Affinage

LILRB2

Leukocyte immunoglobulin-like receptor subfamily B member 2 · UniProt Q8N423

Length
597 aa
Mass
65.0 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1998 High

    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

    PMID:9842885

    Open questions at the time
    • SHP-2 recruitment not directly shown in this study
    • endogenous ligand triggering this inhibition not identified
  2. 2002 High

    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

    PMID:11875462

    Open questions at the time
    • 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
  3. 2002 High

    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

    PMID:11169396 PMID:12390682 PMID:12853576

    Open questions at the time
    • Full four-domain architecture not resolved
    • β2m-free MHC binding not yet characterized
  4. 2006 High

    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

    PMID:17056715

    Open questions at the time
    • Functional consequence of β2m-free MHC recognition in vivo unclear
    • how α3-domain engagement couples to inhibitory signaling not resolved
  5. 2008 High

    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

    PMID:18550825

    Open questions at the time
    • Relative contribution of SHP-1 vs SHP-2 to DC arrest not dissected
    • role of cis- vs trans-MHC engagement not addressed
  6. 2010 Medium

    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

    PMID:14971032 PMID:21063840

    Open questions at the time
    • Transcription factors mediating IL-10-driven promoter activation not fully identified
    • contribution of post-transcriptional regulation unknown
  7. 2013 High

    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

    PMID:24052308

    Open questions at the time
    • Whether LILRB2 on neurons vs microglia mediates the LTP effect not distinguished
    • downstream signaling beyond cofilin not characterized
  8. 2013 High

    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

    PMID:24133137

    Open questions at the time
    • Molecular mechanism of intracellular LILRB2 pool retention and mobilization not defined
    • identity of the intracellular compartment not established
  9. 2014 High

    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

    PMID:24899623

    Open questions at the time
    • Atomic-resolution structure of ANGPTL2–LILRB2 complex not determined
    • downstream signaling pathway in HSCs not fully characterized
  10. 2015 Medium

    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

    PMID:26056041

    Open questions at the time
    • Single lab finding
    • whether the same pathway operates in non-NSCLC tumors not tested
    • autocrine vs paracrine ANGPTL2 source not defined
  11. 2018 High

    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

    PMID:29467366 PMID:30297750 PMID:30352428

    Open questions at the time
    • 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
  12. 2019 High

    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

    PMID:31273318

    Open questions at the time
    • No structure of LILRB2 with non-MHC ligands in full-length context
    • stoichiometry at the cell surface not determined
  13. 2021 Medium

    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

    PMID:33537094 PMID:33538932 PMID:33647792 PMID:33653799

    Open questions at the time
    • 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
  14. 2022 High

    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

    PMID:35717259

    Open questions at the time
    • Molecular interface of LILRB2–TREM2 co-ligation not structurally defined
    • whether co-ligation requires direct receptor–receptor contact or proximity only is unclear
  15. 2022 High

    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

    PMID:36031141 PMID:37481670

    Open questions at the time
    • ANGPTL8 binding domain on LILRB2 not mapped
    • whether ANGPTL8 and ANGPTL2 compete for the same binding site unknown
  16. 2024 Medium

    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

    PMID:37622462 PMID:38393969 PMID:38433526 PMID:38656573 PMID:38705566

    Open questions at the time
    • 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
  17. 2025 High

    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

    PMID:40551156 PMID:40966293

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 6 R-HSA-168256 Immune System 6 R-HSA-112316 Neuronal System 3
Partners
ANGPTL2ANGPTL8HLA-GMARCH9SHP-1SHP-2TLR8TREM2

