Affinage

LILRB4

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

Length
448 aa
Mass
49.4 kDa
Annotated
2026-04-28
99 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LILRB4 (ILT3) is an ITIM-bearing inhibitory immunoreceptor on myeloid cells that functions as a context-dependent immune checkpoint, dampening innate and adaptive immune activation through phosphatase-mediated suppression of activating kinase cascades. Upon engagement by extracellular ligands — APOE in AML (PMID:30333625), fibronectin (FN30 domain) in the tumor microenvironment and at focal adhesions (PMID:34089617, PMID:35689642), galectin-8 in solid tumors (PMID:38232701), CD166/ALCAM on activated T cells (PMID:29263213), and secretogranin 2 from tumor cells (PMID:40707822) — LILRB4 recruits SHP-1 or SHP-2 to its cytoplasmic ITIMs (with Y412 and Y442 critical for T cell suppression and all three ITIMs required for tissue infiltration (PMID:31700117)), leading to dephosphorylation of Syk, Lck, LAT, and Erk (PMID:19833736) and suppression of downstream NF-κB, MAPK, and STAT pathways, which collectively promote tolerogenic APC and MDSC polarization, suppress T and NK cell effector function, and facilitate leukemia cell infiltration (PMID:9151699, PMID:33974041, PMID:37083755). Beyond immune cells, LILRB4 inhibits TRAF6 ubiquitination via SHP-1 in hepatocytes to restrain NF-κB/MAPK-driven inflammation in NAFLD (PMID:29091299), negatively regulates osteoclastogenesis through SHP-1–TRAF6 association (PMID:36331874), and in cardiomyocytes activates SHP-2/TXNIP/NLRP3 pyroptotic signaling during ischemia–reperfusion injury (PMID:40550372).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Establishing LILRB4 as an inhibitory receptor: co-ligation with activating receptors on APCs was shown to dampen calcium flux and tyrosine phosphorylation through SHP-1 recruitment to ITIMs, while also mediating antigen internalization — defining LILRB4's dual role in signal inhibition and antigen processing.

    Evidence Co-ligation assays on monocytes/DCs with calcium flux, phosphorylation, SHP-1 recruitment, and antigen presentation readouts

    PMID:9151699

    Open questions at the time
    • Identity of the natural extracellular ligand unknown
    • Which specific ITIMs are functionally required not yet determined
    • Whether SHP-1 is the sole effector phosphatase unclear
  2. 2002 High

    LILRB4 upregulation on APCs was shown to be induced by CD8+CD28− T suppressor cells, rendering APCs tolerogenic and capable of inducing CD4+ T cell anergy — placing LILRB4 in a feedback circuit of peripheral tolerance.

    Evidence In vitro Ts–APC co-cultures with flow cytometry and MLR assays, replicated in transplant recipients

    PMID:11875462

    Open questions at the time
    • Molecular signals from Ts cells that upregulate LILRB4 not identified
    • Whether LILRB4 ITIM signaling is required for the tolerogenic phenotype not tested
  3. 2006 Medium

    Dissection of intracellular versus extracellular signaling revealed that membrane LILRB4 inhibits NF-κB and costimulatory molecule transcription via its ITIMs, yet a cytoplasmic-deletion mutant retains extracellular T cell–suppressive capacity — establishing a bidirectional signaling model.

    Evidence Cytoplasmic deletion mutants in KG1 cell line with T cell proliferation and NF-κB activity assays

    PMID:17161342

    Open questions at the time
    • Extracellular suppressive mechanism (reverse signaling or ligand decoy) not molecularly defined
    • Single cell line system limits generalizability
  4. 2009 High

    The scope of LILRB4's inhibitory mechanism was broadened beyond SHP-1: co-ligation with FcγRI showed dephosphorylation of Lck, Syk, LAT, and Erk, and pharmacological evidence implicated additional phosphatases, revealing a broader kinase-suppressive program than initially appreciated.

