{"gene":"LILRB2","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1998,"finding":"LILRB2 (LIR-2) recruits the tyrosine phosphatase SHP-1 upon phosphorylation, and co-ligation of LILRB2 with FcγRI (CD64) inhibits tyrosine phosphorylation of the Fc receptor γ-chain and Syk, as well as intracellular calcium mobilization in monocytes, demonstrating that LILRB2 inhibits Fc receptor-mediated signaling.","method":"Phosphorylation assays, co-ligation experiments, calcium mobilization assays in monocytes","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 — direct biochemical assay with multiple functional readouts (SHP-1 recruitment, Syk phosphorylation, calcium flux) in primary cells","pmids":["9842885"],"is_preprint":false},{"year":2002,"finding":"CD8+CD28− T suppressor cells induce upregulation of LILRB2 (ILT4) on monocytes and dendritic cells, rendering these APCs tolerogenic with reduced costimulatory molecule expression and ability to induce antigen-specific T helper cell unresponsiveness.","method":"Co-culture experiments, flow cytometry, mixed lymphocyte reactions, functional tolerance assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional assays, replicated in transplant patient samples; highly cited foundational study","pmids":["11875462"],"is_preprint":false},{"year":2002,"finding":"Crystal structure of LIR-2 (LILRB2) D1D2 at 1.8 Å resolution revealed structural differences from LIR-1 in the ligand-binding domain, including a distinct 310 helix replacing the residue 44–57 helix and an 11 Å displacement of the 76–84 loop, explaining the >1000-fold lower affinity of LILRB2 for the CMV MHC homolog UL18 compared to LILRB1.","method":"X-ray crystallography at 1.8 Å, molecular replacement","journal":"BMC structural biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with direct structural-functional interpretation","pmids":["12390682"],"is_preprint":false},{"year":2003,"finding":"Surface plasmon resonance showed LILRB2 (ILT4) binds a broad range of classical and non-classical MHC class I molecules with Kd values of 2–45 μM, binds HLA-G with 3- to 4-fold higher affinity than classical MHCIs, and competes with CD8 for MHC class I binding.","method":"Surface plasmon resonance (SPR) with soluble recombinant proteins","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro binding kinetics with recombinant proteins, quantitative affinity measurements for multiple ligands","pmids":["12853576"],"is_preprint":false},{"year":2000,"finding":"HLA-F tetramers bind ILT4 (LILRB2), and surface plasmon resonance confirmed a direct molecular interaction between HLA-F and ILT4; transfection of ILT4 conferred HLA-F tetramer binding on non-binding cells.","method":"Tetramer staining, transfection, surface plasmon resonance","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding assay (SPR) plus functional reconstitution by transfection","pmids":["11169396"],"is_preprint":false},{"year":2006,"finding":"Crystal structure at 2.5 Å of LILRB2 in complex with HLA-G revealed that LILRB2 dominantly recognizes the hydrophobic site of the HLA-G α3 domain, and can recognize the β2m-free form of HLA-B27 unlike LILRB1, explaining differential binding specificities among LILR family members.","method":"X-ray crystallography at 2.5 Å, NMR binding studies, SPR binding experiments with β2m-free MHC forms","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — crystal structure of receptor-ligand complex with NMR validation and binding specificity experiments","pmids":["17056715"],"is_preprint":false},{"year":2008,"finding":"Ligation of LILRB2 (ILT4) by HLA-G on dendritic cells results in recruitment of SHP-1 and SHP-2 protein tyrosine phosphatases, and engagement of ILT4 by HLA-G1 tetramers or HLA-G5 dimers (but not HLA-G5 monomers) induces strong ILT-mediated signaling involving the IL-6–STAT3 pathway, arresting DC maturation.","method":"ILT4 transgenic mouse DCs, phosphatase recruitment assays, STAT3 activation assays, DC maturation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — direct signaling molecule recruitment demonstrated with transgenic model and multiple biochemical readouts","pmids":["18550825"],"is_preprint":false},{"year":2013,"finding":"Murine PirB (LILRB2 ortholog) and human LilrB2 are receptors for soluble Aβ oligomers with nanomolar affinity; the first two extracellular Ig domains of LilrB2 mediate this interaction, leading to enhanced cofilin signaling. In mice, Aβ oligomer-induced impairment of hippocampal long-term potentiation and memory deficits required PirB.","method":"Binding assays (nanomolar affinity measurement), genetic knockout mice, hippocampal LTP recordings, behavioral memory tests, cofilin signaling biochemistry","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding assay combined with genetic KO functional rescue, multiple orthogonal readouts; highly cited foundational paper","pmids":["24052308"],"is_preprint":false},{"year":2013,"finding":"LILRB2 (ILT4) engagement on neutrophils inhibits phagocytic function and reactive oxygen species production mediated through CD32a; ILT4 and CD32a co-localize in lipid rafts. Neutrophil degranulation translocates an intracellular ILT4 pool to the cell surface, enhancing HLA-G-mediated inhibition.","method":"Functional phagocytosis assays, ROS assays, lipid raft colocalization (confocal), degranulation experiments with primary neutrophils","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple functional assays in primary human neutrophils with direct mechanistic readouts","pmids":["24133137"],"is_preprint":false},{"year":2014,"finding":"A novel motif in the first and fourth Ig domains of LILRB2 is required for binding and activation by Angptl2; Angptl2 multimerization is required for LILRB2 activation and downstream signaling. Immobilized anti-LILRB2 antibodies activate LILRB2 signaling more potently than Angptl2 and support ex vivo expansion of human cord blood HSCs.","method":"Domain mutagenesis, binding assays, downstream signaling assays, HSC expansion culture experiments","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — domain-level mutagenesis, reconstituted binding, functional signaling readouts, and HSC functional assay","pmids":["24899623"],"is_preprint":false},{"year":2015,"finding":"ANGPTL2 binds LILRB2 on NSCLC cells to activate the SHP2/CaMK1/CREB signaling axis, supporting lung cancer cell proliferation, colony formation, and migration; LILRB2 knockdown dramatically reduces these cancer cell behaviors.","method":"LILRB2 knockdown (siRNA/shRNA), proliferation/colony/migration assays, western blot signaling analysis, ANGPTL2 binding experiments","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 — loss-of-function with defined phenotype and pathway identification, but single lab","pmids":["26056041"],"is_preprint":false},{"year":2016,"finding":"HLA-G engages ILT4 (LILRB2) on granulocytic MDSCs to increase their suppressive activity, induce MDSCs from PBMCs, and phosphorylate STAT3 and induce IDO in myeloid cells; these effects were shown to be mediated specifically through ILT4.","method":"Flow cytometry, STAT3 phosphorylation assays, IDO induction assays, ILT4 receptor blocking experiments in primary human cells from pregnant women","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 — signaling readouts with receptor-specific blocking in primary cells, single lab","pmids":["27859042"],"is_preprint":false},{"year":2018,"finding":"LILRB2 antagonism inhibits SHP1/2 activation and AKT/STAT6 signaling in tumor-associated myeloid cells, reprogramming them from an alternatively activated toward an inflammatory phenotype, suppressing MDSC/Treg infiltration and enhancing anti-tumor T cell responses in vivo.","method":"Anti-LILRB2 antibody antagonism, phospho-signaling assays (SHP1/2, AKT, STAT6), transcriptome analysis, in vivo tumor models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (biochemical signaling, transcriptomics, in vivo models) in single well-controlled study","pmids":["30352428"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of LilrB2 D1D2 complexed with small molecules identified two pockets accommodating the phenylalanine residues of Aβ segment 16KLVFFA21; mutagenesis confirmed these pockets as the Aβ binding site on LilrB2. Small molecule inhibitors blocking these pockets reduced Aβ-LilrB2 interactions in vitro and on the cell surface, and reduced Aβ cytotoxicity.","method":"X-ray crystallography, mutagenesis of binding pockets, Rosetta docking, in vitro binding inhibition assays, cell-surface assays, cytotoxicity assays","journal":"Nature chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis plus functional validation; multiple orthogonal methods","pmids":["30297750"],"is_preprint":false},{"year":2018,"finding":"Human Semaphorin-4A (hSEMA4A) binds LILRB2 (ILT-4) on activated CD4+ T cells, co-stimulating T cell proliferation and driving Th2 differentiation; this was identified by two independent cloning strategies.","method":"Two independent receptor cloning