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 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. Phosphorylation assays, co-ligation experiments, calcium mobilization assays in monocytes European journal of immunology High 9842885
2002 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. Co-culture experiments, flow cytometry, mixed lymphocyte reactions, functional tolerance assays Nature immunology High 11875462
2002 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. X-ray crystallography at 1.8 Å, molecular replacement BMC structural biology High 12390682
2003 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. Surface plasmon resonance (SPR) with soluble recombinant proteins Proceedings of the National Academy of Sciences of the United States of America High 12853576
2000 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. Tetramer staining, transfection, surface plasmon resonance European journal of immunology High 11169396
2006 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. X-ray crystallography at 2.5 Å, NMR binding studies, SPR binding experiments with β2m-free MHC forms Proceedings of the National Academy of Sciences of the United States of America High 17056715
2008 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. ILT4 transgenic mouse DCs, phosphatase recruitment assays, STAT3 activation assays, DC maturation assays Proceedings of the National Academy of Sciences of the United States of America High 18550825
2013 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. Binding assays (nanomolar affinity measurement), genetic knockout mice, hippocampal LTP recordings, behavioral memory tests, cofilin signaling biochemistry Science (New York, N.Y.) High 24052308
2013 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. Functional phagocytosis assays, ROS assays, lipid raft colocalization (confocal), degranulation experiments with primary neutrophils Proceedings of the National Academy of Sciences of the United States of America High 24133137
2014 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. Domain mutagenesis, binding assays, downstream signaling assays, HSC expansion culture experiments Blood High 24899623
2015 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. LILRB2 knockdown (siRNA/shRNA), proliferation/colony/migration assays, western blot signaling analysis, ANGPTL2 binding experiments Oncotarget Medium 26056041
2016 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. Flow cytometry, STAT3 phosphorylation assays, IDO induction assays, ILT4 receptor blocking experiments in primary human cells from pregnant women European journal of immunology Medium 27859042
2018 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. Anti-LILRB2 antibody antagonism, phospho-signaling assays (SHP1/2, AKT, STAT6), transcriptome analysis, in vivo tumor models The Journal of clinical investigation High 30352428
2018 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. X-ray crystallography, mutagenesis of binding pockets, Rosetta docking, in vitro binding inhibition assays, cell-surface assays, cytotoxicity assays Nature chemistry High 30297750
2018 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. Two independent receptor cloning strategies, binding assays, T cell proliferation assays, Th2 differentiation assays Nature communications Medium 29467366
2019 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. X-ray crystallography of full-length four-domain LILRB2 and LILRB1/HLA-G1 complex Cellular & molecular immunology High 31273318
2021 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. 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 for immunotherapy of cancer Medium 33653799
2021 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. NSCLC cell lines, AKT/ERK1/2 inhibitors, ILT4 knockdown lentivirus, Transwell migration, flow cytometry, cytolytic assays, in vivo humanized mouse models Theranostics Medium 33537094
2021 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. RIFIN expression library screening, binding assays with LILRB2 domain deletion constructs, infected erythrocyte binding experiments Biochemical and biophysical research communications Medium 33647792
2022 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. iPSC-derived microglia, TREM2 signaling assays, antagonistic antibody (Ab29), phagocytosis/migration assays, in vivo stereotaxic graft in 5XFAD mice, flow cytometry Molecular neurodegeneration High 35717259
2022 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. Co-IP, ANGPTL8 KO mice, AAV8-mediated liver-specific restoration, RNA-seq, western blot, histological staining Journal of advanced research Medium 36031141
2021 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. Real-time RT-PCR, western blot for MAPK/NF-κB/Akt phosphorylation, anti-LILRB2 antibody blocking in primary human synoviocytes Inflammation Medium 33538932
2023 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. Western blot, immunoprecipitation, histidine pulldown ubiquitination assay, in-situ tumor models in nude BALB/c mice, flow cytometry Cellular oncology (Dordrecht, Netherlands) Medium 38656573
2023 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. PirB-KO bone marrow chimeras, ANGPTL8 KO mice, macrophage migration assays, flow cytometry, ectodomain decoy protein experiments Nature communications High 37481670
2024 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. LILRB2 gain/loss-of-function, western blot for AKT-mTOR signaling, metabolic assays, in vivo tumor growth models Journal of cell science Medium 37622462
2024 LILRB2 silencing attenuates radiation-induced senescence and the senescence-associated secretory phenotype (SASP) in NSCLC by inhibiting the JAK2/STAT3 pathway, thereby increasing radiosensitivity. Lentivirus-mediated LILRB2 silencing, irradiation assays, senescence markers (SA-β-gal, p21, p16), SASP cytokine measurement, JAK2/STAT3 pathway inhibition assays Cancer letters Medium 38705566
2024 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. ANGPTL2-ILT4 interaction assays, ERK1/2 signaling western blot, VEGF-A/MMP-9 ELISA, in vitro angiogenesis assays, in vivo tumor models Cancer science Medium 38433526
2025 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. Direct binding affinity measurements, immunofluorescence colocalization, PirB KO mouse dendritic spine imaging Proceedings of the National Academy of Sciences of the United States of America High 40966293
2025 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. 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 Biology direct Medium 40551156
2018 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. LILRB2 knockdown in cancer cell lines, proliferation/colony/migration assays, in vivo xenograft, western blot for SHP2/CaMK1/CREB pathway Biochemical and biophysical research communications Medium 30343889
2010 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. IL-10 stimulation, flow cytometry, luciferase promoter assay, retroviral LIR-2 expression in DCs and T cells, MLR T cell proliferation assays European journal of immunology Medium 14971032 21063840
2024 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. 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 Cancer immunology research Medium 38393969

