Affinage

LILRB4

Leukocyte immunoglobulin-like receptor subfamily B member 4 · UniProt Q8NHJ6

Length
448 aa
Mass
49.4 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LILRB4 (ILT3) is an ITIM-bearing inhibitory receptor of myeloid cells (monocytes, dendritic cells, macrophages) that, upon engagement, dampens activating immunoreceptor signaling and drives tolerogenic and immunosuppressive programs (PMID:9151699, PMID:19833736). The founding mechanism is recruitment of SH2-containing tyrosine phosphatases to its cytoplasmic ITIMs upon co-ligation with stimulatory receptors, extinguishing calcium flux and the tyrosine phosphorylation of activating kinases (Lck, Syk, LAT, Erk) and suppressing NF-κB/MAPK output and inflammatory cytokine production (PMID:9151699, PMID:19833736, PMID:29091299). Systematic ITIM mutagenesis established that Y412 and Y442 are required for T cell suppression while all three ITIMs (Y360, Y412, Y442) are needed for leukemic tissue infiltration, and domain-swap experiments showed the LILRB4 intracellular tail specifically confers these functions (PMID:31700117). A crystal structure of the two-Ig-domain ectodomain showed an obtuse interdomain angle incompatible with MHC class I binding, predicting non-MHC ligands (PMID:21454581); subsequent screens identified APOE, fibronectin, CD166/ALCAM, galectin-8, and secretogranin-2 as functional ligands that act through SHP-1/SHP-2 recruitment and, for some, SHP-independent STAT3 activation (PMID:29263213, PMID:30333625, PMID:34426457, PMID:38232701, PMID:40707822). Through these axes LILRB4 polarizes myeloid-derived suppressor cells and tumor-associated myeloid cells, upregulates ARG1 and uPAR, and suppresses T cells, supporting AML and solid tumor immune evasion such that genetic deletion or antibody blockade reduces tumor burden and restores T cell function (PMID:30333625, PMID:31213474, PMID:34426457, PMID:33372059, PMID:33974041). The same inhibitory machinery operates beyond cancer: it restrains hepatic and macrophage inflammation (limiting insulin resistance and atherosclerosis via SHP-1/TRAF6/NF-κB) (PMID:29091299, PMID:28743735), curbs NK cytotoxicity and osteoclastogenesis by sensing fibronectin (PMID:37083755, PMID:36331874), and protects against ischemic brain injury (PMID:39217343). A soluble/extracellular form (soluble ILT3, ILT3-Fc) acts in trans through CD166 to inhibit p70S6K and induce CD8+ T suppressor cells via BCL6 upregulation (PMID:17161342, PMID:29263213, PMID:28931525).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 High

    Established LILRB4/ILT3 as an inhibitory receptor by showing co-ligation extinguishes activating-receptor signaling through phosphatase recruitment, defining its core mechanism.

    Evidence Co-ligation calcium/phosphorylation assays and SHP-1 co-IP in primary monocytes/DCs, plus antigen presentation assays

    PMID:9151699

    Open questions at the time
    • Ligand(s) unknown at this stage
    • Relative contribution of individual ITIMs not resolved
  2. 2002 High

    Connected ILT3 upregulation to tolerance induction, showing CD8+ T suppressor cells render APCs tolerogenic, framing ILT3 as an effector of immune tolerance.

    Evidence T suppressor cell–APC co-cultures with flow cytometry and anergy assays, validated in transplant recipients

    PMID:11875462

    Open questions at the time
    • Molecular signaling linking upregulation to tolerogenic output not dissected
    • Ligand still unidentified
  3. 2006 Medium

    Showed the extracellular domain alone mediates suppression independent of cytoplasmic ITIMs, revealing a trans-acting/soluble mode of action distinct from classical ITIM signaling.

    Evidence Cytoplasmic deletion mutants in KG1 cells and recombinant soluble ILT3 in T cell assays

    PMID:17161342

    Open questions at the time
    • Receptor on T cells for the ectodomain not identified here
    • Single lab
  4. 2009 High

    Demonstrated LILRB4 co-ligation with FcγRI suppresses kinase phosphorylation and cytokine output, but pharmacology implicated phosphatases beyond SHP-1, refining the signaling model.

    Evidence Co-ligation assays in THP-1/monocytes with phospho-blotting, TNFα ELISA, and phosphatase inhibitor dissection

    PMID:19833736

    Open questions at the time
    • Identity of non-SHP-1 phosphatase not pinned down
    • Endogenous physiological co-ligand unknown
  5. 2011 High

    Solved the ectodomain structure, showing it is unsuited to MHC class I and predicting non-MHC ligands, redirecting ligand discovery.

    Evidence 1.7 Å crystal structure with engineered disulfide and comparative structural analysis

    PMID:21454581

    Open questions at the time
    • Actual ligand-binding surface confirmed only by inference
    • No ligand co-crystal
  6. 2017 High

    Identified CD166/ALCAM as the receptor for soluble ILT3-Fc on T cells, providing the missing ligand for the ectodomain-mediated suppression and a tumor-inhibitory p70S6K axis.

    Evidence Mass spec/Biacore ligand ID, CD166 knockdown and CRISPR KO, p70S6K blotting, xenograft

    PMID:29263213

    Open questions at the time
    • Whether membrane LILRB4 uses CD166 in cis not addressed
    • Downstream of p70S6K incomplete
  7. 2017 High

    Showed ectopic ILT3 in CLL B cells forms inhibitory ILT3-BCR-SHIP1 clusters to block Akt, extending inhibitory function to lymphoid contexts via a defined phosphatase complex.

    Evidence Deltex1-driven expression, BCR stimulation, Akt blotting, co-IP of ILT3-BCR-SHIP1

    PMID:28931525

    Open questions at the time
    • Physiological relevance outside CLL unclear
    • Ligand triggering in this setting not defined
  8. 2018 High

    Defined the APOE–LILRB4–SHP-2–uPAR–ARG1 axis in monocytic AML, establishing LILRB4 as a druggable driver of leukemic T cell suppression and tissue infiltration.