    Evidence Cross-linking on THP-1 and primary monocytes with phosphoprotein western blot and phosphatase inhibitor reversal

    PMID:19833736

    Open questions at the time
    • Identity of the non-SHP-1 phosphatase(s) not determined
    • Whether identical substrates are targeted in all myeloid cell contexts unknown
  5. 2010 Medium

    Soluble ILT3-Fc was shown to induce CD8+ T suppressor cell differentiation marked by BCL6, SOCS1, and DUSP10 upregulation, providing the molecular gene signature downstream of extracellular LILRB4 engagement on T cells.

    Evidence Soluble ILT3-Fc treatment of human T cells with gene expression profiling and humanized mouse transplant model

    PMID:20132030

    Open questions at the time
    • T cell receptor for soluble ILT3-Fc not identified
    • Whether BCL6 is required for Ts induction not tested with loss-of-function
  6. 2011 High

    The 1.7 Å crystal structure of the LILRB4 ectodomain revealed a distinctive obtuse interdomain angle and electrostatic surface incompatible with MHC class I binding, predicting non-MHC ligands and distinguishing LILRB4 from Group 1 LILRs.

    Evidence X-ray crystallography at 1.7 Å resolution with structural comparison to MHC-binding LILRs

    PMID:21454581

    Open questions at the time
    • No co-crystal with any ligand obtained
    • Structural basis for ligand selectivity unresolved
  7. 2017 High

    Multiple ligands and cell contexts for LILRB4 were identified in parallel: CD166/ALCAM on activated T cells was found by mass spectrometry and SPR [PMID:29263213]; in CLL, LILRB4 clustered with BCR and SHIP1 to inhibit Akt [PMID:28931525]; and in macrophages, LILRB4 deficiency enhanced NF-κB via reduced SHP-1 phosphorylation, promoting atherosclerosis [PMID:28743735].

    Evidence MS/SPR ligand identification with CD166 KO validation; confocal imaging of inhibitory clusters in CLL; double-KO mice with bone marrow transplant in atherosclerosis model

    PMID:28743735 PMID:28931525 PMID:29263213

    Open questions at the time
    • Whether CD166 engagement triggers the same ITIM-dependent pathway as other ligands not shown
    • SHIP1 vs. SHP-1 preference in different cell types not systematically compared
  8. 2018 High

    A full signaling axis was defined in AML: APOE as the extracellular ligand activates LILRB4, which recruits SHP-2 intracellularly to drive uPAR and ARG1 expression, supporting both T cell suppression and leukemia tissue infiltration; separately, in hepatocytes, LILRB4 recruits SHP-1 to block TRAF6 ubiquitination and NF-κB/MAPK signaling in NAFLD.

    Evidence LILRB4 KO and antibody blockade in AML mouse models with pathway analysis [PMID:30333625]; hepatocyte-specific KO/OE with co-IP of SHP1-TRAF6 [PMID:29091299]; decidual macrophage KO with M1/M2 polarization [PMID:28883820]

    PMID:28883820 PMID:29091299 PMID:30333625

    Open questions at the time
    • How APOE-triggered SHP-2 differs from SHP-1-mediated pathways mechanistically not resolved
    • Whether SHP-2 vs. SHP-1 preference is cell-type or ligand determined unknown
  9. 2019 High

    Systematic ITIM mutagenesis resolved that Y412 and Y442 are essential for T cell suppression while all three ITIMs (Y360, Y412, Y442) are required for tissue infiltration; chimeric proteins showed these functions are specific to LILRB4's intracellular domain, not shared with LILRB1; humanized anti-LILRB4 antibody blocking APOE binding confirmed therapeutic tractability.

    Evidence Site-directed mutagenesis with chimeric constructs in vitro and in vivo [PMID:31700117]; anti-LILRB4 antibody in PDX and syngeneic models [PMID:31213474]

    PMID:31213474 PMID:31700117

    Open questions at the time
    • Which phosphatases bind each individual ITIM not mapped
    • Structural basis for ITIM functional specialization unknown
  10. 2021 High

    Fibronectin (specifically the N-terminal FN30 domain) was established as a major LILRB4 ligand with sub-micromolar affinity, defining a 'stromal checkpoint': FN-LILRB4 interaction polarizes myeloid cells toward immunosuppression in tumors, while blockade ameliorates autoimmune disease in lupus-prone mice; LILRB4 KO on TAMs shifted phenotype and improved anti-tumor immunity.