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Tolerization of dendritic cells by T(S) cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nature immunology 622 11875462
2010 Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. Blood 459 20448110
2003 Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G. Proceedings of the National Academy of Sciences of the United States of America 447 12853576
2013 Human LilrB2 is a β-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model. Science (New York, N.Y.) 337 24052308
2003 High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells. Transplant immunology 251 12967778
2005 HLA-G up-regulates ILT2, ILT3, ILT4, and KIR2DL4 in antigen presenting cells, NK cells, and T cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 244 15670976
2006 Structural basis for recognition of the nonclassical MHC molecule HLA-G by the leukocyte Ig-like receptor B2 (LILRB2/LIR2/ILT4/CD85d). Proceedings of the National Academy of Sciences of the United States of America 222 17056715
2004 Alloantigen specific CD8+CD28- FOXP3+ T suppressor cells induce ILT3+ ILT4+ tolerogenic endothelial cells, inhibiting alloreactivity. International immunology 204 15226269
2018 Blocking immunoinhibitory receptor LILRB2 reprograms tumor-associated myeloid cells and promotes antitumor immunity. The Journal of clinical investigation 196 30352428
1998 The MHC class I binding proteins LIR-1 and LIR-2 inhibit Fc receptor-mediated signaling in monocytes. European journal of immunology 173 9842885
2008 Modulation of dendritic cell differentiation by HLA-G and ILT4 requires the IL-6--STAT3 signaling pathway. Proceedings of the National Academy of Sciences of the United States of America 172 18550825
2000 Functional characterization of HLA-F and binding of HLA-F tetramers to ILT2 and ILT4 receptors. European journal of immunology 159 11169396
2021 ILT4 inhibition prevents TAM- and dysfunctional T cell-mediated immunosuppression and enhances the efficacy of anti-PD-L1 therapy in NSCLC with EGFR activation. Theranostics 154 33537094
2009 Tryptophan deprivation induces inhibitory receptors ILT3 and ILT4 on dendritic cells favoring the induction of human CD4+CD25+ Foxp3+ T regulatory cells. Journal of immunology (Baltimore, Md. : 1950) 146 19535644
2008 MiR-10 represses HoxB1a and HoxB3a in zebrafish. PloS one 137 18167555
2011 The miR-10 microRNA precursor family. RNA biology 92 21881411
2014 A motif in LILRB2 critical for Angptl2 binding and activation. Blood 85 24899623
2013 Exocytosis acts as a modulator of the ILT4-mediated inhibition of neutrophil functions. Proceedings of the National Academy of Sciences of the United States of America 82 24133137
2017 Conserved miR-10 family represses proliferation and induces apoptosis in ovarian granulosa cells. Scientific reports 77 28112253
2021 Tumor-derived ILT4 induces T cell senescence and suppresses tumor immunity. Journal for immunotherapy of cancer 75 33653799
2016 HLA-G promotes myeloid-derived suppressor cell accumulation and suppressive activity during human pregnancy through engagement of the receptor ILT4. European journal of immunology 74 27859042
2014 LILRB2 interaction with HLA class I correlates with control of HIV-1 infection. PLoS genetics 74 24603468
2022 ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways. Journal of advanced research 72 36031141
2003 Interleukin-10 induces the upregulation of the inhibitory receptor ILT4 in monocytes from HIV positive individuals. Human immunology 64 12691698
2018 Human Semaphorin-4A drives Th2 responses by binding to receptor ILT-4. Nature communications 58 29467366