    Evidence Mouse AML models, LILRB4 KO, APOE binding, SHP-2 co-IP, ARG1/uPAR assays

    PMID:30333625

    Open questions at the time
    • How APOE selectively engages over other ligands unclear
    • Quantitative ligand affinity not given
  9. 2018 High

    Showed hepatic LILRB4 restrains metabolic inflammation via SHP-1–TRAF6–NF-κB/MAPK, extending the inhibitory mechanism to a protective non-immune-cell role.

    Evidence Hepatocyte-specific KO and overexpression mice, SHP-1 co-IP, TRAF6 ubiquitination assay, metabolic phenotyping

    PMID:29091299

    Open questions at the time
    • Activating ligand in liver not identified
    • Receptor-proximal events upstream of SHP-1 unclear
  10. 2019 High

    Dissected the ITIM code, mapping Y412/Y442 to T cell suppression and all three ITIMs to infiltration, and proved the intracellular domain is functionally specific to LILRB4.

    Evidence Site-directed ITIM mutagenesis and LILRB4/LILRB1 domain-swap chimeras in T cell and AML models

    PMID:31700117

    Open questions at the time
    • Differential phosphatase recruitment by each ITIM not resolved
    • Structural basis of ITIM selectivity unknown
  11. 2021 High

    Identified fibronectin (FN30 module) as a high-affinity ligand mediating myeloid suppression and inhibitory signaling, broadening LILRB4 ligand repertoire to ECM.

    Evidence Ligand screening, BLI/binding kinetics, domain mapping, blocking antibody in tumor explants and lupus-prone mice

    PMID:34089617 PMID:34426457

    Open questions at the time
    • Cis vs trans engagement context-dependent
    • Integration with APOE signaling not resolved here
  12. 2022 Medium

    Showed LILRB4/gp49B co-tethers fibronectin with integrin β1 to suppress FN-induced Syk signaling at focal adhesions, revealing a cis-regulatory triplet.

    Evidence FN pull-down co-IP with integrin β1, confocal co-localization, Syk blotting in WT vs KO macrophages

    PMID:35689642

    Open questions at the time
    • Single lab
    • Direct vs integrin-bridged FN binding not fully separated
  13. 2023 High

    Extended fibronectin sensing to NK cells and bone, showing LILRB4 senses FN on target cells in trans to limit NK cytotoxicity and inhibits osteoclastogenesis via SHP-1–TRAF6–TAK1/NF-κB/MAPK.

    Evidence gp49B-KO NK cytotoxicity with FN30-KO controls and Syk blotting; gp49B-KO bone phenotyping with TRAF6-SHP-1 co-IP

    PMID:36331874 PMID:37083755

    Open questions at the time
    • Threshold of FN density for trans signaling unclear
    • Crosstalk with activating NK receptors not mapped
  14. 2024 High

    Identified galectin-8 and secretogranin-2 as additional ligands acting through SHP recruitment plus SHP-independent STAT3 to drive MDSC induction, showing multiple ligands engage noncompetitively.

    Evidence Ligand screening, binding/competition assays, STAT3/NF-κB readouts, LILRB4-KO and transgenic tumor models

    PMID:38232701 PMID:40707822

    Open questions at the time
    • Hierarchy among multiple ligands in vivo unknown
    • Structural basis of distinct binding sites not solved
  15. 2024 High

    Revealed LILRB4 cell-intrinsic oncogenic and protective roles, transactivated by IKZF1 to drive MM proliferation via STAT3-PFKFB1 and secreting RELT to drive myeloma bone lesions, while microglial LILRB4 protects against ischemic injury.

    Evidence IKZF1 ChIP/reporter and STAT3-PFKFB1 blotting in MM; CRISPR KO with RELT rescue and micro-CT; microglia-specific conditional KO/TG in stroke model with CCL2 inhibition

    PMID:38951916 PMID:39025844 PMID:39217343

    Open questions at the time
    • Whether ligand engagement is required for these intrinsic outputs unclear
    • Tissue-specific signaling divergence not unified
  16. 2025 Medium

    Defined therapeutic and regulatory leverage points: SHP-2-driven cardiomyocyte pyroptosis and homoharringtonine-mediated FTO/m6A suppression of LILRB4, indicating both signaling and expression are targetable.

    Evidence LILRB4-KO and SHP2 inhibitor PHPS1 in cardiac I/R; FTO degradation/m6A assays with CD8 cytotoxicity in AML

    PMID:40550372 PMID:40590394

    Open questions at the time
    • Single-lab mechanisms
    • Cardiac ligand and upstream trigger undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct ligands (APOE, fibronectin, CD166, galectin-8, SCG2) are integrated to select between SHP-dependent and SHP-independent STAT3 outputs, and the structural basis for their noncompetitive binding, remain unresolved.
  • No ligand-bound structure
  • Rules governing context-specific signaling output unknown
  • Relative in vivo dominance of each ligand undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005576 extracellular region 3
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 1
Partners
ALCAM (CD166)APOEFN1INPP5D (SHIP1)ITGB1PTPN11 (SHP-2)PTPN6 (SHP-1)TRAF6
Complex memberships
LILRB4-BCR-SHIP1 inhibitory clusterLILRB4/gp49B-integrin β1 fibronectin co-tethering triplet