    Evidence Bio-layer interferometry for FN30 affinity [PMID:34089617]; anti-ILT3 blockade in human tumor explants [PMID:34426457]; LILRB4-KO tumor models with TAM phenotyping [PMID:33974041]

    PMID:33974041 PMID:34089617 PMID:34426457

    Open questions at the time
    • Whether FN30 and APOE compete for the same binding site not determined
    • Structural basis of FN30-LILRB4 interaction unresolved
  11. 2022 High

    A ternary complex model was established: LILRB4/gp49B co-tethers fibronectin with integrins at focal adhesions, suppressing integrin-mediated Syk phosphorylation — providing a mechanism for how LILRB4 integrates extracellular matrix sensing with inhibitory signaling at adhesion sites.

    Evidence Co-IP of gp49B/integrin β1/FN complex; confocal imaging; Syk phosphorylation in gp49B-deficient macrophages

    PMID:35689642

    Open questions at the time
    • Stoichiometry and dynamics of the ternary complex not characterized
    • Whether integrin subtype specificity matters not addressed
  12. 2023 High

    LILRB4 was shown to regulate NK cell cytotoxicity and osteoclastogenesis via fibronectin engagement: gp49B-deficient NK cells had augmented Syk phosphorylation and superior killing of FN-rich targets, while in osteoclast precursors, FN-LILRB4 interaction recruited SHP-1 to TRAF6 to suppress TAK1/NF-κB/MAPK and limit RANKL-induced osteoclastogenesis.

    Evidence gp49B-KO NK cell cytotoxicity and Syk phosphorylation [PMID:37083755]; gp49B-KO mice with micro-CT and SHP-1–TRAF6 co-IP [PMID:36331874]; SHP-2/STAT6 co-IP in decidual MDSCs [PMID:37461040]

    PMID:36331874 PMID:37083755 PMID:37461040

    Open questions at the time
    • How the same receptor engages SHP-1 in osteoclasts but SHP-2 in AML/MDSCs not explained
    • Whether FN30 binding site overlaps with galectin-8 or APOE binding sites unknown
  13. 2024 High

    Galectin-8 was identified as a high-affinity LILRB4 ligand that binds noncompetitively with APOE, activates STAT3, and inhibits NF-κB to polarize MDSCs in solid tumors; separately, in myeloma, LILRB4 drives osteoclastogenesis via SHP-2/NF-κB-dependent RELT secretion, and IKZF1 was identified as a transcriptional activator of LILRB4 feeding into STAT3-PFKFB1 signaling.

    Evidence Ligand screening with competitive binding and LILRB4-KO tumor models [PMID:38232701]; myeloma xenograft/PDX with cytokine array and RELT rescue [PMID:38951916]; IKZF1 transcriptional assays [PMID:39025844]

    PMID:38232701 PMID:38951916 PMID:39025844

    Open questions at the time
    • Structural basis for noncompetitive APOE/Gal-8 binding not resolved
    • Whether IKZF1-driven LILRB4 expression occurs in non-myeloma contexts unknown
  14. 2025 High

    Secretogranin 2 (SCG2) was discovered as a tumor-derived LILRB4 ligand that triggers SHP recruitment and SHP-independent STAT3 activation to promote immunosuppressive myeloid infiltration; separately, LILRB4 was found to promote pyroptosis in cardiomyocytes via SHP-2/TXNIP/NLRP3 during ischemia–reperfusion, and HHT was shown to suppress LILRB4 via FTO-mediated m6A regulation.

