB2-TLR8), ChIP and dual-luciferase (SPI1), knockdown, NF-κB Western blot, polarization flow cytometry\",\n      \"pmids\": [\"40551156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether LILRB2-TLR8 inhibition requires SHP recruitment untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified C4d as a physiological neuronal LilrB2 ligand mediating PirB-dependent synaptic pruning, integrating complement and the receptor in synapse elimination.\",\n      \"evidence\": \"Nanomolar binding, synaptic co-localization, in vivo dendritic spine imaging in WT vs PirB KO mice\",\n      \"pmids\": [\"40966293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling from C4d engagement to spine loss unmapped\", \"Human LILRB2 dependence inferred from murine PirB\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single ITIM-bearing receptor reconciles inhibitory (SHP1/2) output with activating signaling (ERK, AKT/mTOR, STAT3, co-stimulation) across cell types and ligand classes remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking ligand class/geometry to inhibitory versus activating output\", \"Binding sites for several ligands (ANGPTL8, C4d) not mapped onto the structure\", \"Endogenous tumor ligands driving cell-intrinsic signaling largely unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [3, 4, 5, 18]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 6, 9, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 6, 15]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [9, 12, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 8, 13]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 6, 10, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6, 16, 24, 26]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [7, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 16, 19, 22, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"HLA-G\",\n      \"HLA-F\",\n      \"PTPN6\",\n      \"PTPN11\",\n      \"ANGPTL2\",\n      \"ANGPTL8\",\n      \"TREM2\",\n      \"TLR8\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}