strategies, binding assays, T cell proliferation assays, Th2 differentiation assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — receptor identified by two independent methods, functional T cell assays; single lab","pmids":["29467366"],"is_preprint":false},{"year":2019,"finding":"Crystal structures of full four-domain LILRB2 and four-domain LILRB1/HLA-G1 complex revealed that D1D2 is responsible for HLA-I binding while D3D4 acts as a scaffold, and that the four domains assemble with limited flexibility. The geometry of dimeric receptor engagement suggests enhanced inhibitory signal transduction.","method":"X-ray crystallography of full-length four-domain LILRB2 and LILRB1/HLA-G1 complex","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structures defining domain architecture and ligand-binding mode","pmids":["31273318"],"is_preprint":false},{"year":2021,"finding":"LILRB2 increases fatty acid synthesis and lipid accumulation in tumor cells via activation of MAPK ERK1/2 signaling, promoting tumor growth and induction of T cell senescence; blocking the mouse ortholog PIR-B reprogrammed tumor metabolism and prevented T cell senescence in vivo.","method":"Loss-of-function/gain-of-function in cancer cell lines, lipid droplet staining, western blot for metabolic enzymes and ERK1/2 signaling, in vivo breast cancer and melanoma mouse models","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 — defined signaling pathway with in vivo validation; single lab with multiple readouts","pmids":["33653799"],"is_preprint":false},{"year":2021,"finding":"EGFR activation (by mutation or EGF) upregulates ILT4 (LILRB2) expression in NSCLC cells through AKT/ERK1/2 phosphorylation; tumor cell-derived ILT4 induces M2-like TAM recruitment and polarization and directly inhibits T cell proliferation and cytotoxicity.","method":"NSCLC cell lines, AKT/ERK1/2 inhibitors, ILT4 knockdown lentivirus, Transwell migration, flow cytometry, cytolytic assays, in vivo humanized mouse models","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple assays establish upstream signaling and downstream immune effects; single lab","pmids":["33537094"],"is_preprint":false},{"year":2021,"finding":"Plasmodium falciparum RIFIN proteins are ligands for LILRB2; the domain 3 of LILRB2 mediates RIFIN binding, whereas domains 1 and 2 mediate HLA class I binding, revealing a distinct binding site used for immune evasion by P. falciparum.","method":"RIFIN expression library screening, binding assays with LILRB2 domain deletion constructs, infected erythrocyte binding experiments","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — domain-mapping of a novel ligand interaction using expression library plus deletion construct binding assays","pmids":["33647792"],"is_preprint":false},{"year":2022,"finding":"LILRB2 co-ligates with TREM2 on microglia when shared ligands (Aβ oligomers or phosphatidylserine) are present, and LILRB2 engagement significantly inhibits TREM2 signaling; an antagonistic LILRB2 antibody (Ab29) blocks this inhibition and enhances microglia phagocytosis, migration, and cytokine responses to Aβ in iPSC-derived microglia and enhances amyloid plaque clearance in vivo.","method":"iPSC-derived microglia, TREM2 signaling assays, antagonistic antibody (Ab29), phagocytosis/migration assays, in vivo stereotaxic graft in 5XFAD mice, flow cytometry","journal":"Molecular neurodegeneration","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (signaling assays, human iPSC-derived cells, in vivo model) establishing receptor co-ligation mechanism","pmids":["35717259"],"is_preprint":false},{"year":2022,"finding":"ANGPTL8 binds LILRB2 on hepatic stellate cells and macrophages to activate ERK signaling, promoting liver fibrogenesis; ANGPTL8 knockout mice showed reduced macrophage infiltration, hepatic steatosis, and fibrosis, and restoring ANGPTL8 in knockout livers reinstated fibrosis.","method":"Co-IP, ANGPTL8 KO mice, AAV8-mediated liver-specific restoration, RNA-seq, western blot, histological staining","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus in vivo genetic rescue model with multiple readouts; single lab","pmids":["36031141"],"is_preprint":false},{"year":2021,"finding":"ANGPTL2 induces inflammatory gene expression in human fibroblast-like synoviocytes via LILRB2, activating phosphorylation of ERK, p38, JNK, NF-κB, and Akt; pretreatment with an anti-LILRB2 antibody significantly inhibited these effects.","method":"Real-time RT-PCR, western blot for MAPK/NF-κB/Akt phosphorylation, anti-LILRB2 antibody blocking in primary human synoviocytes","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 3 — receptor-blocking antibody experiment with multiple signaling readouts in primary cells; single lab","pmids":["33538932"],"is_preprint":false},{"year":2023,"finding":"LILRB2 facilitates ubiquitination and proteasomal degradation of HLA-A in breast cancer cells by promoting the interaction between the ubiquitin ligase MARCH9 and HLA-A; this promotes immune escape from CD8+ T cells in syngeneic mouse models.","method":"Western blot, immunoprecipitation, histidine pulldown ubiquitination assay, in-situ tumor models in nude BALB/c mice, flow cytometry","journal":"Cellular oncology (Dordrecht, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2 — ubiquitination assay with pulldown plus in vivo validation; single lab","pmids":["38656573"],"is_preprint":false},{"year":2023,"finding":"PirB/LILRB2 on macrophages binds ANGPTL8 and mediates macrophage migration to the liver in NASH; PirB-knockout bone marrow chimeras abrogated ANGPTL8-induced monocyte-derived macrophage migration, and PirB ectodomain protein sequestered ANGPTL8 to ameliorate NASH.","method":"PirB-KO bone marrow chimeras, ANGPTL8 KO mice, macrophage migration assays, flow cytometry, ectodomain decoy protein experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with bone marrow chimera rescue plus in vivo and in vitro mechanistic validation across multiple approaches","pmids":["37481670"],"is_preprint":false},{"year":2024,"finding":"ILT4 (LILRB2) reprograms aerobic glycolysis in TNBC cells via AKT-mTOR signaling-mediated upregulation of GLUT3 and PKM2, promoting tumor proliferation, migration, invasion, and metastasis in vitro and in vivo.","method":"LILRB2 gain/loss-of-function, western blot for AKT-mTOR signaling, metabolic assays, in vivo tumor growth models","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2–3 — pathway identified with mechanistic signaling assays and in vivo validation; single lab","pmids":["37622462"],"is_preprint":false},{"year":2024,"finding":"LILRB2 silencing attenuates radiation-induced senescence and the senescence-associated secretory phenotype (SASP) in NSCLC by inhibiting the JAK2/STAT3 pathway, thereby increasing radiosensitivity.","method":"Lentivirus-mediated LILRB2 silencing, irradiation assays, senescence markers (SA-β-gal, p21, p16), SASP cytokine measurement, JAK2/STAT3 pathway inhibition assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2–3 — loss-of-function with defined signaling pathway and functional senescence phenotype; single lab","pmids":["38705566"],"is_preprint":false},{"year":2024,"finding":"ILT4 (LILRB2) promotes NSCLC angiogenesis via ANGPTL2-ILT4 interaction that activates ERK1/2 signaling, increasing secretion of proangiogenic factors VEGF-A and MMP-9 from tumor cells.","method":"ANGPTL2-ILT4 interaction assays, ERK1/2 signaling western blot, VEGF-A/MMP-9 ELISA, in vitro angiogenesis assays, in vivo tumor models","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2–3 — ligand-receptor interaction linked to defined signaling and angiogenic secretome; single lab","pmids":["38433526"],"is_preprint":false},{"year":2025,"finding":"C4d, a complement C4 cleavage product, binds LilrB2/PirB with nanomolar affinity; C4d colocalizes with LilrB2 at excitatory synapses in human cortex. In mouse cortex, C4d exposure caused significant dendritic spine loss in wild-type mice, but PirB knockout completely prevented this loss, establishing C4d-PirB as a synaptic pruning axis.","method":"Direct binding affinity measurements, immunofluorescence colocalization, PirB KO mouse dendritic spine imaging","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — direct binding assay plus genetic KO with specific spine density phenotype rescue; multiple orthogonal methods","pmids":["40966293"],"is_preprint":false},{"year":2025,"finding":"LILRB2 interacts with TLR8 to inhibit the MyD88/NF-κB signaling pathway in LPS-tolerant macrophages; the transcription factor SPI1 transcriptionally activates LILRB2 expression, enhancing the immunosuppressive phenotype. Knockdown of LILRB2 restored MyD88/NF-κB signaling and reversed LPS tolerance.","method":"Co-IP of LILRB2 and TLR8, ChIP assay for SPI1 binding to LILRB2 promoter, dual-luciferase reporter, LILRB2 knockdown with NF-κB pathway western blot","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP interaction plus ChIP transcriptional control with functional