    Evidence Myeloid-specific LILRB4 transgenic and SCG2-KO mice with binding and signaling assays [PMID:40707822]; LILRB4-KO mice in I/R with SHP2 inhibitor [PMID:40550372]; FTO degradation and m6A assays in AML [PMID:40590394]

    PMID:40550372 PMID:40590394 PMID:40707822

    Open questions at the time
    • SCG2 binding site on LILRB4 relative to other ligands not mapped
    • How LILRB4 switches from anti-inflammatory to pro-pyroptotic signaling in cardiomyocytes not explained
    • Whether m6A regulation of LILRB4 is generalizable beyond AML unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for multi-ligand binding at the ectodomain (APOE, FN30, galectin-8, CD166, SCG2); the molecular determinants that switch LILRB4 between SHP-1- and SHP-2-dependent pathways in different cell types; and whether the extracellular ITIM-independent suppressive activity involves reverse signaling through a T cell counter-receptor.
  • No co-crystal structure with any ligand
  • SHP-1 vs. SHP-2 selectivity mechanism unknown
  • Reverse signaling mechanism molecularly undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0060089 molecular transducer activity 4
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-168256 Immune System 7 R-HSA-1643685 Disease 5 R-HSA-5357801 Programmed Cell Death 1
Partners
ALCAMAPOEFN1LGALS8SHIP1SHP-1SHP-2TRAF6