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 ILT3/LILRB4 co-ligation with stimulatory receptors on APCs dramatically blunts calcium influx and tyrosine phosphorylation triggered by those receptors; signal extinction involves recruitment of SH2-containing protein tyrosine phosphatase 1 (SHP-1) to ILT3 upon cross-linking. ILT3 also mediates antigen internalization and delivery to intracellular compartments for MHC-II processing and T cell presentation. Co-ligation assays with calcium flux and tyrosine phosphorylation readouts; SHP-1 co-immunoprecipitation after cross-linking; internalization and antigen presentation assays in primary monocytes/DCs The Journal of experimental medicine High 9151699
2002 CD8+CD28− alloantigen-specific T suppressor cells induce upregulation of ILT3 and ILT4 on monocytes and dendritic cells, rendering APCs tolerogenic with reduced costimulatory molecule expression and capacity to induce antigen-specific unresponsiveness in CD4+ T helper cells. In vitro co-culture of T suppressor cells with APCs; flow cytometry for ILT3/ILT4 and costimulatory molecules; allogeneic T cell proliferation and anergy assays Nature immunology High 11875462
2003 Tolerogenic DCs with high ILT3 and ILT4 expression anergize alloreactive CD4+CD45RO+CD25+ T cells and convert them into regulatory T cells; IL-10 and IFN-α also induce ILT3 and ILT4 upregulation in DCs, rendering them tolerogenic, indicating a common cytokine-driven mechanism. In vitro cytokine stimulation (IL-10, IFN-α) of DCs; co-culture with T cells; flow cytometry and functional suppression assays Transplant immunology Medium 12967778
2004 Alloantigen-specific CD8+CD28−FOXP3+ T suppressor cells interact with endothelial cells and induce upregulation of ILT3 and ILT4 on endothelial cells, downregulating costimulatory/adhesion molecules and rendering endothelial cells tolerogenic; tolerized endothelial cells in turn elicit differentiation of additional CD8+CD28−FOXP3+ T suppressor cells. RT-PCR; in vitro co-culture of T suppressor cells with HUVECs; flow cytometry; luciferase transcription assays International immunology Medium 15226269
2006 IL-10 stimulation of human endothelial cells upregulates ILT3 and ILT4 surface expression via STAT-3 signaling and involves glucocorticoid-induced leucine zipper (GILZ); blocking ILT3/ILT4 with antibodies nearly completely restores T cell proliferation inhibited by IL-10-pretreated endothelial cells, and overexpression of ILT3 in co-cultures significantly reduces T cell proliferation. IL-10 stimulation of HUVECs; blocking antibody experiments in endothelial-T cell co-cultures; ILT3 overexpression; STAT-3 signaling analysis European journal of immunology Medium 17163451
2007 Overexpression of membrane ILT3 in APCs inhibits NF-κB activation and transcription of costimulatory molecules; soluble ILT3 (sILT3) released by alternative splicing that eliminates the transmembrane domain is immunosuppressive, inducing CD8+ T suppressor cells and impairing T cell responses, effects reversible by anti-ILT3 mAb or sILT3 depletion. Humanized SCID mouse model; soluble ILT3 protein from patient serum; mixed lymphocyte culture; anti-ILT3 mAb blocking; immunohistochemistry; RT-PCR for splice variants JOP : Journal of the pancreas Medium 17993722
2009 LILRB4 co-ligation with FcγRI (CD64) on THP-1 monocytic cells potently inhibits TNFα production and reduces phosphorylation of Lck, Syk, LAT, Erk, and c-Cbl but not α-actinin-4; LILRB4 aggregates to sites of CD64 activation upon co-ligation; phosphatase inhibitor pervanadate reverses inhibition but SHP-1-specific inhibitor sodium stibogluconate does not, implicating phosphatase(s) other than SHP-1. Co-ligation assays on THP-1 cells and primary monocytes; TNFα ELISA; phospho-protein western blotting; phosphatase inhibitor experiments; confocal microscopy of receptor aggregation The Journal of biological chemistry High 19833736
2011 Crystal structure of the LILRB4 ectodomain resolved to 1.7 Å reveals two immunoglobulin domains; D2 domain (most similar to D4 of other LILRs) contains unique 3(10) helices; reduced D1-D2 interdomain contacts produce an obtuse interdomain angle (~107°); electrostatic and conformational analysis indicates LILRB4 is unsuited to MHC class I ligation, consistent with binding non-MHC class I ligands; distinctive surface patches on D1 and D1-D2 hinge region are candidate ligand-binding sites. Protein crystallography (1.7 Å resolution); engineered disulfide bond in D2 for stability; structural comparison with MHC-binding LILRs The Journal of biological chemistry High 21454581
2010 Overexpression of membrane ILT3 in APCs inhibits tyrosine phosphorylation, NF-κB and MAPK p38 activity, and transcription of costimulatory molecules, cytokines, and chemokines; soluble ILT3-Fc (containing only the extracellular Ig-like domain fused to mutated IgG1 Fc) acts extracellularly to induce CD4 T helper anergy and differentiation of antigen-specific CD8 T suppressor cells in vitro and in vivo. ILT3 overexpression in dendritic cell lines; ILT3-Fc recombinant protein treatment; NF-κB reporter assays; in vitro and in vivo (humanized NOD/SCID) tolerance models International reviews of immunology Medium 20132030
2006 ILT3 cytoplasmic deletion mutant (ILT3Δ) retains suppressive activity in T cell proliferation and cytotoxicity assays (unlike ILT4Δ which loses activity), demonstrating that the extracellular domain of ILT3 mediates suppression independently of the cytoplasmic ITIMs; soluble recombinant ILT3 inhibits T helper and cytotoxic function and induces CD8+ T suppressor cell differentiation. Cytoplasmic deletion mutants transfected into KG1 dendritic-like cell line; T cell proliferation and cytotoxicity assays; recombinant soluble ILT3 treatment International immunopharmacology Medium 17161342
2012 ILT3-Fc-induced CD8+ T suppressor cells show significant upregulation of BCL6 (a transcriptional repressor of IL-2, IFN-γ, IL-5, and granzyme B), SOCS1, and DUSP10; these genes define the Ts signature and are targeted by miRNAs suppressed by ILT3-Fc; ILT3-Fc induces tolerance to allogeneic human islets and reverses rejection in a humanized NOD/SCID model. Gene expression profiling; ILT3-Fc treatment of CD8+ T cells; BCL6 functional analysis; humanized NOD/SCID mouse model; miRNA analysis Experimental and molecular pathology Medium 23018130
