Affinage

LILRB3

Leukocyte immunoglobulin-like receptor subfamily B member 3 · UniProt O75022

Length
631 aa
Mass
69.4 kDa
Annotated
2026-06-10
20 papers in source corpus 12 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LILRB3 is an ITIM-bearing inhibitory receptor of myeloid cells that functions as an immunosuppressive checkpoint, dampening innate effector responses upon ligand engagement (PMID:32870822, PMID:31915259). On primary monocytes its ligation drives potent suppression of T cell proliferation and, in humanized mice, induces tolerance permitting allogeneic engraftment (PMID:32870822); on resting neutrophils, continuous LILRB3 ligation inhibits IgA-mediated ROS production, phagocytosis, and microbial killing (PMID:31915259). The extracellular domain engages a structurally diverse ligand repertoire: MHC class I (PMID:34686865, PMID:34740904), an APOE4-specific surface patch resolved at atomic resolution as a 2:2 hetero-tetrameric APOE4–LILRB3 complex (PMID:36588123), galectin-4 and galectin-7 on immunosuppressive myeloid cells (PMID:38113030), and a cytokeratin 8–associated complex on necrotic glandular epithelium recognized in an allele-specific manner (PMID:26769854). Receptor signaling bifurcates by context: epithelial recognition of MHC class I on transformed cells couples to an SHP2–ROCK2 mechanical pathway that extrudes precancerous cells independently of NK or CD8+ T cells (PMID:34686865, PMID:34740904), whereas in AML the intracellular domain constitutively associates with TRAF2 and, upon activation, recruits cFLIP to upregulate NF-κB and promote leukemic survival, with A20-mediated feedback disrupting the LILRB3–TRAF2 interaction to restore SHP-1/2 inhibitory dominance (PMID:35122056). In AML cells, blockade derepresses myeloid differentiation factors (PU.1, C/EBP, IRF) and reduces AKT, cyclin D1, and Rb phosphorylation, while agonism sustains survival via cholesterol metabolism (PMID:38098451); APOE4 engagement likewise activates microglia into a pro-inflammatory state in a LILRB3-dependent manner (PMID:36588123). A cluster of four missense SNPs proximal to a SHP1/2-binding ITIM associates with kidney transplant failure in African Americans, linking impaired LILRB3 inhibitory signaling to inflammation and monocyte ferroptosis (PMID:40065170).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2013 Low

    Established that LILRB3 and the near-identical LILRA6 are functionally opposite paired receptors, with LILRB3 signaling via cytoplasmic ITIMs while its sister receptor signals through an activating FcRgamma/ITAM module.

    Evidence mRNA expression profiling across PBMC fractions, copy number analysis, and receptor domain characterization

    PMID:24096970

    Open questions at the time
    • No direct functional reconstitution of ITIM-driven inhibitory signaling
    • Ligand identity not addressed
    • Primarily genetic/expression correlation
  2. 2016 Medium

    Identified the first defined LILRB3 ligand as a cytokeratin 8-associated complex on necrotic epithelial cells, recognized in an allele-specific manner, addressing what LILRB3 senses on damaged tissue.

    Evidence Recombinant receptor pulldown, cytokeratin 8 knockdown, and LILRB3*12 reporter cell activation with co-localization

    PMID:26769854

    Open questions at the time
    • Allele-specificity limits generalization to all LILRB3 variants
    • Downstream signaling consequence not mapped
    • Physiological context of necrotic-cell sensing not defined
  3. 2020 High

    Defined LILRB3 as an immunosuppressive myeloid checkpoint by showing agonistic ligation of monocytes suppresses T cell responses and induces transplant tolerance in vivo.

    Evidence Agonistic monoclonal antibody assays on primary human monocytes, T cell proliferation readout, and humanized mouse allograft engraftment

    PMID:32870822

    Open questions at the time
    • Natural ligand driving the tolerogenic response not identified
    • Intracellular signaling intermediates not dissected
  4. 2020 Medium

    Extended the inhibitory checkpoint role to neutrophils, showing LILRB3 ligation restrains IgA-mediated effector functions and that surface receptor is shed upon activation.

    Evidence IP-mass spectrometry, flow cytometry, PLB-985 differentiation model, and functional ROS/phagocytosis/killing assays under continuous ligation

    PMID:31915259

    Open questions at the time
    • Mechanism of activation-induced surface release unknown
    • Endogenous neutrophil ligand not defined
  5. 2021 High

    Revealed a context-dependent activating signaling axis in AML, distinct from canonical ITIM inhibition, explaining how LILRB3 promotes leukemic survival and the feedback that restores inhibition.