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 LILRB4 (ILT3) co-ligation to stimulatory receptors on APCs blunts increased [Ca2+]i and tyrosine phosphorylation via recruitment of SHP-1 (SH2-containing protein tyrosine phosphatase 1) to its cytoplasmic ITIMs; additionally, ILT3 mediates antigen internalization and delivery to intracellular compartments for processing and T cell presentation. Co-ligation assays on monocytes/DCs; calcium flux measurement; tyrosine phosphorylation assay; SHP-1 recruitment assay; antigen internalization and presentation assay The Journal of experimental medicine High 9151699
2002 CD8+CD28- T suppressor (Ts) cells induce upregulation of ILT3 and ILT4 on monocytes and dendritic cells, rendering APCs tolerogenic with reduced costimulatory molecule expression, and these tolerogenic APCs induce antigen-specific CD4+ T helper cell unresponsiveness. In vitro co-culture of Ts cells with APCs; flow cytometry for ILT3/ILT4 and costimulatory molecule expression; MLR proliferation assay Nature immunology High 11875462
2006 Membrane-expressed ILT3 signals intracellularly to inhibit NF-κB activation and transcription of costimulatory molecules; ILT3 cytoplasmic deletion mutants (ILT3Δ) retain extracellular suppressive activity on T cells, demonstrating extracellular signaling capacity independent of ITIMs, whereas ILT4Δ loses suppressive activity entirely, requiring its cytoplasmic ITIMs. Cytoplasmic deletion mutant transfection in KG1 dendritic-like cell line; T cell proliferation and CMC assays; NF-κB activity assay International immunopharmacology Medium 17161342
2009 LILRB4 co-ligates with FcγRI (CD64) on monocytes, aggregates to sites of activation, and inhibits FcγRI-mediated TNF-α production by dephosphorylating multiple signaling proteins including Lck, Syk, LAT, and Erk, but not alpha-actinin-4; phosphatase inhibitor reversal implicates phosphatases other than SHP-1. Cross-linking assay on THP-1 cells and primary monocytes; ELISA for TNF-α; phosphoprotein western blot; pharmacological inhibitors of phosphatases (sodium pervanadate, sodium stibogluconate) The Journal of biological chemistry High 19833736
2011 Crystal structure of the LILRB4 ectodomain resolved to 1.7 Å reveals two Ig-like domains with a distinctive obtuse interdomain angle (~107°) and 3(10) helices in the D2 domain; structural comparison indicates LILRB4 is electrostatically and conformationally unsuited to MHC class I ligation, predicting non-MHC ligands. X-ray crystallography (1.7 Å); engineered disulfide bond in D2 domain for stability; structural comparison with Group 1 LILRs The Journal of biological chemistry High 21454581
2017 ILT3 (LILRB4) ligand on activated T cells is CD166/ALCAM, identified by flow cytometry, mass spectrometry, and Biacore; ILT3.Fc binding to CD166 inhibits CD4+ Th proliferation and induces CD8+CD28- T suppressor cells; CD166 knockdown abolishes these effects; ILT3.Fc inhibits tumor cell growth via inhibition of the p70S6K signaling pathway. Flow cytometry; mass spectrometry; Biacore surface plasmon resonance; CD166 knockdown by nucleofection; CRISPR-Cas9 CD166 knockout; in vitro and in vivo tumor models Journal of immunology High 29263213
2018 In AML cells, LILRB4 supports tumour cell tissue infiltration and suppresses T cell activity through a signalling pathway involving extracellular APOE as ligand, intracellular SHP-2 recruitment, and downstream activation of uPAR and ARG1; deletion or antibody blockade of LILRB4 impedes AML development in mouse models. Mouse AML models; human AML cells; LILRB4 knockout; antibody blockade; ARG1 and uPAR pathway analysis; T cell suppression assays; tissue infiltration assays Nature High 30333625
2018 Hepatic LILRB4 recruits SHP1 to inhibit TRAF6 ubiquitination, thereby inactivating NF-κB and MAPK cascades; hepatocyte-specific LILRB4 knockout exacerbates high-fat diet-induced NAFLD including insulin resistance, lipid accumulation and inflammation, while overexpression reverses these phenotypes. Hepatocyte-specific knockout (LILRB4-HKO); overexpression transgenic mice; ob/ob model; SHP1 co-immunoprecipitation; TRAF6 ubiquitination assay; NF-κB and MAPK activity Hepatology High 29091299
2019 LILRB4 ITIMs Y412 and Y442, but not Y360, are required for T cell inhibition by AML cells; all three ITIMs (Y360, Y412, Y442) are needed for leukemia cell tissue infiltration; the intracellular domain of LILRB4 (but not LILRB1) specifically mediates these functions, as shown by chimeric protein experiments. Site-directed mutagenesis of ITIM tyrosines; chimeric LILRB4/LILRB1 constructs; in vitro T cell suppression assays; in vivo AML infiltration mouse models Cellular & molecular immunology High 31700117
2019 Humanized anti-LILRB4 antibody h128-3 blocks the LILRB4/APOE interaction, reverses T cell suppression, inhibits AML cell tissue infiltration, and mediates ADCC and ADCP, confirming APOE as the functional extracellular ligand triggering LILRB4 signaling in AML. Patient-derived xenograft mice; syngeneic immunocompetent AML mice; antibody blocking experiments; T cell functional assays; ADCC/ADCP assays; chemotherapy combination Cancer immunology research High 31213474