2009 The inhibitory receptor LILRB4 (ILT3) modulates antigen presenting cell phenotype and, along with LILRB2 (ILT4), is upregulated in response to Salmonella infection. BMC immunology 57 19860908
2004 Interleukin 10 regulates cell surface and soluble LIR-2 (CD85d) expression on dendritic cells resulting in T cell hyporesponsiveness in vitro. European journal of immunology 57 14971032
2015 ANGPTL2/LILRB2 signaling promotes the propagation of lung cancer cells. Oncotarget 56 26056041
2017 Modulation of LILRB2 protein and mRNA expressions in septic shock patients and after ex vivo lipopolysaccharide stimulation. Human immunology 55 28341250
2018 Inhibiting amyloid-β cytotoxicity through its interaction with the cell surface receptor LilrB2 by structure-based design. Nature chemistry 54 30297750
2013 Rapamycin induces ILT3(high)ILT4(high) dendritic cells promoting a new immunoregulatory pathway. Kidney international 50 24107844
2002 Crystal structure of LIR-2 (ILT4) at 1.8 A: differences from LIR-1 (ILT2) in regions implicated in the binding of the Human Cytomegalovirus class I MHC homolog UL18. BMC structural biology 49 12390682
2007 Mechanisms of prolongation of allograft survival by HLA-G/ILT4-modified dendritic cells. Human immunology 44 17400062
2019 Structures of the four Ig-like domain LILRB2 and the four-domain LILRB1 and HLA-G1 complex. Cellular & molecular immunology 43 31273318
2022 LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions. Molecular neurodegeneration 42 35717259
2017 Intratumor heterogeneity of immune checkpoints in primary renal cell cancer: Focus on HLA-G/ILT2/ILT4. Oncoimmunology 41 28932645
2014 Implications of the miR-10 family in chemotherapy response of NPM1-mutated AML. Blood 40 24596420
2023 LILRB2/PirB mediates macrophage recruitment in fibrogenesis of nonalcoholic steatohepatitis. Nature communications 39 37481670
2018 Downregulation of ILT4+ dendritic cells in recurrent miscarriage and recurrent implantation failure. American journal of reproductive immunology (New York, N.Y. : 1989) 37 29904967
2011 LILRA3 binds both classical and non-classical HLA class I molecules but with reduced affinities compared to LILRB1/LILRB2: structural evidence. PloS one 36 21559424
2008 Rapamycin downregulates the inhibitory receptors ILT2, ILT3, ILT4 on human dendritic cells and yet induces T cell hyporesponsiveness independent of FoxP3 induction. Immunology letters 36 18652845
2008 Niflumic acid renders dendritic cells tolerogenic and up-regulates inhibitory molecules ILT3 and ILT4. International immunopharmacology 34 18486911
2017 The impact of HLA-G, LILRB1 and LILRB2 gene polymorphisms on susceptibility to and severity of endometriosis. Molecular genetics and genomics : MGG 32 29234882
2023 Inhibition of LILRB2 by a Novel Blocking Antibody Designed to Reprogram Immunosuppressive Macrophages to Drive T-Cell Activation in Tumors. Molecular cancer therapeutics 31 36780212
2020 The immune-checkpoint HLA-G/ILT4 is involved in the regulation of VEGF expression in clear cell renal cell carcinoma. BMC cancer 31 32620162
2021 Antifibrotic factor KLF4 is repressed by the miR-10/TFAP2A/TBX5 axis in dermal fibroblasts: insights from twins discordant for systemic sclerosis. Annals of the rheumatic diseases 30 34750102
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2017 Real-Time Analysis of Binding Events between Different Aβ1-42 Species and Human Lilrb2 by Dual Polarization Interferometry. Analytical chemistry 20 28219245
2016 Activation of LILRB2 signal pathway in temporal lobe epilepsy patients and in a pilocarpine induced epilepsy model. Experimental neurology 19 27637803