2017 ILT3.Fc binds to CD166/ALCAM on the surface of activated T cells (identified by flow cytometry, mass spectrometry, and Biacore); CD166 knockdown abrogates ILT3.Fc-mediated inhibition of CD4+ T helper proliferation and induction of CD8+CD28− T suppressor cells; ILT3.Fc-CD166 interaction inhibits tumor cell growth via inactivation of the p70S6K signaling pathway; CRISPR-Cas9 knockout of CD166 abolishes ILT3.Fc binding and tumor-inhibitory effect. Flow cytometry; mass spectrometry; Biacore binding kinetics; nucleofection-based CD166 knockdown; CRISPR-Cas9 knockout; p70S6K western blotting; in vivo NOD.Cg-Prkdc Il-2rg/SzJ mouse xenograft Journal of immunology High 29263213
2017 In CLL B cells, ILT3 is ectopically expressed driven by the transcription factor Deltex1 (a suppressor of antigen receptor signaling); ILT3 triggering inhibits Akt kinase activation upon BCR stimulation by forming inhibitory clusters of ILT3, BCRs, and SHIP1 (INPP5D) at the cell surface. Transcriptional profiling of p66Shc-deficient CLL cells; Deltex1 overexpression; BCR stimulation with anti-IgM; Akt phosphorylation western blotting; co-immunoprecipitation of ILT3-BCR-SHIP1 clusters; flow cytometry Blood High 28931525
2018 LILRB4 on monocytic AML cells supports tumor infiltration and T cell suppression via a signaling pathway involving APOE as extracellular ligand, SHP-2 recruitment, uPAR upregulation, and ARG1 expression; deletion of LILRB4 or antibody blockade impedes AML development in mouse models. Mouse AML models (syngeneic and human cell xenograft); LILRB4 knockout; APOE-LILRB4 binding; SHP-2 co-immunoprecipitation; uPAR and ARG1 functional assays; T cell suppression co-culture; tissue infiltration assays Nature High 30333625
2018 Hepatic LILRB4 recruits SHP-1 to inhibit TRAF6 ubiquitination, subsequently inactivating NF-κB and MAPK cascades; hepatocyte-specific LILRB4 knockout exacerbates HFD-induced insulin resistance, hepatic lipid accumulation, and inflammation, while overexpression reverses these phenotypes. Hepatocyte-specific LILRB4 knockout mice; LILRB4 overexpression in ob/ob mice; SHP-1 co-immunoprecipitation; TRAF6 ubiquitination assay; NF-κB and MAPK activation western blotting; metabolic phenotyping Hepatology High 29091299
2019 LILRB4 ITIMs: Y412 and Y442 phosphorylation sites are required for T cell suppression, while Y360 is not; all three ITIMs (Y360, Y412, Y442) are required for leukemia cell tissue infiltration; the intracellular domain of LILRB4 (not LILRB1) specifically mediates T cell suppression and AML cell migration in chimeric protein swap experiments. Site-directed mutagenesis of LILRB4 ITIM tyrosines; chimeric LILRB4/LILRB1 intracellular domain swap constructs; in vitro T cell suppression co-culture; in vivo AML infiltration mouse models Cellular & molecular immunology High 31700117
2019 Humanized anti-LILRB4 antibody h128-3 blocks LILRB4-APOE interaction and exerts anti-AML activity through four mechanisms: reversal of T cell suppression, inhibition of AML cell tissue infiltration, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis. LILRB4-APOE blocking assay; patient-derived xenograft mice; syngeneic immunocompetent AML mice; ADCC and ADCP functional assays; T cell co-culture Cancer immunology research High 31213474
2017 LILRB4 deficiency in macrophages promotes atherosclerosis by decreasing SHP-1 phosphorylation, which enhances NF-κB signaling-mediated inflammatory responses; bone marrow-specific LILRB4 deficiency recapitulates the pro-atherosclerotic phenotype. LILRB4−/−ApoE−/− double-knockout mice on HFD; bone marrow transplantation; SHP-1 phosphorylation western blotting; NF-κB activation assays; in vitro macrophage stimulation Clinical science Medium 28743735
2021 Fibronectin is a functional ligand for ILT3/LILRB4; fibronectin-ILT3 interaction polarizes myeloid cells toward a suppressive state; anti-ILT3 antibody blocking this interaction reprograms tumor-associated myeloid cells toward a stimulatory phenotype in human tumor explants. Ligand screening approach; myeloid cell polarization assays; anti-ILT3 blocking antibody; ex vivo human tumor explant treatment; phenotypic cytokine/surface marker analysis Cancer immunology research High 34426457
2021 Human LILRB4 and murine gp49B bind fibronectin with sub-micromolar affinity; the major binding site is the N-terminal 30-kDa module (FN30), distinct from the integrin-binding site; blockade of LILRB4-fibronectin interaction with anti-LILRB4 antibodies or recombinant FN30-Fc ameliorates autoimmune disease in lupus-prone BXSB/Yaa mice. Bio-layer interferometry binding kinetics; FN domain mapping; LILRB4-KO and blocking antibody in BXSB/Yaa mice; functional autoimmunity readouts International immunology High 34089617
2022 LILRB4/gp49B co-tethers fibronectin in cooperation with integrin β1 in cis on macrophages, forming a regulatory triplet; adherence to immobilized FN induces Syk phosphorylation that is augmented in gp49B-deficient macrophages, demonstrating that gp49B suppresses integrin-mediated pro-inflammatory Syk signaling at focal adhesions. FN pull-down co-immunoprecipitation with gp49B and integrin β1; confocal co-localization microscopy; Syk phosphorylation western blotting in WT vs gp49B-KO macrophages; RAW264.7 and THP-1 cell models International immunology Medium 35689642
2023 Fibronectin on target cells attenuates NK cell natural cytotoxicity via gp49B/LILRB4; gp49B-deficient NK cells show augmented Syk phosphorylation upon FN binding and enhanced killing of fibronectin-rich Lewis lung carcinoma cells (but not FN30-knockout cells), demonstrating that LILRB4 senses fibronectin on target cells in trans to deliver inhibitory signals in NK cells. gp49B-KO NK cells; cytotoxicity assays against FN-rich and FN-poor tumor cells; FN30-knockout target cells; Syk phosphorylation analysis; confocal and flow cytometric analysis of gp49B/integrin co-engagement International immunology High 37083755
2023 Fibronectin-LILRB4/gp49B interaction negatively regulates osteoclastogenesis: gp49B-deficient mice show reduced trabecular bone; FN N-terminal 30-kDa fragment promotes gp49B-mediated inhibition of osteoclast differentiation by increasing SHP-1 phosphorylation and TRAF6-SHP-1 association, thereby suppressing RANKL-induced TAK1/NF-κB/MAPK signaling. gp49B-KO mice with bone phenotyping (micro-CT, histology); RAW264.7 osteoclastogenesis assays with FN30; SHP-1 phosphorylation; TRAF6-SHP-1 co-immunoprecipitation; TAK1/NF-κB/MAPK western blotting International immunology High 36331874