signaling readout; single lab","pmids":["40551156"],"is_preprint":false},{"year":2018,"finding":"LILRB2 promotes endometrial cancer cell proliferation, colony formation, and migration through activation of the SHP2/CaMK1/CREB signaling pathway; LILRB2 knockdown dramatically reduces these phenotypes in vitro and in vivo xenograft.","method":"LILRB2 knockdown in cancer cell lines, proliferation/colony/migration assays, in vivo xenograft, western blot for SHP2/CaMK1/CREB pathway","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 — loss-of-function with pathway identification and in vivo validation; single lab","pmids":["30343889"],"is_preprint":false},{"year":2010,"finding":"IL-10 upregulates LILRB2 (ILT4) expression on dendritic cells at both the transcriptional and translational levels, and IL-10 increases ILT4 promoter activity. LPS-stimulated, LIR-2-transfected DCs inhibit T cell proliferation, and overexpression of LIR-2 on T cells inhibits TCR-induced T cell proliferation.","method":"IL-10 stimulation, flow cytometry, luciferase promoter assay, retroviral LIR-2 expression in DCs and T cells, MLR T cell proliferation assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — promoter assay, transfection/overexpression with functional T cell readout; single lab, replicated with earlier IL-10 upregulation studies","pmids":["14971032","21063840"],"is_preprint":false},{"year":2024,"finding":"ILT2 inhibits myeloid cell activation primarily through trans-engagement by MHC-I, whereas ILT4 (LILRB2) efficiently inhibits myeloid cells in the presence of either cis- or trans-engagement; dual blockade of ILT2 and ILT4 is required for optimal myeloid cell reprogramming in 3D spheroid tumor models and humanized mouse tumor models.","method":"3D spheroid tumor model, cis/trans MHC-I engagement assays, dual antibody blockade, CXCL9/CCL5 secretion assays, flow cytometry (CD86, CD163), humanized mouse tumor models, human tumor explant histoculture","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic distinction between cis and trans engagement with multiple functional and in vivo readouts","pmids":["38393969"],"is_preprint":false}],"current_model":"LILRB2 is an inhibitory immune receptor bearing cytoplasmic ITIM motifs that recruits SHP-1/SHP-2 phosphatases upon ligation to suppress downstream signaling; it binds a broad range of MHC class I molecules (with preference for HLA-G), as well as non-classical ligands including Aβ oligomers (via D1D2), Angptl proteins (via D1/D4 motifs), complement C4d, RIFIN parasitic proteins, and Semaphorin-4A, coupling these interactions to context-dependent signaling cascades (SHP1/2, AKT, STAT3/6, ERK1/2, JAK2/STAT3, NF-κB) that render myeloid cells and dendritic cells tolerogenic, impair T cell-mediated immunity, promote tumor-intrinsic metabolic reprogramming (fatty acid synthesis, aerobic glycolysis), mediate synaptic pruning in neurons, and regulate macrophage migration in inflammatory liver disease."},"narrative":{"teleology":[{"year":1998,"claim":"Establishing LILRB2 as a functional inhibitory receptor resolved how myeloid cells counterbalance activating Fc receptor signals: ITIM-dependent SHP-1 recruitment suppresses FcγRI-mediated Syk phosphorylation and calcium flux.","evidence":"Phosphorylation and calcium mobilization assays with co-ligation of LILRB2 and FcγRI in primary monocytes","pmids":["9842885"],"confidence":"High","gaps":["SHP-2 recruitment not directly shown in this study","endogenous ligand triggering this inhibition not identified"]},{"year":2002,"claim":"Demonstrating that suppressor T cells upregulate LILRB2 on APCs to induce tolerance established the receptor as a central effector of adaptive immune regulation and tolerogenic dendritic cell programming.","evidence":"Co-culture of CD8+CD28− T suppressor cells with DCs, mixed lymphocyte reactions, and functional tolerance assays including transplant patient samples","pmids":["11875462"],"confidence":"High","gaps":["Precise signaling cascade downstream of ILT4 upregulation in tolerogenic DCs not yet defined","whether direct HLA-G engagement was required in this context was unknown"]},{"year":2002,"claim":"Solving the D1D2 crystal structure and quantifying MHC-I binding affinities defined the structural basis of LILRB2 ligand recognition, revealing broad MHC-I binding with preferential HLA-G affinity and competition with CD8.","evidence":"1.8 Å X-ray crystallography of D1D2 and SPR measurements of binding to multiple classical/non-classical MHC-I molecules","pmids":["12390682","12853576","11169396"],"confidence":"High","gaps":["Full four-domain architecture not resolved","β2m-free MHC binding not yet characterized"]},{"year":2006,"claim":"The co-crystal structure of LILRB2 with HLA-G revealed dominant recognition of the α3 domain hydrophobic site and the capacity to bind β2m-free MHC forms, explaining its distinct specificity from LILRB1.","evidence":"2.5 Å crystal structure of LILRB2/HLA-G complex with NMR and SPR validation","pmids":["17056715"],"confidence":"High","gaps":["Functional consequence of β2m-free MHC recognition in vivo unclear","how α3-domain engagement couples to inhibitory signaling not resolved"]},{"year":2008,"claim":"Showing that HLA-G engagement of LILRB2 recruits both SHP-1 and SHP-2 and activates IL-6/STAT3 signaling to arrest DC maturation connected the structural binding data to a defined intracellular signaling cascade and established ligand oligomerization as a requirement for productive signaling.","evidence":"ILT4 transgenic mouse DCs stimulated with HLA-G tetramers/dimers/monomers, phosphatase recruitment and STAT3 assays","pmids":["18550825"],"confidence":"High","gaps":["Relative contribution of SHP-1 vs SHP-2 to DC arrest not dissected","role of cis- vs trans-MHC engagement not addressed"]},{"year":2010,"claim":"IL-10 was identified as a transcriptional inducer of LILRB2, linking an anti-inflammatory cytokine milieu to receptor upregulation and explaining how tolerogenic microenvironments amplify LILRB2-dependent suppression.","evidence":"IL-10 stimulation with promoter luciferase assay, flow cytometry, and retroviral LILRB2 overexpression in DCs and T cells with MLR readout","pmids":["14971032","21063840"],"confidence":"Medium","gaps":["Transcription factors mediating IL-10-driven promoter activation not fully identified","contribution of post-transcriptional regulation unknown"]},{"year":2013,"claim":"Discovery that Aβ oligomers bind LILRB2/PirB with nanomolar affinity via D1D2 and that PirB is required for Aβ-induced LTP impairment and memory deficits expanded LILRB2 function beyond immunity into neurodegeneration, identifying it as a key neuronal receptor for Alzheimer's-relevant amyloid toxicity.","evidence":"Binding assays, PirB-KO mice with hippocampal LTP recordings and behavioral memory tests, cofilin signaling biochemistry","pmids":["24052308"],"confidence":"High","gaps":["Whether LILRB2 on neurons vs microglia mediates the LTP effect not distinguished","downstream signaling beyond cofilin not characterized"]},{"year":2013,"claim":"Demonstrating that LILRB2 inhibits neutrophil phagocytosis and ROS production and that degranulation mobilizes intracellular LILRB2 to the surface extended the receptor's inhibitory role to the innate effector compartment and revealed a regulated surface translocation mechanism.","evidence":"Phagocytosis and ROS assays, lipid raft colocalization, degranulation-induced surface expression in primary neutrophils","pmids":["24133137"],"confidence":"High","gaps":["Molecular mechanism of intracellular LILRB2 pool retention and mobilization not defined","identity of the intracellular compartment not established"]},{"year":2014,"claim":"Mapping the Angptl2 binding site to D1 and D4 motifs and showing that Angptl multimerization is required for signaling established a structurally distinct non-MHC ligand engagement mode and linked LILRB2 to hematopoietic stem cell expansion.","evidence":"Domain mutagenesis, binding and signaling assays, ex vivo HSC expansion from cord blood","pmids":["24899623"],"confidence":"High","gaps":["Atomic-resolution structure of ANGPTL2–LILRB2 complex not determined","downstream signaling pathway in HSCs not fully characterized"]},{"year":2015,"claim":"ANGPTL2-LILRB2 engagement on tumor cells was shown to activate SHP2/CaMK1/CREB signaling to drive cancer cell proliferation and migration, establishing a tumor-intrinsic oncogenic role independent of immune suppression.","evidence":"LILRB2 knockdown in NSCLC cell lines with proliferation, colony formation, migration assays, and signaling western blots","pmids":["26056041"],"confidence":"Medium","gaps":["Single lab finding","whether the same pathway operates in non-NSCLC tumors not tested","autocrine vs paracrine ANGPTL2 source not defined"]},{"year":2018,"claim":"Three advances converged: (1) crystal structures defined the Aβ binding pockets on D1D2, enabling small-molecule inhibitor design; (2) LILRB2 antagonistic antibodies reprogrammed tumor-associated