2018 Immune inhibitory receptor LILRB2 is critical for the endometrial cancer progression. Biochemical and biophysical research communications 18 30343889
2024 LILRB2 inhibition enhances radiation sensitivity in non-small cell lung cancer by attenuating radiation-induced senescence. Cancer letters 17 38705566
2019 Taenia solium and Taenia crassiceps: miRNomes of the larvae and effects of miR-10-5p and let-7-5p on murine peritoneal macrophages. Bioscience reports 17 31694049
2018 Pediatric tolerogenic DCs expressing CD4 and immunoglobulin-like transcript receptor (ILT)-4 secrete IL-10 in response to Fc and adenosine. European journal of immunology 17 29244203
1999 lir-2, lir-1 and lin-26 encode a new class of zinc-finger proteins and are organized in two overlapping operons both in Caenorhabditis elegans and in Caenorhabditis briggsae. Genetics 17 10224256
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2021 ILT4 in Colorectal Cancer Cells Induces Suppressive T Cell Contexture and Disease Progression. OncoTargets and therapy 15 34321889
2021 The emerging role of miR-10 family in gastric cancer. Cell cycle (Georgetown, Tex.) 14 34229543
2016 Analysis of the Expression and Function of Immunoglobulin-Like Transcript 4 (ILT4, LILRB2) in Dendritic Cells from Patients with Systemic Lupus Erythematosus. Journal of immunology research 14 27057555
2013 Upregulation of the inhibitory receptor ILT4 in monocytes from septic patients. Human immunology 14 23911358
2006 ILT3+ ILT4+ tolerogenic endothelial cells in transplantation. Transplantation 14 16829792
2023 LILRB2-containing small extracellular vesicles from glioblastoma promote tumor progression by promoting the formation and expansion of myeloid-derived suppressor cells. Cancer immunology, immunotherapy : CII 13 36853330
2020 Rewired functional regulatory networks among miRNA isoforms (isomiRs) from let-7 and miR-10 gene families in cancer. Computational and structural biotechnology journal 13 32542110
2019 The Expression of ILT4 in Myeloid Dendritic Cells in Patients with Hepatocellular Carcinoma. Immunological investigations 13 31044626
2024 ILT2 and ILT4 Drive Myeloid Suppression via Both Overlapping and Distinct Mechanisms. Cancer immunology research 11 38393969
2022 Genetic diversity of the LILRB1 and LILRB2 coding regions in an admixed Brazilian population sample. HLA 11 35754199
2022 Antibody-Mediated LILRB2-Receptor Antagonism Induces Human Myeloid-Derived Suppressor Cells to Kill Mycobacterium tuberculosis. Frontiers in immunology 11 35757769
2014 Downregulation of immunoglobulin-like transcript-4 (ILT4) in patients with psoriatic arthritis. PloS one 11 24676037
2024 LILRB2 promotes immune escape in breast cancer cells via enhanced HLA-A degradation. Cellular oncology (Dordrecht, Netherlands) 10 38656573
2024 Genome-Wide Association Analysis Identifies LILRB2 Gene for Pathological Myopia. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 10 39207058
2021 Identification of novel Aβ-LilrB2 inhibitors as potential therapeutic agents for Alzheimer's disease. Molecular and cellular neurosciences 10 34029694
2018 MiR-10 targets NgR to modulate the proliferation of microglial cells and the secretion of inflammatory cytokines. Experimental and molecular pathology 10 30312597
2022 Placental Malaria is Associated with Higher LILRB2 Expression in Monocyte Subsets and Lower Anti-Malarial IgG Antibodies During Infancy. Frontiers in immunology 9 35911674
2020 MicroRNA-377 Alleviates Myocardial Injury Induced by Hypoxia/Reoxygenation via Downregulating LILRB2 Expression. Dose-response : a publication of International Hormesis Society 9 32647500
2025 LILRB2 blockade facilitates macrophage repolarization and enhances T cell-mediated antitumor immunity. Journal for immunotherapy of cancer 8 40246582