2017 LILRB4 deficiency in macrophages promotes atherosclerosis development via decreased Shp1 phosphorylation, which enhances NF-κB-mediated inflammatory responses; bone marrow transplantation confirms the effect is macrophage-intrinsic. LILRB4-/-ApoE-/- double knockout mice; high-fat diet atherosclerosis model; bone marrow transplantation; Shp1 phosphorylation assay; NF-κB activity measurement Clinical science High 28743735
2021 Fibronectin is a functional ligand of ILT3/LILRB4 in the tumor microenvironment; fibronectin-ILT3 interaction polarizes myeloid cells toward a suppressive state, and this is reversed by an ILT3-specific blocking antibody, defining a 'stromal checkpoint' mechanism. Ligand screening approach; myeloid cell polarization assays; ex vivo human tumor explant treatment with anti-ILT3; functional phenotyping Cancer immunology research High 34426457
2021 Fibronectin (specifically the N-terminal 30 kDa domain, FN30) is identified as a physiological ligand for both human LILRB4 and murine gp49B with sub-micromolar affinity; blockade of B4-FN binding ameliorates autoimmune disease in lupus-prone BXSB/Yaa mice. Bio-layer interferometry; recombinant FN30-Fc fusion protein; BXSB/Yaa mouse autoimmune model; antibody blockade experiments International immunology High 34089617
2021 LILRB4 on tumor-associated macrophages suppresses anti-tumor immunity; LILRB4 knockout or antibody blockade reduces tumor burden, increases effector-to-Treg ratio, and shifts TAM phenotype toward less suppressive; LILRB4 (gp49B in mice) signals through ITIMs on macrophages. LILRB4-/- mice; anti-LILRB4 antibody treatment; tumor challenge models; flow cytometry of tumor infiltrates; TAM phenotyping The Journal of experimental medicine High 33974041
2017 ILT3 (LILRB4) expressed on CLL B cells inhibits Akt kinase activation upon BCR stimulation by mediating dynamic coalescence of ILT3, BCRs, and SHIP1 (phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1) into inhibitory clusters at the cell surface; ILT3 expression in CLL is driven by Deltex1. Flow cytometry; confocal imaging of inhibitory clusters; Akt phosphorylation assay; BCR stimulation assay; Deltex1 manipulation Blood High 28931525
2023 Fibronectin on target cells attenuates NK cell natural cytotoxicity via LILRB4/gp49B; gp49B-deficient NK cells show augmented Syk tyrosine phosphorylation and increased killing of fibronectin-rich tumor cells, indicating LILRB4 delivers an inhibitory signal upon trans-engagement with fibronectin on target cells. Flow cytometry; gp49B-deficient NK cells; NK cell cytotoxicity assays against FN-rich and FN-poor target cells; FN30-KO target cells; Syk phosphorylation biochemical assay International immunology High 37083755
2022 LILRB4/gp49B and integrin co-tether fibronectin on macrophages in a triplet configuration (B4/gp49B-FN-integrin); gp49B deficiency augments FN-induced Syk phosphorylation, indicating LILRB4 suppresses integrin-mediated pro-inflammatory signaling at focal adhesion sites. FN pull-down/co-IP showing gp49B and integrin β1 in same complex; confocal fluorescent imaging; Syk phosphorylation in gp49B-deficient macrophages; RAW264.7 and THP-1 cell adhesion assays International immunology High 35689642
2023 Fibronectin-LILRB4/gp49B interaction negatively regulates RANKL-induced osteoclastogenesis by increasing SHP-1 phosphorylation and TRAF6-SHP-1 association, suppressing downstream TAK1, NF-κB, and MAPK phosphorylation; gp49B-deficient mice show increased osteoclast formation and trabecular bone loss. gp49B knockout mice; micro-CT; osteoclast differentiation assays; SHP-1 co-IP with TRAF6; TAK1/NF-κB/MAPK phosphorylation western blot; FN30 fragment treatment International immunology High 36331874
2023 LILRB4 signaling in decidual MDSCs operates through SHP-2/STAT6 pathway; T. gondii-induced downregulation of LILRB4 reduces p-SHP2 and p-STAT6, decreasing Arg-1 and IL-10 expression; SHP-2 was found to directly bind STAT6, which then binds the Arg-1 and IL-10 promoters. LILRB4-/- pregnant mouse model; anti-LILRB4 neutralizing antibody on human primary dMDSCs; SHP-2/STAT6 co-IP; chromatin promoter binding assay; western blot for p-SHP2, p-STAT6, Arg-1, IL-10 Parasites & vectors Medium 37461040
2024 Galectin-8 (Gal-8) is a high-affinity functional ligand of LILRB4 in solid tumors; Gal-8 ligation induces M-MDSC polarization 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. Ligand screening; binding affinity assays; STAT3 and NF-κB activity assays; MDSC induction assays; LILRB4 KO mouse tumor models; competitive binding analysis Cell reports. Medicine High 38232701
2024 LILRB4 on multiple myeloma cells promotes osteoclast differentiation and bone lesion by inducing secretion of RELT cytokine via a p-SHP2/NF-κB signaling pathway; LILRB4 KO abrogates osteoclastogenesis and bone damage; exogenous RELT rescues the phenotype in LILRB4-KO cells. LILRB4-WT and KO conditioned media osteoclast assays; xenograft/syngeneic/PDX models with micro-CT; cytokine array; RNA-seq; luciferase reporter; Co-IP; western blot; RELT rescue experiment Journal of experimental & clinical cancer research High 38951916
2024 Microglia LILRB4 limits CD8+ T cell infiltration into ischemic brain by a CCL2-mediated mechanism and via arginase-1 activity; conditional LILRB4 KO in microglia increases CD8+ T cell recruitment and worsens infarct, while LILRB4 overexpression is neuroprotective after stroke. Microglia-specific LILRB4 conditional KO and overexpression transgenic mice (Cre-loxP); tMCAO stroke model; scRNA-seq; spatial transcriptomics; flow cytometry; immunofluorescence; T cell migration assays with CCL2 inhibition and recombinant arginase-1 Journal of neuroinflammation High 39217343