    Evidence Reciprocal Co-IP identifying TRAF2/cFLIP, NF-kB reporter assays, antagonist antibody blockade, and in vivo AML models

    PMID:35122056

    Open questions at the time
    • Ligand triggering the AML TRAF2-NF-kB axis not identified
    • Switch determinants between activating and inhibitory modes incompletely defined
  6. 2021 High

    Demonstrated a non-immune role in epithelial cell competition, where LILRB3 recognition of MHC class I on transformed cells drives mechanical extrusion via SHP2-ROCK2 independently of cytotoxic lymphocytes.

    Evidence Live cell-competition imaging, LILRB3 knockdown, Co-IP, and SHP2/ROCK2 inhibitor and knockdown epistasis in epithelial extrusion assays

    PMID:34686865 PMID:34740904

    Open questions at the time
    • How an inhibitory receptor couples to a force-generating ROCK2 pathway mechanistically unresolved
    • Generality across epithelial tissues not established
  7. 2023 High

    Provided atomic-resolution structural and functional evidence for isoform-specific APOE4 binding, defining a 2:2 receptor clustering geometry and linking LILRB3 to microglial pro-inflammatory activation.

    Evidence X-ray crystallography of the APOE4-LILRB3 complex, biochemical binding assays, and LILRB3 knockdown in HMC3 microglia with inflammatory readouts

    PMID:36588123

    Open questions at the time
    • Downstream signaling from APOE4-induced clustering not biochemically mapped
    • Relevance to neurodegenerative disease in vivo not tested
  8. 2023 Medium

    Mapped downstream effectors of LILRB3 in AML, showing blockade derepresses myeloid differentiation and proliferation signaling while agonism sustains survival via cholesterol metabolism.

    Evidence Antibody blockade/agonism, western blot of AKT/cyclin D1/Rb phosphorylation, transcriptomics, and CAR T cell assays in vitro and in vivo

    PMID:38098451

    Open questions at the time
    • Direct biochemical link between receptor and AKT/cyclin D1 axis not established
    • Single lab
  9. 2024 Medium

    Identified galectin-4 and galectin-7 as activating ligands on immunosuppressive myeloid cells, linking ligand engagement to tumor-promoting immunosuppression that is T cell-dependent.

    Evidence Ligand-receptor binding assays, myeloid-specific LILRB3 transgenic tumor model, antagonist antibody blockade, and T cell depletion epistasis

    PMID:38113030

    Open questions at the time
    • Intracellular signaling triggered by galectins not dissected
    • Single lab
  10. 2024 Medium

    Established post-transcriptional regulation of LILRB3, with miR-103a-2-5p directly suppressing its expression and thereby reducing AML growth through the Nrf2/HO-1 redox axis.

    Evidence Dual luciferase 3'-UTR reporter, qPCR, western blot, apoptosis flow cytometry, and in vivo AML model with delivered miRNA

    PMID:38486250

    Open questions at the time
    • Whether endogenous miR-103a-2-5p regulates LILRB3 physiologically not established
    • Connection between receptor level and Nrf2/HO-1 axis is correlative
  11. 2025 Low

    Linked LILRB3 ITIM-proximal genetic variation to disease, associating a four-SNP cluster with kidney transplant failure and implicating impaired inhibitory signaling in inflammation and monocyte ferroptosis.

    Evidence Genomic SNP association, blood RNA-seq, biopsy multiomics, and APOL1 epistasis analysis

    PMID:40065170

    Open questions at the time
    • No direct biochemical demonstration that the SNPs disrupt SHP1/2 binding or ITIM function
    • Causality versus association not resolved
    • Mechanistic link to ferroptosis correlative

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single ITIM-bearing receptor switches between SHP-1/2 inhibition, TRAF2-NF-kB activation, and SHP2-ROCK2 mechanical signaling depending on ligand and cell type.
  • Ligand-specific signaling bias not defined
  • Stoichiometry/clustering rules linking ligand geometry to output unknown
  • No unified structural model across ligands

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1643685 Disease 2
Partners
A20APOE4CFLIPROCK2SHP1SHP2TRAF2