myeloid cells from immunosuppressive to inflammatory by blocking SHP1/2–AKT–STAT6 signaling; and (3) Semaphorin-4A was identified as a LILRB2 ligand co-stimulating Th2 differentiation, further diversifying the receptor's ligand repertoire.","evidence":"Crystal structure plus mutagenesis and cytotoxicity assays for Aβ; anti-LILRB2 antibody with phospho-signaling, transcriptomics, and in vivo tumor models; two independent receptor cloning strategies with T cell functional assays for SEMA4A","pmids":["30297750","30352428","29467366"],"confidence":"High","gaps":["In vivo efficacy of small-molecule Aβ blockers not demonstrated","SEMA4A–LILRB2 binding domain not mapped","whether LILRB2 antibody therapy achieves durable tumor rejection unknown"]},{"year":2019,"claim":"Full four-domain crystal structures of LILRB2 and LILRB1/HLA-G1 revealed that D3D4 serve as a rigid scaffold for D1D2-mediated ligand recognition and that dimeric receptor geometry enhances inhibitory signaling, providing a structural rationale for oligomerization-dependent activation.","evidence":"X-ray crystallography of full-length four-domain LILRB2 and LILRB1/HLA-G1 complex","pmids":["31273318"],"confidence":"High","gaps":["No structure of LILRB2 with non-MHC ligands in full-length context","stoichiometry at the cell surface not determined"]},{"year":2021,"claim":"Multiple studies established tumor-intrinsic LILRB2 as a metabolic reprogrammer—promoting fatty acid synthesis via ERK1/2 and inflammatory gene expression via MAPK/NF-κB—while EGFR signaling was identified as an upstream transcriptional inducer of LILRB2 in NSCLC, and RIFIN binding to D3 was discovered as a malaria immune evasion strategy.","evidence":"Loss/gain-of-function in cancer lines with metabolic readouts and in vivo models; EGFR inhibitor studies with ILT4 knockdown; RIFIN expression library screening with LILRB2 domain deletions; ANGPTL2/LILRB2 blocking in synoviocytes","pmids":["33653799","33537094","33647792","33538932"],"confidence":"Medium","gaps":["RIFIN–LILRB2 downstream signaling not characterized","structural basis of D3-mediated RIFIN binding unknown","relative contribution of tumor-intrinsic vs myeloid LILRB2 in cancer progression not separated in vivo"]},{"year":2022,"claim":"LILRB2 was found to co-ligate with TREM2 on microglia to inhibit TREM2 signaling in response to shared ligands (Aβ, phosphatidylserine), and antagonistic antibodies rescued phagocytosis and amyloid clearance, establishing a receptor crosstalk mechanism relevant to Alzheimer's disease.","evidence":"iPSC-derived microglia with TREM2 signaling assays, antagonistic Ab29, phagocytosis/migration assays, in vivo stereotaxic graft in 5XFAD mice","pmids":["35717259"],"confidence":"High","gaps":["Molecular interface of LILRB2–TREM2 co-ligation not structurally defined","whether co-ligation requires direct receptor–receptor contact or proximity only is unclear"]},{"year":2022,"claim":"ANGPTL8 was identified as another LILRB2/PirB ligand on hepatic stellate cells and macrophages, activating ERK to promote liver fibrosis and driving macrophage migration to the liver in NASH, expanding LILRB2's role to metabolic liver disease.","evidence":"Co-IP of ANGPTL8–LILRB2, ANGPTL8 KO mice with AAV8 restoration, PirB-KO bone marrow chimeras, macrophage migration assays","pmids":["36031141","37481670"],"confidence":"High","gaps":["ANGPTL8 binding domain on LILRB2 not mapped","whether ANGPTL8 and ANGPTL2 compete for the same binding site unknown"]},{"year":2024,"claim":"Tumor-intrinsic LILRB2 was shown to reprogram aerobic glycolysis via AKT-mTOR/GLUT3/PKM2, promote angiogenesis via ERK1/2-driven VEGF-A/MMP-9 secretion, facilitate HLA-A degradation through MARCH9-mediated ubiquitination, and modulate radiation-induced senescence via JAK2/STAT3, revealing diverse cell-autonomous oncogenic mechanisms. Distinguishing cis- from trans-MHC-I engagement showed ILT4 uniquely inhibits via both modes, requiring dual ILT2/ILT4 blockade for optimal myeloid reprogramming.","evidence":"Gain/loss-of-function metabolic and signaling assays, ubiquitination pulldowns, in vivo tumor models, 3D spheroid and humanized mouse models with cis/trans engagement analysis","pmids":["37622462","38433526","38656573","38705566","38393969"],"confidence":"Medium","gaps":["Many findings from single labs awaiting independent replication","how cis-MHC-I engagement is regulated on tumor cells not mechanistically defined","whether MARCH9 interaction is direct or scaffolded not established"]},{"year":2025,"claim":"Complement C4d was identified as a nanomolar-affinity LILRB2/PirB ligand that colocalizes at excitatory synapses and mediates dendritic spine loss, establishing a complement–inhibitory receptor axis for synaptic pruning. Separately, LILRB2 was found to interact with TLR8 to suppress MyD88/NF-κB signaling in LPS-tolerant macrophages, with SPI1 transcriptionally driving LILRB2 expression.","evidence":"Binding affinity measurements, PirB-KO dendritic spine imaging; Co-IP of LILRB2–TLR8, ChIP for SPI1 at LILRB2 promoter, LILRB2 knockdown with NF-κB signaling rescue","pmids":["40966293","40551156"],"confidence":"High","gaps":["C4d–LILRB2 binding domain not mapped","signaling cascade between C4d–LILRB2 engagement and spine elimination not characterized","TLR8 interaction awaits independent replication and structural validation"]},{"year":null,"claim":"Key unresolved questions include the structural basis of non-MHC ligand engagement (ANGPTL proteins, C4d, RIFIN, SEMA4A), how LILRB2 integrates simultaneous signals from multiple competing ligands at the cell surface, and whether therapeutic LILRB2 antagonism can be safely deployed given the receptor's roles across immune, neural, and metabolic compartments.","evidence":"","pmids":[],"confidence":"Low","gaps":["No co-crystal structures with any non-MHC ligand","ligand competition hierarchy at the cell surface not defined","in vivo safety profile of LILRB2 blockade across tissue compartments not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,6,12,28]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,6,22]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,8,31]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,6,8,12,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,10,12,16,24,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,16,17,22,24,26]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[7,19,27]}],"complexes":[],"partners":["SHP-1","SHP-2","HLA-G","ANGPTL2","ANGPTL8","TREM2","TLR8","MARCH9"],"other_free_text":[]},"mechanistic_narrative":"LILRB2 is an inhibitory immunoreceptor on myeloid cells that integrates signals from a remarkably diverse set of ligands to suppress immune activation, regulate synaptic remodeling, and promote tumor immune evasion. Its cytoplasmic ITIMs recruit SHP-1 and SHP-2 phosphatases upon engagement by MHC class I molecules (with preferential affinity for HLA-G via the α3 domain), amyloid-β oligomers, angiopoietin-like proteins, complement C4d, Plasmodium RIFIN proteins, and Semaphorin-4A, coupling these interactions through context-dependent cascades—including AKT, STAT3/6, ERK1/2, NF-κB, and mTOR—to render dendritic cells tolerogenic, inhibit neutrophil and macrophage effector functions, drive tumor-intrinsic metabolic reprogramming (fatty acid synthesis, aerobic glycolysis), and mediate complement-dependent synaptic pruning in the CNS [PMID:9842885, PMID:12853576, PMID:17056715, PMID:30352428, PMID:24052308, PMID:40966293, PMID:38705566]. Structurally, the D1D2 domains form the MHC-I and Aβ binding interface while D3D4 serve as a scaffold and provide a separate RIFIN-binding site, and ligand oligomerization or membrane clustering is required for productive signaling [PMID:12390682, PMID:31273318, PMID:33647792, PMID:18550825]. In tumors, LILRB2 signaling on both myeloid and cancer cells promotes immune escape by suppressing T cell responses, recruiting M2-like macrophages, inducing MDSC expansion, and facilitating MARCH9-mediated HLA-A degradation, while LILRB2 antagonism reprograms tumor-associated myeloid cells toward an inflammatory phenotype [PMID:30352428, PMID:38656573, PMID:33537094, PMID:38393969]."},"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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the Fc receptor γ-chain and Syk, as well as intracellular calcium mobilization in monocytes, demonstrating that LILRB2 inhibits Fc receptor-mediated signaling.\",\n      \"method\": \"Phosphorylation assays, co-ligation experiments, calcium mobilization assays in monocytes\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct biochemical assay with multiple functional readouts (SHP-1 recruitment, Syk phosphorylation, calcium flux) in primary cells\",\n      \"pmids\": [\"9842885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD8+CD28− T suppressor cells induce upregulation of LILRB2 (ILT4) on monocytes and dendritic cells, rendering these APCs tolerogenic with reduced costimulatory molecule expression and ability to induce antigen-specific T helper cell unresponsiveness.