2020 ILT3/LILRB4 promotes the suppressive phenotype of tumor-educated monocytic MDSCs; anti-ILT3 antibody treatment impairs acquisition of MDSC suppressor phenotype and reduces T cell suppression; combined ILT3 blockade with anti-PD1 enhances T cell IFNγ secretion. SK-MEL-5 cancer cell/PBMC co-culture MDSC generation; anti-ILT3 antibody blockade; T cell proliferation and IFNγ assays; flow cytometry phenotyping; anti-PD1 combination Molecular cancer research Medium 33372059
2021 In solid tumors, LILRB4-knockout mice or anti-LILRB4 antibody treatment reduces tumor burden and increases survival; LILRB4 absence increases tumor immune infiltrates, raises Teff/Treg ratio, shifts TAMs toward less suppressive phenotype, and reduces CD8+ T cell exhaustion; murine gp49B is the LILRB4 ortholog with two cytoplasmic ITIMs (vs three in human). LILRB4−/− mice; anti-LILRB4 antibody treatment; syngeneic tumor models; flow cytometry of tumor-infiltrating lymphocytes and macrophages; survival analysis The Journal of experimental medicine High 33974041
2022 gp49B (murine LILRB4) deficiency inhibits tumor metastasis and reduces monocytic MDSC tumor infiltration; gp49B-KO MDSCs show impaired pro-tumor functions (Treg activation, cancer cell migration, tumor angiogenesis) and increased plasma exosome miR-1 family miRNAs with anti-tumor properties. gp49B−/− tumor-bearing mice; tumor metastasis assays; MDSC transfer experiments; exosome miRNA profiling; functional MDSC co-culture assays Oncoimmunology Medium 35402083
2024 Galectin-8 (Gal-8) is a high-affinity functional ligand of LILRB4 that drives M-MDSC induction by activating STAT3 and inhibiting NF-κB; Gal-8 and APOE bind LILRB4 noncompetitively at distinct sites; LILRB4 knockout attenuates Gal-8-driven tumor growth in vivo. Ligand screening; binding affinity measurements; STAT3 and NF-κB activation assays in MDSC induction; competitive binding assays; LILRB4-KO mouse tumor models Cell reports. Medicine High 38232701
2024 Microglia-specific LILRB4 conditional knockout exacerbates ischemic brain injury by promoting CD8+ T cell infiltration; LILRB4-KD microglia show increased CCL2 secretion mediating CD8+ T cell recruitment, which is reversed by CCL2 inhibition; LILRB4 overexpression in microglia is neuroprotective. Microglia-specific Cre-loxP LILRB4 conditional KO and TG overexpression mice; tMCAO model; flow cytometry; scRNA-seq; spatial transcriptomics; T cell migration assays; CCL2 inhibition; recombinant arginase-1 Journal of neuroinflammation High 39217343
2023 LILRB4 regulates decidual MDSC function via a SHP-2/STAT6 pathway: T. gondii infection reduces STAT3 phosphorylation, decreasing LILRB4 expression on dMDSCs, which reduces p-SHP2 and p-STAT6 levels; SHP-2 directly binds STAT6, which binds the Arg-1 and IL-10 gene promoters to regulate their expression. LILRB4−/− pregnant mice infected with T. gondii; anti-LILRB4 neutralizing antibody in human dMDSCs; SHP-2/STAT6 co-immunoprecipitation; STAT6 ChIP on Arg-1 and IL-10 promoters; western blotting Parasites & vectors Medium 37461040
2025 Secretogranin 2 (SCG2) is a functional ligand of LILRB4 on monocytic cells; tumor-derived SCG2 promotes tumor growth in myeloid-specific LILRB4 transgenic mice in a T cell-dependent manner; LILRB4 blockade abrogates SCG2-induced immunosuppression; mechanistically, SCG2-LILRB4 interaction triggers SHP recruitment and SHP-independent STAT3 activation. LILRB4-SCG2 binding assay; myeloid-specific LILRB4 transgenic mice; SCG2-knockout host mice; T cell depletion; anti-LILRB4 blockade; SHP co-immunoprecipitation; STAT3 activation assays Nature immunology High 40707822
2024 LILRB4 on multiple myeloma cells promotes osteoclastogenesis and bone lesion by secreting RELT cytokine through a p-SHP2/NF-κB/RELT signaling pathway; LILRB4-KO conditioned medium does not promote osteoclast differentiation; exogenous RELT restores bone damage in LILRB4-KO cells. Conditioned medium osteoclast differentiation assays; xenograft and PDX models with micro-CT; cytokine array; RNA-seq; Co-IP; luciferase reporter; CRISPR-Cas9 LILRB4 deletion; RELT rescue experiments Journal of experimental & clinical cancer research High 38951916
2025 In myocardial ischemia-reperfusion injury, LILRB4 promotes inflammation and pyroptosis via SHP-2 phosphorylation/activation, increasing TXNIP, NLRP3, Caspase-1, and GSDMD expression; SHP2 inhibitor PHPS1 mitigates LILRB4-driven inflammation; LILRB4-KO mice show reduced pyroptosis markers and inflammatory cytokines after I/R. LILRB4 overexpression and knockdown in H9C2 cells and rat myocardium; LILRB4-KO mice; I/R and H/R models; SHP-2 phosphorylation western blotting; NLRP3/Caspase-1/GSDMD expression; SHP2 inhibitor PHPS1 Biochimica et biophysica acta. Molecular basis of disease Medium 40550372
2024 In multiple myeloma, IKZF1 transactivates LILRB4 expression to activate downstream STAT3-PFKFB1 signaling supporting MM cell proliferation; LILRB4 knockdown delays MM cell growth in vitro and in vivo. IKZF1 ChIP/luciferase reporter for LILRB4 transcription; LILRB4 knockdown; STAT3 and PFKFB1 western blotting; in vivo MM xenograft models Cell death & disease Medium 39025844
2020 ILT3-Fc treatment inhibits release of inflammatory microRNA-containing exosomes from alloactivated CD4+ T cells; these inflammatory exosomes can diminish the suppressive activity of ILT3-Fc-induced CD8+ T suppressor cells at high effector-to-suppressor ratios. Exosome isolation from mixed lymphocyte cultures ± ILT3-Fc; miRNA profiling; suppressor cell activity assays with exosome addition Human immunology Low 24862932
2025 Homoharringtonine (HHT) suppresses LILRB4 expression in monocytic AML by promoting FTO degradation, which increases global m6A RNA methylation, subsequently reducing expression of MLL1 and LILRB4; reduced LILRB4 enhances CD8+ T cell cytotoxicity against THP-1 cells. RNA-seq; FTO protein degradation assays; m6A level measurement; LILRB4 mRNA/protein western blotting; CD8+ T cell cytotoxicity assays; in vivo AML xenograft mouse models Cell proliferation Medium 40590394