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 LILRB3 intracellular domain is constitutively associated with the adaptor protein TRAF2. Upon LILRB3 activation in AML cells, cFLIP is recruited and NF-κB is upregulated, enhancing leukemic cell survival and inhibiting T-cell anti-tumor activity. Hyperactivation of NF-κB triggers a negative feedback loop via A20, which disrupts the LILRB3-TRAF2 interaction, causing SHP-1/2-mediated inhibitory activity of LILRB3 to become dominant. Co-immunoprecipitation, signaling pathway analysis, NF-κB reporter assays, antagonizing antibody blockade, in vivo AML progression models Nature cancer High 35122056
2021 LILRB3 expressed on non-transformed epithelial cells recognizes MHC class I that is highly expressed on transformed cells. This MHC class I–LILRB3 interaction triggers an SHP2-ROCK2 signaling pathway that generates a mechanical force to extrude transformed (precancerous) cells from the epithelial layer, leading to their apoptosis and clearance independently of NK or CD8+ T cell activity. Live imaging of cell competition, loss-of-function (LILRB3 knockdown), co-immunoprecipitation, epistasis analysis with SHP2 and ROCK2 inhibitors/knockdowns, in vitro epithelial extrusion assays Nature immunology High 34686865 34740904
2020 LILRB3 ligation on primary human monocytes by an agonistic monoclonal antibody induces phenotypic and functional changes leading to potent inhibition of immune responses in vitro, including significant reduction in T cell proliferation. Agonizing LILRB3 in humanized mice induced tolerance and permitted efficient engraftment of allogeneic cells, establishing LILRB3 as an immunosuppressive myeloid checkpoint receptor. Monoclonal antibody panel, primary human monocyte stimulation assays, T cell proliferation assay, humanized mouse allograft engraftment model JCI insight High 32870822
2023 APOE4, but not APOE2, specifically binds LilrB3. Two discrete immunoglobulin-like domains of the LilrB3 extracellular domain recognize a positively charged surface patch on the N-terminal domain of APOE4. The crystal structure reveals a hetero-tetrameric complex (two APOE4 molecules engaging two LilrB3 molecules), bringing intracellular signaling motifs into close proximity. APOE4, but not APOE2, activates human microglia (HMC3) into a pro-inflammatory state in a LilrB3-dependent manner. X-ray crystallography (atomic structure of APOE4–LilrB3 complex), biochemical binding assays, LilrB3 knockdown in microglia, functional inflammatory assays Cell research High 36588123
2016 Specific allelic variants of LILRB3 (notably LILRB3*12) bind a ligand on necrotic glandular epithelial cells that is associated with cytokeratin 8. Immunoprecipitation of the ligand from epithelial cell lysates using recombinant LILRB3*12 identified cytokeratins 8, 18, and 19. Knockdown of cytokeratin 8 in epithelial cells abrogated LILRB3 ligand expression. Purified cytokeratin 8-associated proteins activated LILRB3*12 reporter cells. Recombinant receptor binding assay, immunoprecipitation, cytokeratin 8 knockdown, LILRB3 reporter cell activation assay, co-localization by immunofluorescence Oncotarget Medium 26769854
2020 LILRB3 (but not LILRA6) is expressed on the surface of resting human neutrophils and is released from the surface upon neutrophil activation. Continuous ligation of LILRB3 inhibits key IgA-mediated effector functions including reactive oxygen species production, phagocytic uptake, and microbial killing, establishing LILRB3 as an inhibitory checkpoint on neutrophil activation. Immunoprecipitation followed by mass spectrometry (detecting LILRB3 in neutrophil lysates), flow cytometry, PLB-985 differentiation model, functional assays (ROS, phagocytosis, microbial killing) with continuous LILRB3 ligation Journal of immunology Medium 31915259
2024 Galectin-4 and galectin-7 are ligands that induce activation of LILRB3 on immunosuppressive myeloid cells (MDSCs). Blockade of LILRB3 signaling by an antagonistic antibody inhibited immunosuppressive myeloid cell activity and impeded tumor development in myeloid-specific LILRB3 transgenic mice through a T cell-dependent mechanism. Ligand-receptor binding assays identifying galectin-4 and galectin-7 as LILRB3 ligands, LILRB3 transgenic mouse tumor model, antibody blockade, T cell depletion epistasis Cancer immunology research Medium 38113030
2013 LILRB3 and LILRA6 share identical extracellular domains. LILRB3 mediates inhibitory signaling via immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic tail, whereas LILRA6 signals through association with the activating adaptor FcRγ (which bears an ITAM). LILRA6 expression level on monocytes correlates with copy number of the LILRA6 gene. mRNA expression analysis across PBMC fractions, copy number variation analysis, receptor domain characterization Immunogenetics Low 24096970
2025 A cluster of four consecutive missense SNPs (LILRB3-4SNPs) in LILRB3 at amino acids 617–618, proximal to a SHP1/2 phosphatase-binding ITIM, is strongly associated with kidney transplant failure in African Americans. Multiomics analysis of blood and biopsies showed that recipients with LILRB3-4SNPs exhibited enhanced inflammation and monocyte ferroptosis, suggesting these mutations functionally impair ITIM-mediated SHP1/2 signaling. Blood RNA sequencing, genomic SNP association analysis, multiomics (transcriptomics + biopsy proteomics), APOL1 epistasis analysis Nature medicine Low 40065170
2023 LILRB3 blockade with antagonist antibodies upregulates myeloid lineage differentiation transcription factors (PU.1, C/EBP family, IRF) and decreases phosphorylation of AKT, cyclin D1, and retinoblastoma protein in AML cells, inhibiting leukemia cell proliferation. Conversely, LILRB3 agonism enhances leukemia survival through upregulation of cholesterol metabolism pathways. Antibody blockade/agonism, western blot (phosphorylation), transcriptomic analysis, in vitro and in vivo CAR T cell assays Cancer research Medium 38098451
2024 miR-103a-2-5p directly targets the 3'-UTR of LILRB3 mRNA (confirmed by dual luciferase reporter assay), suppressing LILRB3 expression and thereby inhibiting AML cell growth, reducing CD8+ T cell apoptosis, suppressing the Nrf2/HO-1 axis, and reducing the GSH/ROS ratio leading to increased intracellular ROS and AML cell apoptosis. Dual luciferase reporter assay (direct 3'-UTR targeting), qPCR, western blot, flow cytometry (apoptosis, cell cycle), in vivo mouse AML model with CLP-delivered miRNA Journal of translational medicine Medium 38486250