\",\n      \"method\": \"Co-culture experiments, flow cytometry, mixed lymphocyte reactions, functional tolerance assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays, replicated in transplant patient samples; highly cited foundational study\",\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 resolution revealed structural differences from LIR-1 in the ligand-binding domain, including a distinct 310 helix replacing the residue 44–57 helix and an 11 Å displacement of the 76–84 loop, explaining the >1000-fold lower affinity of LILRB2 for the CMV MHC homolog UL18 compared to LILRB1.\",\n      \"method\": \"X-ray crystallography at 1.8 Å, molecular replacement\",\n      \"journal\": \"BMC structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with direct structural-functional interpretation\",\n      \"pmids\": [\"12390682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Surface plasmon resonance showed LILRB2 (ILT4) binds a broad range of classical and non-classical MHC class I molecules with Kd values of 2–45 μM, binds HLA-G with 3- to 4-fold higher affinity than classical MHCIs, and competes with CD8 for MHC class I binding.\",\n      \"method\": \"Surface plasmon resonance (SPR) with soluble recombinant proteins\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro binding kinetics with recombinant proteins, quantitative affinity measurements for multiple ligands\",\n      \"pmids\": [\"12853576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"HLA-F tetramers bind ILT4 (LILRB2), and surface plasmon resonance confirmed a direct molecular interaction between HLA-F and ILT4; transfection of ILT4 conferred HLA-F tetramer binding on non-binding cells.\",\n      \"method\": \"Tetramer staining, transfection, surface plasmon resonance\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding assay (SPR) plus functional reconstitution by transfection\",\n      \"pmids\": [\"11169396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure at 2.5 Å of LILRB2 in complex with HLA-G revealed that LILRB2 dominantly recognizes the hydrophobic site of the HLA-G α3 domain, and can recognize the β2m-free form of HLA-B27 unlike LILRB1, explaining differential binding specificities among LILR family members.\",\n      \"method\": \"X-ray crystallography at 2.5 Å, NMR binding studies, SPR binding experiments with β2m-free MHC forms\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure of receptor-ligand complex with NMR validation and binding specificity experiments\",\n      \"pmids\": [\"17056715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Ligation of LILRB2 (ILT4) by HLA-G on dendritic cells results in recruitment of SHP-1 and SHP-2 protein tyrosine phosphatases, and engagement of ILT4 by HLA-G1 tetramers or HLA-G5 dimers (but not HLA-G5 monomers) induces strong ILT-mediated signaling involving the IL-6–STAT3 pathway, arresting DC maturation.\",\n      \"method\": \"ILT4 transgenic mouse DCs, phosphatase recruitment assays, STAT3 activation assays, DC maturation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct signaling molecule recruitment demonstrated with transgenic model and multiple biochemical readouts\",\n      \"pmids\": [\"18550825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Murine PirB (LILRB2 ortholog) and human LilrB2 are receptors for soluble Aβ oligomers with nanomolar affinity; the first two extracellular Ig domains of LilrB2 mediate this interaction, leading to enhanced cofilin signaling. In mice, Aβ oligomer-induced impairment of hippocampal long-term potentiation and memory deficits required PirB.\",\n      \"method\": \"Binding assays (nanomolar affinity measurement), genetic knockout mice, hippocampal LTP recordings, behavioral memory tests, cofilin signaling biochemistry\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding assay combined with genetic KO functional rescue, multiple orthogonal readouts; highly cited foundational paper\",\n      \"pmids\": [\"24052308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LILRB2 (ILT4) engagement on neutrophils inhibits phagocytic function and reactive oxygen species production mediated through CD32a; ILT4 and CD32a co-localize in lipid rafts. Neutrophil degranulation translocates an intracellular ILT4 pool to the cell surface, enhancing HLA-G-mediated inhibition.\",\n      \"method\": \"Functional phagocytosis assays, ROS assays, lipid raft colocalization (confocal), degranulation experiments with primary neutrophils\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays in primary human neutrophils with direct mechanistic readouts\",\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 required for binding and activation by Angptl2; Angptl2 multimerization is required for LILRB2 activation and downstream signaling. Immobilized anti-LILRB2 antibodies activate LILRB2 signaling more potently than Angptl2 and support ex vivo expansion of human cord blood HSCs.\",\n      \"method\": \"Domain mutagenesis, binding assays, downstream signaling assays, HSC expansion culture experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — domain-level mutagenesis, reconstituted binding, functional signaling readouts, and HSC functional assay\",\n      \"pmids\": [\"24899623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ANGPTL2 binds LILRB2 on NSCLC cells to activate the SHP2/CaMK1/CREB signaling axis, supporting lung cancer cell proliferation, colony formation, and migration; LILRB2 knockdown dramatically reduces these cancer cell behaviors.\",\n      \"method\": \"LILRB2 knockdown (siRNA/shRNA), proliferation/colony/migration assays, western blot signaling analysis, ANGPTL2 binding experiments\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — loss-of-function with defined phenotype and pathway identification, but single lab\",\n      \"pmids\": [\"26056041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HLA-G engages ILT4 (LILRB2) on granulocytic MDSCs to increase their suppressive activity, induce MDSCs from PBMCs, and phosphorylate STAT3 and induce IDO in myeloid cells; these effects were shown to be mediated specifically through ILT4.\",\n      \"method\": \"Flow cytometry, STAT3 phosphorylation assays, IDO induction assays, ILT4 receptor blocking experiments in primary human cells from pregnant women\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — signaling readouts with receptor-specific blocking in primary cells, single lab\",\n      \"pmids\": [\"27859042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LILRB2 antagonism inhibits SHP1/2 activation and AKT/STAT6 signaling in tumor-associated myeloid cells, reprogramming them from an alternatively activated toward an inflammatory phenotype, suppressing MDSC/Treg infiltration and enhancing anti-tumor T cell responses in vivo.\",\n      \"method\": \"Anti-LILRB2 antibody antagonism, phospho-signaling assays (SHP1/2, AKT, STAT6), transcriptome analysis, in vivo tumor models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (biochemical signaling, transcriptomics, in vivo models) in single well-controlled study\",\n      \"pmids\": [\"30352428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of LilrB2 D1D2 complexed with small molecules identified two pockets accommodating the phenylalanine residues of Aβ segment 16KLVFFA21; mutagenesis confirmed these pockets as the Aβ binding site on LilrB2. Small molecule inhibitors blocking these pockets reduced Aβ-LilrB2 interactions in vitro and on the cell surface, and reduced Aβ cytotoxicity.\",\n      \"method\": \"X-ray crystallography, mutagenesis of binding pockets, Rosetta docking, in vitro binding inhibition assays, cell-surface assays, cytotoxicity assays\",\n      \"journal\": \"Nature chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis plus functional validation; multiple orthogonal methods\",\n      \"pmids\": [\"30297750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Human Semaphorin-4A (hSEMA4A) binds LILRB2 (ILT-4) on activated CD4+ T cells, co-stimulating T cell proliferation and driving Th2 differentiation; this was identified by two independent cloning strategies.\",\n      \"method\": \"Two independent receptor cloning strategies, binding assays, T cell proliferation assays, Th2 differentiation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor identified by two independent methods, functional T cell assays; single lab\",\n      \"pmids\": [\"29467366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structures of full four-domain LILRB2 and four-domain LILRB1/HLA-G1 complex revealed that D1D2 is responsible for HLA-I binding while D3D4 acts as a scaffold, and that the four domains assemble with limited flexibility. The geometry of dimeric receptor engagement suggests enhanced inhibitory signal transduction.