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 624 11875462
1997 A novel inhibitory receptor (ILT3) expressed on monocytes, macrophages, and dendritic cells involved in antigen processing. The Journal of experimental medicine 357 9151699
2005 Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3. Blood 318 16030186
2018 LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration. Nature 253 30333625
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 246 15670976
2004 Alloantigen specific CD8+CD28- FOXP3+ T suppressor cells induce ILT3+ ILT4+ tolerogenic endothelial cells, inhibiting alloreactivity. International immunology 204 15226269
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
2021 LILRB4 suppresses immunity in solid tumors and is a potential target for immunotherapy. The Journal of experimental medicine 116 33974041
2018 A Novel Anti-LILRB4 CAR-T Cell for the Treatment of Monocytic AML. Molecular therapy : the journal of the American Society of Gene Therapy 115 30131301
2012 Expression of immunoglobulin-like transcript (ILT)2 and ILT3 in human gastric cancer and its clinical significance. Molecular medicine reports 78 22246571
2019 Disrupting LILRB4/APOE Interaction by an Efficacious Humanized Antibody Reverses T-cell Suppression and Blocks AML Development. Cancer immunology research 72 31213474
2004 Immunoglobulin-like transcripts ILT2, ILT3 and ILT7 are expressed by human dendritic cells and down-regulated following activation. Gene 67 15094202
2019 LILRB4 ITIMs mediate the T cell suppression and infiltration of acute myeloid leukemia cells. Cellular & molecular immunology 66 31700117
2020 ILT3 (LILRB4) Promotes the Immunosuppressive Function of Tumor-Educated Human Monocytic Myeloid-Derived Suppressor Cells. Molecular cancer research : MCR 60 33372059
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
2006 Aspirin-treated human DCs up-regulate ILT-3 and induce hyporesponsiveness and regulatory activity in responder T cells. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 56 16869801
2012 Expression of immune inhibitory receptor ILT3 in acute myeloid leukemia with monocytic differentiation. Cytometry. Part B, Clinical cytometry 55 23027709
2007 Central role of ILT3 in the T suppressor cell cascade. Cellular immunology 52 17923119
2021 The Fibronectin-ILT3 Interaction Functions as a Stromal Checkpoint that Suppresses Myeloid Cells. Cancer immunology research 50 34426457
2013 Rapamycin induces ILT3(high)ILT4(high) dendritic cells promoting a new immunoregulatory pathway. Kidney international 50 24107844
2007 Expression of inhibitory receptor ILT3 on neoplastic B cells is associated with lymphoid tissue involvement in chronic lymphocytic leukemia. Cytometry. Part B, Clinical cytometry 50 17266150
2020 LILRB4-targeting Antibody-Drug Conjugates for the Treatment of Acute Myeloid Leukemia. Molecular cancer therapeutics 47 32879051
2022 LILRB4 promotes tumor metastasis by regulating MDSCs and inhibiting miR-1 family miRNAs. Oncoimmunology 46 35402083
2018 Hepatic leukocyte immunoglobulin-like receptor B4 (LILRB4) attenuates nonalcoholic fatty liver disease via SHP1-TRAF6 pathway. Hepatology (Baltimore, Md.) 46 29091299
2017 Decidual Macrophage Functional Polarization during Abnormal Pregnancy due to Toxoplasma gondii: Role for LILRB4. Frontiers in immunology 46 28883820
2008 CD8+ T suppressor cells and the ILT3 master switch. Human immunology 44 18817834
2020 ILT3 promotes tumor cell motility and angiogenesis in non-small cell lung cancer. Cancer letters 43 33152402
2009 Leukocyte Ig-like receptor B4 (LILRB4) is a potent inhibitor of FcgammaRI-mediated monocyte activation via dephosphorylation of multiple kinases. The Journal of biological chemistry 43 19833736
2017 ILT3.Fc-CD166 Interaction Induces Inactivation of p70 S6 Kinase and Inhibits Tumor Cell Growth. Journal of immunology (Baltimore, Md. : 1950) 42 29263213
2011 Crystal structure of leukocyte Ig-like receptor LILRB4 (ILT3/LIR-5/CD85k): a myeloid inhibitory receptor involved in immune tolerance. The Journal of biological chemistry 42 21454581
2010 Membrane and soluble ILT3 are critical to the generation of T suppressor cells and induction of immunological tolerance. International reviews of immunology 41 20132030
2007 IL-10 inhibits endothelium-dependent T cell costimulation by up-regulation of ILT3/4 in human vascular endothelial cells. European journal of immunology 37 17163451
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 LILRB4 deficiency aggravates the development of atherosclerosis and plaque instability by increasing the macrophage inflammatory response via NF-κB signaling. Clinical science (London, England : 1979) 32 28743735
2012 Functional genetic polymorphisms in ILT3 are associated with decreased surface expression on dendritic cells and increased serum cytokines in lupus patients. Annals of the rheumatic diseases 31 22904259