2024 ANGPTL2 knockdown induces autophagy to relieve alveolar macrophage pyroptosis by reducing LILRB2-mediated inhibition of TREM2. Journal of cellular and molecular medicine 8 38758159
2021 Functional analysis of a putative Bombyx mori cypovirus miRNA BmCPV-miR-10 and its effect on virus replication. Insect molecular biology 8 34296485
2022 CircATIC inhibits esophageal carcinoma progression and promotes radiosensitivity by elevating RHCG through sponging miR-10-3p. Thoracic cancer 7 35307984
2022 miR-10 and Its Negative Correlation with Serum IL-35 Concentration and Positive Correlation with STAT5a Expression in Patients with Rheumatoid Arthritis. International journal of molecular sciences 7 35887269
2020 miR-10 involved in salinity-induced stress responses and targets TBC1D5 in the sea cucumber, Apostichopus japonicas. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 7 31904427
2024 Phase I dose escalation study of IO-108, an anti-LILRB2 antibody, in patients with advanced solid tumors. Journal for immunotherapy of cancer 6 39567210
2023 ILT4 reprograms glucose metabolism to promote tumor progression in triple-negative breast cancer. Journal of cell science 6 37622462
2024 Analysis of HLA-G 14 bp Insertion/Deletion Polymorphism and HLA-G, ILT2 and ILT4 Expression in Head and Neck Squamous Cell Carcinoma Patients. Diseases (Basel, Switzerland) 5 38391781
2024 ILT4 facilitates angiogenesis in non-small cell lung cancer. Cancer science 5 38433526
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2010 IL-10 enhances promoter activity of ILT4 gene and up-regulates its expression in THP-1 cells. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 5 21063840
2008 Changes in the expression of the immunoglobulin-like transcript 3 (ILT3) and ILT4 receptors in renal allograft recipients: effect of donor and recipient aging. Transplantation proceedings 5 19010139
2025 SPI1 upregulated LILRB2 to enhance the immunosuppressive phenotype of LPS-tolerant macrophages by inhibiting TLR8-mediated MyD88/NF-κB signaling. Biology direct 4 40551156
2023 Identification and characterization of the conformation and size of amyloid-β (42) oligomers targeting the receptor LilrB2. Physical chemistry chemical physics : PCCP 3 37700616
2025 miR-10-5p mediated susceptibility to chlorantraniliprole by targeting for SfGSTe1 in Spodoptera frugiperda (Smith). Scientific reports 2 40473727
2025 C4d, a high-affinity LilrB2 ligand, is elevated in Alzheimer's disease and mediates synapse pruning. Proceedings of the National Academy of Sciences of the United States of America 2 40966293
2022 Recognition of Aβ oligomer by LilrB2 acceptor: a tetracoordinated zipper mechanism. Journal of molecular modeling 2 36125588
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2009 Crystallization and preliminary X-ray analysis of the low-affinity complex between human leukocyte antigen-G (HLA-G) and leukocyte Ig-like receptor B2 (LILRB2). Protein and peptide letters 2 19356145
2026 A Subset of Pro-inflammatory CXCL10+ LILRB2+ Macrophages Derives From Recipient Monocytes and Drives Renal Allograft Rejection. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 1 41517835
2025 Targeting ILT4 to Improve Immunotherapy Efficacy in Solid Tumour: From Bench to Bedside. ImmunoTargets and therapy 1 40989721
2024 Dexamethasone promotes renal fibrosis by upregulating ILT4 expression in myeloid-derived suppressor cells. Journal of cellular and molecular medicine 1 38676361
2026 Unlocking the promise of innate biology through the HLA-G/ILT2/ILT4 pathway. Journal for immunotherapy of cancer 0 41692513