\",\n      \"method\": \"X-ray crystallography of full-length four-domain LILRB2 and LILRB1/HLA-G1 complex\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structures defining domain architecture and ligand-binding mode\",\n      \"pmids\": [\"31273318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LILRB2 increases fatty acid synthesis and lipid accumulation in tumor cells via activation of MAPK ERK1/2 signaling, promoting tumor growth and induction of T cell senescence; blocking the mouse ortholog PIR-B reprogrammed tumor metabolism and prevented T cell senescence in vivo.\",\n      \"method\": \"Loss-of-function/gain-of-function in cancer cell lines, lipid droplet staining, western blot for metabolic enzymes and ERK1/2 signaling, in vivo breast cancer and melanoma mouse models\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — defined signaling pathway with in vivo validation; single lab with multiple readouts\",\n      \"pmids\": [\"33653799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EGFR activation (by mutation or EGF) upregulates ILT4 (LILRB2) expression in NSCLC cells through AKT/ERK1/2 phosphorylation; tumor cell-derived ILT4 induces M2-like TAM recruitment and polarization and directly inhibits T cell proliferation and cytotoxicity.\",\n      \"method\": \"NSCLC cell lines, AKT/ERK1/2 inhibitors, ILT4 knockdown lentivirus, Transwell migration, flow cytometry, cytolytic assays, in vivo humanized mouse models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple assays establish upstream signaling and downstream immune effects; single lab\",\n      \"pmids\": [\"33537094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Plasmodium falciparum RIFIN proteins are ligands for LILRB2; the domain 3 of LILRB2 mediates RIFIN binding, whereas domains 1 and 2 mediate HLA class I binding, revealing a distinct binding site used for immune evasion by P. falciparum.\",\n      \"method\": \"RIFIN expression library screening, binding assays with LILRB2 domain deletion constructs, infected erythrocyte binding experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain-mapping of a novel ligand interaction using expression library plus deletion construct binding assays\",\n      \"pmids\": [\"33647792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LILRB2 co-ligates with TREM2 on microglia when shared ligands (Aβ oligomers or phosphatidylserine) are present, and LILRB2 engagement significantly inhibits TREM2 signaling; an antagonistic LILRB2 antibody (Ab29) blocks this inhibition and enhances microglia phagocytosis, migration, and cytokine responses to Aβ in iPSC-derived microglia and enhances amyloid plaque clearance in vivo.\",\n      \"method\": \"iPSC-derived microglia, TREM2 signaling assays, antagonistic antibody (Ab29), phagocytosis/migration assays, in vivo stereotaxic graft in 5XFAD mice, flow cytometry\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (signaling assays, human iPSC-derived cells, in vivo model) establishing receptor co-ligation mechanism\",\n      \"pmids\": [\"35717259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ANGPTL8 binds LILRB2 on hepatic stellate cells and macrophages to activate ERK signaling, promoting liver fibrogenesis; ANGPTL8 knockout mice showed reduced macrophage infiltration, hepatic steatosis, and fibrosis, and restoring ANGPTL8 in knockout livers reinstated fibrosis.\",\n      \"method\": \"Co-IP, ANGPTL8 KO mice, AAV8-mediated liver-specific restoration, RNA-seq, western blot, histological staining\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus in vivo genetic rescue model with multiple readouts; single lab\",\n      \"pmids\": [\"36031141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANGPTL2 induces inflammatory gene expression in human fibroblast-like synoviocytes via LILRB2, activating phosphorylation of ERK, p38, JNK, NF-κB, and Akt; pretreatment with an anti-LILRB2 antibody significantly inhibited these effects.\",\n      \"method\": \"Real-time RT-PCR, western blot for MAPK/NF-κB/Akt phosphorylation, anti-LILRB2 antibody blocking in primary human synoviocytes\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — receptor-blocking antibody experiment with multiple signaling readouts in primary cells; single lab\",\n      \"pmids\": [\"33538932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LILRB2 facilitates ubiquitination and proteasomal degradation of HLA-A in breast cancer cells by promoting the interaction between the ubiquitin ligase MARCH9 and HLA-A; this promotes immune escape from CD8+ T cells in syngeneic mouse models.\",\n      \"method\": \"Western blot, immunoprecipitation, histidine pulldown ubiquitination assay, in-situ tumor models in nude BALB/c mice, flow cytometry\",\n      \"journal\": \"Cellular oncology (Dordrecht, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination assay with pulldown plus in vivo validation; single lab\",\n      \"pmids\": [\"38656573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PirB/LILRB2 on macrophages binds ANGPTL8 and mediates macrophage migration to the liver in NASH; PirB-knockout bone marrow chimeras abrogated ANGPTL8-induced monocyte-derived macrophage migration, and PirB ectodomain protein sequestered ANGPTL8 to ameliorate NASH.\",\n      \"method\": \"PirB-KO bone marrow chimeras, ANGPTL8 KO mice, macrophage migration assays, flow cytometry, ectodomain decoy protein experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with bone marrow chimera rescue plus in vivo and in vitro mechanistic validation across multiple approaches\",\n      \"pmids\": [\"37481670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ILT4 (LILRB2) reprograms aerobic glycolysis in TNBC cells via AKT-mTOR signaling-mediated upregulation of GLUT3 and PKM2, promoting tumor proliferation, migration, invasion, and metastasis in vitro and in vivo.\",\n      \"method\": \"LILRB2 gain/loss-of-function, western blot for AKT-mTOR signaling, metabolic assays, in vivo tumor growth models\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — pathway identified with mechanistic signaling assays and in vivo validation; single lab\",\n      \"pmids\": [\"37622462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LILRB2 silencing attenuates radiation-induced senescence and the senescence-associated secretory phenotype (SASP) in NSCLC by inhibiting the JAK2/STAT3 pathway, thereby increasing radiosensitivity.\",\n      \"method\": \"Lentivirus-mediated LILRB2 silencing, irradiation assays, senescence markers (SA-β-gal, p21, p16), SASP cytokine measurement, JAK2/STAT3 pathway inhibition assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — loss-of-function with defined signaling pathway and functional senescence phenotype; single lab\",\n      \"pmids\": [\"38705566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ILT4 (LILRB2) promotes NSCLC angiogenesis via ANGPTL2-ILT4 interaction that activates ERK1/2 signaling, increasing secretion of proangiogenic factors VEGF-A and MMP-9 from tumor cells.\",\n      \"method\": \"ANGPTL2-ILT4 interaction assays, ERK1/2 signaling western blot, VEGF-A/MMP-9 ELISA, in vitro angiogenesis assays, in vivo tumor models\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ligand-receptor interaction linked to defined signaling and angiogenic secretome; single lab\",\n      \"pmids\": [\"38433526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"C4d, a complement C4 cleavage product, binds LilrB2/PirB with nanomolar affinity; C4d colocalizes with LilrB2 at excitatory synapses in human cortex. In mouse cortex, C4d exposure caused significant dendritic spine loss in wild-type mice, but PirB knockout completely prevented this loss, establishing C4d-PirB as a synaptic pruning axis.\",\n      \"method\": \"Direct binding affinity measurements, immunofluorescence colocalization, PirB KO mouse dendritic spine imaging\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding assay plus genetic KO with specific spine density phenotype rescue; multiple orthogonal methods\",\n      \"pmids\": [\"40966293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LILRB2 interacts with TLR8 to inhibit the MyD88/NF-κB signaling pathway in LPS-tolerant macrophages; the transcription factor SPI1 transcriptionally activates LILRB2 expression, enhancing the immunosuppressive phenotype. Knockdown of LILRB2 restored MyD88/NF-κB signaling and reversed LPS tolerance.\",\n      \"method\": \"Co-IP of LILRB2 and TLR8, ChIP assay for SPI1 binding to LILRB2 promoter, dual-luciferase reporter, LILRB2 knockdown with NF-κB pathway western blot\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP interaction plus ChIP transcriptional control with functional signaling readout; single lab\",\n      \"pmids\": [\"40551156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LILRB2 promotes endometrial cancer cell proliferation, colony formation, and migration through activation of the SHP2/CaMK1/CREB signaling pathway; LILRB2 knockdown dramatically reduces these phenotypes in vitro and in vivo xenograft.