2022 LILRB4, an immune checkpoint on myeloid cells. Blood science (Baltimore, Md.) 30 35957669
2024 Discovery of galectin-8 as an LILRB4 ligand driving M-MDSCs defines a class of antibodies to fight solid tumors. Cell reports. Medicine 28 38232701
2016 Tolerogenic immunoreceptor ILT3/LILRB4 paradoxically marks pathogenic auto-antibody-producing plasmablasts and plasma cells in non-treated SLE. International immunology 28 27742834
2024 Microglia LILRB4 upregulation reduces brain damage after acute ischemic stroke by limiting CD8+ T cell recruitment. Journal of neuroinflammation 27 39217343
2020 LILRB4, from the immune system to the disease target. American journal of translational research 27 32774691
2021 Blockade of checkpoint ILT3/LILRB4/gp49B binding to fibronectin ameliorates autoimmune disease in BXSB/Yaa mice. International immunology 25 34089617
2012 Induction of antigen-specific human T suppressor cells by membrane and soluble ILT3. Experimental and molecular pathology 25 23018130
2017 Ectopic ILT3 controls BCR-dependent activation of Akt in B-cell chronic lymphocytic leukemia. Blood 23 28931525
2023 A target discovery pipeline identified ILT3 as a target for immunotherapy of multiple myeloma. Cell reports. Medicine 22 37467717
2007 Pancreas cancer and the role of soluble immunoglobulin-like transcript 3 (ILT3). JOP : Journal of the pancreas 21 17993722
2020 LILRB4 expression in chronic myelomonocytic leukemia and myelodysplastic syndrome based on response to hypomethylating agents. Leukemia & lymphoma 20 32036728
2018 Leukocyte immunoglobulin-like receptor B4 (LILRB4) negatively mediates the pathological cardiac hypertrophy by suppressing fibrosis, inflammation and apoptosis via the activation of NF-κB signaling. Biochemical and biophysical research communications 20 30581005
2020 Leukocyte immunoglobulin-like receptor B1 and B4 (LILRB1 and LILRB4): Highly sensitive and specific markers of acute myeloid leukemia with monocytic differentiation. Cytometry. Part B, Clinical cytometry 19 32918786
2018 LILRB4 Decrease on uDCs Exacerbate Abnormal Pregnancy Outcomes Following Toxoplasma gondii Infection. Frontiers in microbiology 19 29643846
2010 Gene profile analysis of CD8(+) ILT3-Fc induced T suppressor cells. Human immunology 17 20974207
2024 LILRB4 on multiple myeloma cells promotes bone lesion by p-SHP2/NF-κB/RELT signal pathway. Journal of experimental & clinical cancer research : CR 16 38951916
2020 Suppression of Experimental Autoimmune Encephalomyelitis by ILT3.Fc. Journal of immunology (Baltimore, Md. : 1950) 15 33361206
2024 LILRB4 Checkpoint for Immunotherapy: Structure, Mechanism and Disease Targets. Biomolecules 14 38397424
2023 Fibronectin on target cells attenuates natural cytotoxicity of NK cells via myeloid immune checkpoint ILT3/LILRB4/gp49B. International immunology 14 37083755
2022 NK cells require immune checkpoint receptor LILRB4/gp49B to control neurotropic Zika virus infections in mice. JCI insight 14 35132958
2019 Augmented ILT3/LILRB4 Expression of Peripheral Blood Antibody Secreting Cells in the Acute Phase of Kawasaki Disease. The Pediatric infectious disease journal 14 30882741
2006 ILT3+ ILT4+ tolerogenic endothelial cells in transplantation. Transplantation 14 16829792
2024 LILRB4 represents a promising target for immunotherapy by dual targeting tumor cells and myeloid-derived suppressive cells in multiple myeloma. Haematologica 13 38813706
2023 LILRB4 regulates the function of decidual MDSCs via the SHP-2/STAT6 pathway during Toxoplasma gondii infection. Parasites & vectors 13 37461040
2024 LILRB4 regulates multiple myeloma development through STAT3-PFKFB1 pathway. Cell death & disease 12 39025844
2023 Fibronectin-LILRB4/gp49B interaction negatively regulates osteoclastogenesis through inhibition of RANKL-induced TRAF6/TAK1/NF-kB/MAPK signaling. International immunology 12 36331874
2022 Myeloid immune checkpoint ILT3/LILRB4/gp49B can co-tether fibronectin with integrin on macrophages. International immunology 12 35689642
2006 Immunosuppressive activity of recombinant ILT3. International immunopharmacology 11 17161342
2011 Induction of CD4+ CD25+ Foxp3+ T regulatory cells by dendritic cells derived from ILT3 lentivirus-transduced human CD34+ cells. Transplant immunology 10 22005288
2000 Common polymorphisms and alternative splicing in the ILT3 gene are not associated with atopy. European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics 10 10940079
2025 Secretogranin 2 binds LILRB4 resulting in immunosuppression. Nature immunology 9 40707822
2021 Characterization of the Leucocyte Immunoglobulin-like Receptor B4 (Lilrb4) Expression in Microglia. Biology 8 34943215
2021 Biomimetic design of inhibitors of immune checkpoint LILRB4. Biophysical chemistry 8 34963077