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Identification of Susceptibility Loci in IL6, RPS9/LILRB3, and an Intergenic Locus on Chromosome 21q22 in Takayasu Arteritis in a Genome-Wide Association Study. Arthritis & rheumatology (Hoboken, N.J.) 87 25604533
2005 Structural and functional modeling of human lysozyme reveals a unique nonapeptide, HL9, with anti-HIV activity. Biochemistry 69 15779891
2021 LILRB3 supports acute myeloid leukemia development and regulates T-cell antitumor immune responses through the TRAF2-cFLIP-NF-κB signaling axis. Nature cancer 54 35122056
2020 LILRB3 (ILT5) is a myeloid cell checkpoint that elicits profound immunomodulation. JCI insight 44 32870822
2021 Epithelial cells remove precancerous cells by cell competition via MHC class I-LILRB3 interaction. Nature immunology 37 34686865
2013 Diversity of the human LILRB3/A6 locus encoding a myeloid inhibitory and activating receptor pair. Immunogenetics 32 24096970
2023 LilrB3 is a putative cell surface receptor of APOE4. Cell research 27 36588123
2020 The Orphan Immune Receptor LILRB3 Modulates Fc Receptor-Mediated Functions of Neutrophils. Journal of immunology (Baltimore, Md. : 1950) 25 31915259
2016 Allele-specific recognition by LILRB3 and LILRA6 of a cytokeratin 8-associated ligand on necrotic glandular epithelial cells. Oncotarget 25 26769854
2024 LILRB3 Supports Immunosuppressive Activity of Myeloid Cells and Tumor Development. Cancer immunology research 18 38113030
2011 Computational study of bindings of HL9, a nonapeptide fragment of human lysozyme, to HIV-1 fusion protein gp41. Bioorganic & medicinal chemistry letters 15 21334893
2023 LILRB3 Modulates Acute Myeloid Leukemia Progression and Acts as an Effective Target for CAR T-cell Therapy. Cancer research 14 38098451
2024 CLPs-miR-103a-2-5p inhibits proliferation and promotes cell apoptosis in AML cells by targeting LILRB3 and Nrf2/HO-1 axis, regulating CD8 + T cell response. Journal of translational medicine 13 38486250
2021 KLRD1, FOSL2 and LILRB3 as potential biomarkers for plaques progression in acute myocardial infarction and stable coronary artery disease. BMC cardiovascular disorders 13 34271875
2025 LILRB3 genetic variation is associated with kidney transplant failure in African American recipients. Nature medicine 7 40065170
2021 Characterization of LILRB3 and LILRA6 allelic variants in the Japanese population. Journal of human genetics 6 33526815
2022 Distinct frequency patterns of LILRB3 and LILRA6 allelic variants in Europeans. Immunogenetics 5 36449053
2025 JoGo-LILR caller: Unveiling and navigating the complex diversity of LILRB3-LILRA6 copy number haplotype structures with whole-genome sequencing. Human immunology 3 40054016
2021 Transformed Cell Exclusion Occurs through MHC Class I/LILRB3 Interactions. Cancer discovery 1 34740904
2026 LILRB3 inhibition reverses immunosuppression in glioma: a nanoparticle-based therapeutic strategy. Journal of nanobiotechnology 0 41937130

Missed literature

Know a paper Affinage missed for LILRB3? Flag it for the maintainers and the community.

No submissions yet.