2024 IKZF1 transactivates LILRB4 expression in multiple myeloma, activating downstream STAT3-PFKFB1 signaling to support MM cell proliferation; LILRB4 knockdown delays MM growth in vitro and in vivo. IKZF1 transcriptional regulation assays; STAT3 and PFKFB1 pathway analysis; LILRB4 knockdown; in vitro proliferation and in vivo xenograft models Cell death & disease Medium 39025844
2025 Secretogranin 2 (SCG2), a granin-family secretory protein, binds LILRB4 on monocytic cells; tumor-derived SCG2 promotes tumor growth in myeloid-specific LILRB4 transgenic mice in a T cell-dependent manner; SCG2-LILRB4 interaction triggers SHP recruitment and SHP-independent STAT3 activation; SCG2 deficiency impairs immunosuppressive monocytic cell infiltration. Myeloid-specific LILRB4 transgenic mouse model; SCG2 deficient mice; binding assays; T cell depletion; LILRB4 blockade; SHP co-IP; STAT3 phosphorylation assays Nature immunology High 40707822
2020 ILT3 (LILRB4) promotes the immunosuppressive function of monocytic MDSCs; anti-ILT3 antibody treatment impairs MDSC suppressor phenotype acquisition and reduces T cell suppression capacity; combined with anti-PD1, ILT3 blockade enhances T cell IFN-γ secretion. Co-culture MDSC generation with SK-MEL-5 cancer cells; anti-ILT3 antibody treatment; CD8+ T cell proliferation and IFN-γ secretion assays; flow cytometry phenotyping Molecular cancer research Medium 33372059
2020 ILT3 overexpression in NSCLC cells recruits SHP2 and SHIP1 and activates ERK1/2 signaling to mediate EMT and tumor cell motility; additionally upregulates VEGF-A for angiogenesis; interaction with ApoE ligand upregulated by ILT3 itself contributes to these effects. ILT3 overexpression in NSCLC lines; SHP2/SHIP1 co-immunoprecipitation; ERK1/2 phosphorylation assay; EMT markers; VEGF-A ELISA; murine metastasis models Cancer letters Medium 33152402
2010 Soluble ILT3-Fc (containing only the extracellular Ig-like domain) induces CD8+ T suppressor cell differentiation associated with significant upregulation of BCL6 (a transcriptional repressor of IL-2, IFN-γ, IL-5, and granzyme B), SOCS1, and DUSP10, defining the gene signature of ILT3-Fc-induced Ts cells. Soluble ILT3-Fc treatment of human T cells; gene expression profiling; BCL6, SOCS1, DUSP10 functional validation; humanized NOD/SCID transplant model International reviews of immunology Medium 20132030
2022 LILRB4/gp49B (murine ortholog) promotes M2 polarization of MDSCs and tumor metastasis; gp49B deficiency inhibited monocytic MDSC tumor infiltration and impaired Treg activation, cancer cell migration promotion, and tumor angiogenesis; gp49B knockout increased plasma exosomal miR-1 family miRNAs with anti-tumor activity. gp49B-/- mouse tumor metastasis models; M-MDSC characterization; Treg activation assays; plasma exosome miRNA profiling; cancer cell migration assay Oncoimmunology Medium 35402083
2018 LILRB4 deficiency in decidual macrophages strengthens M1 activation and weakens M2 tolerance functions; T. gondii infection downregulates LILRB4 on decidual macrophages, shifting arginine metabolic enzyme expression (iNOS vs. Arg-1) and cytokine profiles, contributing to abnormal pregnancy outcomes. LILRB4-/- pregnant mouse model; T. gondii infection; anti-LILRB4 neutralizing antibody on human primary decidual macrophages; M1/M2 surface molecule quantification; arginine metabolic enzyme measurement; cytokine profiling Frontiers in immunology Medium 28883820
2025 LILRB4 promotes inflammation and pyroptosis in myocardial ischemia-reperfusion injury by activating SHP-2 phosphorylation, which upregulates TXNIP/NLRP3/Caspase-1/GSDMD signaling; LILRB4 KO mice show diminished inflammatory cytokines and reduced pyroptotic protein expression after I/R. LILRB4-/- mice; adenoviral overexpression/knockdown in H9C2 cardiomyocytes; I/R and H/R models; SHP2 inhibitor PHPS1; western blot for p-SHP2, TXNIP, NLRP3, Caspase-1, GSDMD; ELISA for cytokines Biochimica et biophysica acta. Molecular basis of disease Medium 40550372
2025 Homoharringtonine (HHT) suppresses LILRB4 expression by promoting FTO (m6A demethylase) degradation, increasing global RNA m6A levels, which reduces expression of downstream targets MLL1 and LILRB4, thereby enhancing CD8+ T cell cytotoxicity against monocytic AML cells. RNA-seq; functional assays; m6A quantification; FTO degradation assay; MLL1 and LILRB4 mRNA/protein measurement; in vitro cytotoxicity assays; AML xenograft mouse models Cell proliferation Medium 40590394
2022 NK cells require LILRB4/gp49B for proper function during neurotropic Zika virus infection; LILRB4 KO mice show increased neurological disease severity with reduced viral clearance, associated with altered NK cell maturation, diminished glucose consumption, reduced IFN-γ and granzyme B production, and impaired cytotoxicity. LILRB4 KO mice; neonatal ZIKV infection model; NK cell functional assays (granzyme B, IFN-γ, cytotoxicity); NK cell metabolic assay (glucose consumption); phenotypic characterization of NK maturation stages JCI insight Medium 35132958