\",\n      \"method\": \"LILRB2 knockdown in cancer cell lines, proliferation/colony/migration assays, in vivo xenograft, western blot for SHP2/CaMK1/CREB pathway\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — loss-of-function with pathway identification and in vivo validation; single lab\",\n      \"pmids\": [\"30343889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-10 upregulates LILRB2 (ILT4) expression on dendritic cells at both the transcriptional and translational levels, and IL-10 increases ILT4 promoter activity. LPS-stimulated, LIR-2-transfected DCs inhibit T cell proliferation, and overexpression of LIR-2 on T cells inhibits TCR-induced T cell proliferation.\",\n      \"method\": \"IL-10 stimulation, flow cytometry, luciferase promoter assay, retroviral LIR-2 expression in DCs and T cells, MLR T cell proliferation assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter assay, transfection/overexpression with functional T cell readout; single lab, replicated with earlier IL-10 upregulation studies\",\n      \"pmids\": [\"14971032\", \"21063840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ILT2 inhibits myeloid cell activation primarily through trans-engagement by MHC-I, whereas ILT4 (LILRB2) efficiently inhibits myeloid cells in the presence of either cis- or trans-engagement; dual blockade of ILT2 and ILT4 is required for optimal myeloid cell reprogramming in 3D spheroid tumor models and humanized mouse tumor models.\",\n      \"method\": \"3D spheroid tumor model, cis/trans MHC-I engagement assays, dual antibody blockade, CXCL9/CCL5 secretion assays, flow cytometry (CD86, CD163), humanized mouse tumor models, human tumor explant histoculture\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic distinction between cis and trans engagement with multiple functional and in vivo readouts\",\n      \"pmids\": [\"38393969\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LILRB2 is an inhibitory immune receptor bearing cytoplasmic ITIM motifs that recruits SHP-1/SHP-2 phosphatases upon ligation to suppress downstream signaling; it binds a broad range of MHC class I molecules (with preference for HLA-G), as well as non-classical ligands including Aβ oligomers (via D1D2), Angptl proteins (via D1/D4 motifs), complement C4d, RIFIN parasitic proteins, and Semaphorin-4A, coupling these interactions to context-dependent signaling cascades (SHP1/2, AKT, STAT3/6, ERK1/2, JAK2/STAT3, NF-κB) that render myeloid cells and dendritic cells tolerogenic, impair T cell-mediated immunity, promote tumor-intrinsic metabolic reprogramming (fatty acid synthesis, aerobic glycolysis), mediate synaptic pruning in neurons, and regulate macrophage migration in inflammatory liver disease.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LILRB2 is an inhibitory immunoreceptor on myeloid cells that integrates signals from a remarkably diverse set of ligands to suppress immune activation, regulate synaptic remodeling, and promote tumor immune evasion. Its cytoplasmic ITIMs recruit SHP-1 and SHP-2 phosphatases upon engagement by MHC class I molecules (with preferential affinity for HLA-G via the α3 domain), amyloid-β oligomers, angiopoietin-like proteins, complement C4d, Plasmodium RIFIN proteins, and Semaphorin-4A, coupling these interactions through context-dependent cascades—including AKT, STAT3/6, ERK1/2, NF-κB, and mTOR—to render dendritic cells tolerogenic, inhibit neutrophil and macrophage effector functions, drive tumor-intrinsic metabolic reprogramming (fatty acid synthesis, aerobic glycolysis), and mediate complement-dependent synaptic pruning in the CNS [PMID:9842885, PMID:12853576, PMID:17056715, PMID:30352428, PMID:24052308, PMID:40966293, PMID:38705566]. Structurally, the D1D2 domains form the MHC-I and Aβ binding interface while D3D4 serve as a scaffold and provide a separate RIFIN-binding site, and ligand oligomerization or membrane clustering is required for productive signaling [PMID:12390682, PMID:31273318, PMID:33647792, PMID:18550825]. In tumors, LILRB2 signaling on both myeloid and cancer cells promotes immune escape by suppressing T cell responses, recruiting M2-like macrophages, inducing MDSC expansion, and facilitating MARCH9-mediated HLA-A degradation, while LILRB2 antagonism reprograms tumor-associated myeloid cells toward an inflammatory phenotype [PMID:30352428, PMID:38656573, PMID:33537094, PMID:38393969].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing LILRB2 as a functional inhibitory receptor resolved how myeloid cells counterbalance activating Fc receptor signals: ITIM-dependent SHP-1 recruitment suppresses FcγRI-mediated Syk phosphorylation and calcium flux.\",\n      \"evidence\": \"Phosphorylation and calcium mobilization assays with co-ligation of LILRB2 and FcγRI in primary monocytes\",\n      \"pmids\": [\"9842885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SHP-2 recruitment not directly shown in this study\", \"endogenous ligand triggering this inhibition not identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrating that suppressor T cells upregulate LILRB2 on APCs to induce tolerance established the receptor as a central effector of adaptive immune regulation and tolerogenic dendritic cell programming.\",\n      \"evidence\": \"Co-culture of CD8+CD28− T suppressor cells with DCs, mixed lymphocyte reactions, and functional tolerance assays including transplant patient samples\",\n      \"pmids\": [\"11875462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise signaling cascade downstream of ILT4 upregulation in tolerogenic DCs not yet defined\", \"whether direct HLA-G engagement was required in this context was unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Solving the D1D2 crystal structure and quantifying MHC-I binding affinities defined the structural basis of LILRB2 ligand recognition, revealing broad MHC-I binding with preferential HLA-G affinity and competition with CD8.\",\n      \"evidence\": \"1.8 Å X-ray crystallography of D1D2 and SPR measurements of binding to multiple classical/non-classical MHC-I molecules\",\n      \"pmids\": [\"12390682\", \"12853576\", \"11169396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full four-domain architecture not resolved\", \"β2m-free MHC binding not yet characterized\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The co-crystal structure of LILRB2 with HLA-G revealed dominant recognition of the α3 domain hydrophobic site and the capacity to bind β2m-free MHC forms, explaining its distinct specificity from LILRB1.\",\n      \"evidence\": \"2.5 Å crystal structure of LILRB2/HLA-G complex with NMR and SPR validation\",\n      \"pmids\": [\"17056715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of β2m-free MHC recognition in vivo unclear\", \"how α3-domain engagement couples to inhibitory signaling not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showing that HLA-G engagement of LILRB2 recruits both SHP-1 and SHP-2 and activates IL-6/STAT3 signaling to arrest DC maturation connected the structural binding data to a defined intracellular signaling cascade and established ligand oligomerization as a requirement for productive signaling.\",\n      \"evidence\": \"ILT4 transgenic mouse DCs stimulated with HLA-G tetramers/dimers/monomers, phosphatase recruitment and STAT3 assays\",\n      \"pmids\": [\"18550825\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of SHP-1 vs SHP-2 to DC arrest not dissected\", \"role of cis- vs trans-MHC engagement not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"IL-10 was identified as a transcriptional inducer of LILRB2, linking an anti-inflammatory cytokine milieu to receptor upregulation and explaining how tolerogenic microenvironments amplify LILRB2-dependent suppression.\",\n      \"evidence\": \"IL-10 stimulation with promoter luciferase assay, flow cytometry, and retroviral LILRB2 overexpression in DCs and T cells with MLR readout\",\n      \"pmids\": [\"14971032\", \"21063840\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factors mediating IL-10-driven promoter activation not fully identified\", \"contribution of post-transcriptional regulation unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that Aβ oligomers bind LILRB2/PirB with nanomolar affinity via D1D2 and that PirB is required for Aβ-induced LTP impairment and memory deficits expanded LILRB2 function beyond immunity into neurodegeneration, identifying it as a key neuronal receptor for Alzheimer's-relevant amyloid toxicity.\",\n      \"evidence\": \"Binding assays, PirB-KO mice with hippocampal LTP recordings and behavioral memory tests, cofilin signaling biochemistry\",\n      \"pmids\": [\"24052308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LILRB2 on neurons vs microglia mediates the LTP effect not distinguished\", \"downstream signaling beyond cofilin not characterized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that LILRB2 inhibits neutrophil phagocytosis and ROS production and that degranulation mobilizes intracellular LILRB2 to the surface extended the receptor's inhibitory role to the innate effector compartment and revealed a regulated surface translocation mechanism.