2014 ILT3.Fc inhibits the production of exosomes containing inflammatory microRNA in supernatants of alloactivated T cells. Human immunology 7 24862932
2024 NLRP12/C1qA positive feedback in tumor-associated macrophages regulates immunosuppression through LILRB4/NF-κB pathway in lung adenocarcinoma. Cancer immunology, immunotherapy : CII 6 39527158
2022 Co-localization of Fibronectin Receptors LILRB4/gp49B and Integrin on Dendritic Cell Surface. The Tohoku journal of experimental medicine 6 35691913
2020 Correction to: LILRB4 ITIMs mediate the T cell suppression and infiltration of acute myeloid leukemia cells. Cellular & molecular immunology 6 32005951
2025 LILRB4 in tumor-associated macrophage regulates macrophage polarization and glioblastoma progression via STAT3/IL10 axis. Gene 5 41038302
2024 Downregulation of LILRB4 Promotes Human Aortic Smooth Muscle Cell Contractile Phenotypic Switch and Apoptosis in Aortic Dissection. Cardiovascular toxicology 5 38324114
2024 LILRB4 knockdown inhibits aortic dissection development by regulating pyroptosis and the JAK2/STAT3 signaling pathway. Scientific reports 5 38971897
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
2023 Fc gamma receptors promote antibody-induced LILRB4 internalization and immune regulation of monocytic AML. Antibody therapeutics 4 38235377
2020 CD85k Contributes to Regulatory T Cell Function in Chronic Viral Infections. International journal of molecular sciences 4 33375121
2016 Effect of Mesenchymal Stem Cells on ILT3 Expression in the Splenocytes of Skin Graft Recipient Mice. Iranian journal of immunology : IJI 4 27999239
2025 A phase 1 study of IO-202, an anti-LILRB4 antibody, in chronic myelomonocytic leukemia and acute myeloid leukemia. Blood neoplasia 3 40919482
2025 LILRB4 exacerbates myocardial ischemia-reperfusion injury by promoting inflammation and pyroptosis. Biochimica et biophysica acta. Molecular basis of disease 2 40550372
2025 Homoharringtonine Promotes FTO Degradation to Suppress LILRB4-Mediated Immune Evasion in Acute Monocytic Leukaemia. Cell proliferation 2 40590394
2025 Uncovering the Associations of LILRB4 Genotypes With Parkinson's Disease: From Clinical Traits to Potential Pathologies. CNS neuroscience & therapeutics 2 40702763
2024 Lilrb4 ameliorates ileal injury in rats with hemorrhagic shock and suppresses the activation of NF-κB signaling pathway. Biochimica et biophysica acta. Molecular basis of disease 2 38367899
2024 Disruption of Circadian Clock Induces Abnormal Mammary Morphology and Aggressive Basal Tumorigenesis by Enhancing LILRB4 Signaling. bioRxiv : the preprint server for biology 2 38562905
2023 Molecular regulatory mechanism of LILRB4 in the immune response. Central-European journal of immunology 2 37206591
2011 [ILT3+/ILT4+ tolerogenic dendritic cells and their influence on allograft survival]. Biomedica : revista del Instituto Nacional de Salud 2 22159546
2026 LILRB4 shapes an immunosuppressive microenvironment to drive cervical cancer progression through tumor-infiltrating myeloid cell expansion and CD8+ T-cell suppression. Cellular and molecular life sciences : CMLS 1 41776053
2025 LILRB4 as a novel immunotherapeutic target for multiple diseases. Biochemical pharmacology 1 39842553
2025 Presence of LILRB4 SNP rs1048801 modulates acute myeloid leukemia progression and inhibits CD4+ T cells proliferation. Journal of leukocyte biology 1 40275747
2025 The immune checkpoint LILRB4 promotes immune evasion and is correlated with disease progression and secondary malignancies in chronic lymphocytic leukemia. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 1 40516328
2026 Dual epitope anti-LILRB4 synthetic T-cell receptor and antigen receptor (STAR)-T-cell therapy for relapsed/refractory acute myeloid leukemia. Signal transduction and targeted therapy 0 42225613
2025 LILRB4 specific overexpression in myeloid cells promotes tumor progression and immunosuppression in mouse models. Biochemical and biophysical research communications 0 40048761
2025 LILRB4 regulates circadian disruption-induced mammary tumorigenesis via non-canonical WNT signaling pathway. Oncogene 0 41102383
2025 The combination of LILRB4-targeting NK cell engagers and cGAS-STING agonists enhances the anti-multiple myeloma immune activity of NK cells. PloS one 0 41417876
2025 Ginsenoside Rg2 upregulates expression of Lilrb4 and inhibits the NF-κB signaling pathway to alleviate hemorrhagic shock/reperfusion-induced intestinal injury. Journal of clinical biochemistry and nutrition 0 41841109
2024 A Switch Protein Adapter for Anti-LILRB4 CAR-T Cells. European journal of immunology 0 39663681
2023 LILRB4/gp49B Co-Localizes with Integrin via Fibronectin at Focal Adhesion Sites on Mast Cells. The Tohoku journal of experimental medicine 0 36642505

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