Source papers

Stage 0 corpus · 99 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
1997 A novel inhibitory receptor (ILT3) expressed on monocytes, macrophages, and dendritic cells involved in antigen processing. The Journal of experimental medicine 356 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 316 16030186
2003 High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells. Transplant immunology 251 12967778
2018 LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration. Nature 248 30333625
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
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
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 113 30131301
2021 LILRB4 suppresses immunity in solid tumors and is a potential target for immunotherapy. The Journal of experimental medicine 111 33974041
2012 Expression of immunoglobulin-like transcript (ILT)2 and ILT3 in human gastric cancer and its clinical significance. Molecular medicine reports 77 22246571
2019 Disrupting LILRB4/APOE Interaction by an Efficacious Humanized Antibody Reverses T-cell Suppression and Blocks AML Development. Cancer immunology research 71 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 59 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
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2021 The Fibronectin-ILT3 Interaction Functions as a Stromal Checkpoint that Suppresses Myeloid Cells. Cancer immunology research 49 34426457
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2018 Hepatic leukocyte immunoglobulin-like receptor B4 (LILRB4) attenuates nonalcoholic fatty liver disease via SHP1-TRAF6 pathway. Hepatology (Baltimore, Md.) 46 29091299
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2022 LILRB4 promotes tumor metastasis by regulating MDSCs and inhibiting miR-1 family miRNAs. Oncoimmunology 45 35402083
2008 CD8+ T suppressor cells and the ILT3 master switch. Human immunology 44 18817834
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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
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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
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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
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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
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2016 Tolerogenic immunoreceptor ILT3/LILRB4 paradoxically marks pathogenic auto-antibody-producing plasmablasts and plasma cells in non-treated SLE. International immunology 28 27742834
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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
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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
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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
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2024 Downregulation of LILRB4 Promotes Human Aortic Smooth Muscle Cell Contractile Phenotypic Switch and Apoptosis in Aortic Dissection. Cardiovascular toxicology 5 38324114
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
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2025 LILRB4 exacerbates myocardial ischemia-reperfusion injury by promoting inflammation and pyroptosis. Biochimica et biophysica acta. Molecular basis of disease 1 40550372
2025 Uncovering the Associations of LILRB4 Genotypes With Parkinson's Disease: From Clinical Traits to Potential Pathologies. CNS neuroscience & therapeutics 1 40702763
2025 A phase 1 study of IO-202, an anti-LILRB4 antibody, in chronic myelomonocytic leukemia and acute myeloid leukemia. Blood neoplasia 1 40919482
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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
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