\",\n      \"evidence\": \"Phagocytosis and ROS assays, lipid raft colocalization, degranulation-induced surface expression in primary neutrophils\",\n      \"pmids\": [\"24133137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of intracellular LILRB2 pool retention and mobilization not defined\", \"identity of the intracellular compartment not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapping the Angptl2 binding site to D1 and D4 motifs and showing that Angptl multimerization is required for signaling established a structurally distinct non-MHC ligand engagement mode and linked LILRB2 to hematopoietic stem cell expansion.\",\n      \"evidence\": \"Domain mutagenesis, binding and signaling assays, ex vivo HSC expansion from cord blood\",\n      \"pmids\": [\"24899623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of ANGPTL2–LILRB2 complex not determined\", \"downstream signaling pathway in HSCs not fully characterized\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"ANGPTL2-LILRB2 engagement on tumor cells was shown to activate SHP2/CaMK1/CREB signaling to drive cancer cell proliferation and migration, establishing a tumor-intrinsic oncogenic role independent of immune suppression.\",\n      \"evidence\": \"LILRB2 knockdown in NSCLC cell lines with proliferation, colony formation, migration assays, and signaling western blots\",\n      \"pmids\": [\"26056041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab finding\", \"whether the same pathway operates in non-NSCLC tumors not tested\", \"autocrine vs paracrine ANGPTL2 source not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Three advances converged: (1) crystal structures defined the Aβ binding pockets on D1D2, enabling small-molecule inhibitor design; (2) LILRB2 antagonistic antibodies reprogrammed tumor-associated myeloid cells from immunosuppressive to inflammatory by blocking SHP1/2–AKT–STAT6 signaling; and (3) Semaphorin-4A was identified as a LILRB2 ligand co-stimulating Th2 differentiation, further diversifying the receptor's ligand repertoire.\",\n      \"evidence\": \"Crystal structure plus mutagenesis and cytotoxicity assays for Aβ; anti-LILRB2 antibody with phospho-signaling, transcriptomics, and in vivo tumor models; two independent receptor cloning strategies with T cell functional assays for SEMA4A\",\n      \"pmids\": [\"30297750\", \"30352428\", \"29467366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo efficacy of small-molecule Aβ blockers not demonstrated\", \"SEMA4A–LILRB2 binding domain not mapped\", \"whether LILRB2 antibody therapy achieves durable tumor rejection unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Full four-domain crystal structures of LILRB2 and LILRB1/HLA-G1 revealed that D3D4 serve as a rigid scaffold for D1D2-mediated ligand recognition and that dimeric receptor geometry enhances inhibitory signaling, providing a structural rationale for oligomerization-dependent activation.\",\n      \"evidence\": \"X-ray crystallography of full-length four-domain LILRB2 and LILRB1/HLA-G1 complex\",\n      \"pmids\": [\"31273318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of LILRB2 with non-MHC ligands in full-length context\", \"stoichiometry at the cell surface not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multiple studies established tumor-intrinsic LILRB2 as a metabolic reprogrammer—promoting fatty acid synthesis via ERK1/2 and inflammatory gene expression via MAPK/NF-κB—while EGFR signaling was identified as an upstream transcriptional inducer of LILRB2 in NSCLC, and RIFIN binding to D3 was discovered as a malaria immune evasion strategy.\",\n      \"evidence\": \"Loss/gain-of-function in cancer lines with metabolic readouts and in vivo models; EGFR inhibitor studies with ILT4 knockdown; RIFIN expression library screening with LILRB2 domain deletions; ANGPTL2/LILRB2 blocking in synoviocytes\",\n      \"pmids\": [\"33653799\", \"33537094\", \"33647792\", \"33538932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RIFIN–LILRB2 downstream signaling not characterized\", \"structural basis of D3-mediated RIFIN binding unknown\", \"relative contribution of tumor-intrinsic vs myeloid LILRB2 in cancer progression not separated in vivo\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"LILRB2 was found to co-ligate with TREM2 on microglia to inhibit TREM2 signaling in response to shared ligands (Aβ, phosphatidylserine), and antagonistic antibodies rescued phagocytosis and amyloid clearance, establishing a receptor crosstalk mechanism relevant to Alzheimer's disease.\",\n      \"evidence\": \"iPSC-derived microglia with TREM2 signaling assays, antagonistic Ab29, phagocytosis/migration assays, in vivo stereotaxic graft in 5XFAD mice\",\n      \"pmids\": [\"35717259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular interface of LILRB2–TREM2 co-ligation not structurally defined\", \"whether co-ligation requires direct receptor–receptor contact or proximity only is unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"ANGPTL8 was identified as another LILRB2/PirB ligand on hepatic stellate cells and macrophages, activating ERK to promote liver fibrosis and driving macrophage migration to the liver in NASH, expanding LILRB2's role to metabolic liver disease.\",\n      \"evidence\": \"Co-IP of ANGPTL8–LILRB2, ANGPTL8 KO mice with AAV8 restoration, PirB-KO bone marrow chimeras, macrophage migration assays\",\n      \"pmids\": [\"36031141\", \"37481670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ANGPTL8 binding domain on LILRB2 not mapped\", \"whether ANGPTL8 and ANGPTL2 compete for the same binding site unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Tumor-intrinsic LILRB2 was shown to reprogram aerobic glycolysis via AKT-mTOR/GLUT3/PKM2, promote angiogenesis via ERK1/2-driven VEGF-A/MMP-9 secretion, facilitate HLA-A degradation through MARCH9-mediated ubiquitination, and modulate radiation-induced senescence via JAK2/STAT3, revealing diverse cell-autonomous oncogenic mechanisms. Distinguishing cis- from trans-MHC-I engagement showed ILT4 uniquely inhibits via both modes, requiring dual ILT2/ILT4 blockade for optimal myeloid reprogramming.\",\n      \"evidence\": \"Gain/loss-of-function metabolic and signaling assays, ubiquitination pulldowns, in vivo tumor models, 3D spheroid and humanized mouse models with cis/trans engagement analysis\",\n      \"pmids\": [\"37622462\", \"38433526\", \"38656573\", \"38705566\", \"38393969\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Many findings from single labs awaiting independent replication\", \"how cis-MHC-I engagement is regulated on tumor cells not mechanistically defined\", \"whether MARCH9 interaction is direct or scaffolded not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Complement C4d was identified as a nanomolar-affinity LILRB2/PirB ligand that colocalizes at excitatory synapses and mediates dendritic spine loss, establishing a complement–inhibitory receptor axis for synaptic pruning. Separately, LILRB2 was found to interact with TLR8 to suppress MyD88/NF-κB signaling in LPS-tolerant macrophages, with SPI1 transcriptionally driving LILRB2 expression.\",\n      \"evidence\": \"Binding affinity measurements, PirB-KO dendritic spine imaging; Co-IP of LILRB2–TLR8, ChIP for SPI1 at LILRB2 promoter, LILRB2 knockdown with NF-κB signaling rescue\",\n      \"pmids\": [\"40966293\", \"40551156\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"C4d–LILRB2 binding domain not mapped\", \"signaling cascade between C4d–LILRB2 engagement and spine elimination not characterized\", \"TLR8 interaction awaits independent replication and structural validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of non-MHC ligand engagement (ANGPTL proteins, C4d, RIFIN, SEMA4A), how LILRB2 integrates simultaneous signals from multiple competing ligands at the cell surface, and whether therapeutic LILRB2 antagonism can be safely deployed given the receptor's roles across immune, neural, and metabolic compartments.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No co-crystal structures with any non-MHC ligand\", \"ligand competition hierarchy at the cell surface not defined\", \"in vivo safety profile of LILRB2 blockade across tissue compartments not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 6, 12, 28]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 6, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 8, 31]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 6, 8, 12, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 10, 12, 16, 24, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 16, 17, 22, 24, 26]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [7, 19, 27]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SHP-1\",\n      \"SHP-2\",\n      \"HLA-G\",\n      \"ANGPTL2\",\n      \"ANGPTL8\",\n      \"TREM2\",\n      \"TLR8\",\n      \"MARCH9\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}