LILRB3

LILRB3 is an inhibitory immunoreceptor expressed on myeloid cells that integrates multiple extracellular ligand inputs to control immune activation, cell survival, and tissue surveillance. Its cytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs) recruit SHP-1/SHP-2 phosphatases to suppress myeloid effector functions — including IgA-mediated neutrophil antimicrobial responses and monocyte-driven T cell proliferation — establishing it as a myeloid immune checkpoint (PMID:31915259, PMID:32870822, PMID:24096970). The intracellular domain also constitutively associates with TRAF2; upon activation, cFLIP recruitment drives NF-κB-dependent survival signaling in AML cells, with A20-mediated feedback restoring SHP-1/2 dominance, while LILRB3 blockade promotes myeloid differentiation and suppresses AKT/cyclin D1 signaling (PMID:35122056, PMID:38098451). The extracellular immunoglobulin-like domains recognize diverse ligands — MHC class I (triggering SHP2-ROCK2-dependent epithelial cell extrusion of transformed cells), APOE4 (forming a heterotetrameric complex that activates microglial inflammation), cytokeratins 8/18/19 on necrotic epithelial cells, and galectins-4/7 on immunosuppressive myeloid cells — linking LILRB3 to cancer immunosurveillance, neuroinflammation, and tumor immune evasion (PMID:34686865, PMID:36588123, PMID:26769854, PMID:38113030).

1. 2013 Medium

   Establishing the signaling architecture: LILRB3 was shown to signal through cytoplasmic ITIMs while sharing identical extracellular domains with its paired activating receptor LILRA6, defining LILRB3 as an inhibitory counterpart in a paired receptor system on monocytes.

   Evidence mRNA expression analysis, genetic characterization, and functional domain annotation

   PMID:24096970

   Open questions at the time

   • No direct demonstration of SHP-1/2 recruitment to LILRB3 ITIMs in this study
   • Endogenous ligand unknown at this point
   • Downstream signaling consequences not measured
2. 2016 Medium

   Identification of the first endogenous ligand: allele-specific variants of LILRB3 were found to bind cytokeratins 8/18/19 exposed on necrotic glandular epithelial cells, revealing that LILRB3 senses damage-associated signals in an allele-dependent manner.

   Evidence Immunoprecipitation from cell lysates, reporter cell activation assay, siRNA knockdown of cytokeratin 8

   PMID:26769854

   Open questions at the time

   • Binding restricted to LILRB3*12 allele — generalizability to other alleles unclear
   • Structural basis of allele-specific recognition unresolved
   • Downstream signaling pathway upon cytokeratin engagement not characterized
3. 2020 Medium

   Functional demonstration as a myeloid immune checkpoint: LILRB3 ligation on monocytes suppressed T cell proliferation and enabled allograft tolerance in humanized mice, while on neutrophils it inhibited IgA-mediated antimicrobial effector functions, establishing its broad immunosuppressive role across myeloid lineages.

   Evidence Agonistic monoclonal antibodies on primary monocytes and neutrophils, T cell proliferation assays, ROS/phagocytosis/killing assays, humanized mouse allograft model

   PMID:31915259 PMID:32870822

   Open questions at the time

   • Endogenous ligand driving these checkpoint functions in vivo not identified
   • Relative contribution of SHP-1 versus SHP-2 to different effector outputs not dissected
   • Mechanism of LILRB3 shedding from activated neutrophils not characterized
4. 2021 High

   Discovery of a dual intracellular signaling switch: LILRB3 constitutively associates with TRAF2, and activation recruits cFLIP to drive NF-κB-mediated leukemic cell survival; hyperactivated NF-κB induces A20, which disrupts the TRAF2 interaction and restores SHP-1/2-dominated inhibitory signaling, revealing an intrinsic toggle between pro-survival and inhibitory pathways.

   Evidence Reciprocal co-immunoprecipitation, domain mapping, NF-κB reporter assays, mutagenesis, in vivo AML models, antagonistic antibody blockade

   PMID:35122056

   Open questions at the time

   • Structural basis of TRAF2 binding to LILRB3 intracellular domain not resolved
   • Whether A20 feedback operates in non-leukemic myeloid cells unknown
   • Threshold of NF-κB activation required to trigger the switch not quantified
5. 2021 High

   Revealing a cell-autonomous tumor surveillance mechanism: non-transformed epithelial cells expressing LILRB3 recognize MHC class I upregulated on transformed neighbors and activate SHP2-ROCK2 signaling to mechanically extrude precancerous cells, independent of adaptive immunity.

   Evidence Live-cell imaging, genetic knockdown/knockout, co-immunoprecipitation, epithelial cell competition assays, pharmacological inhibitors

   PMID:34686865 PMID:34740904

   Open questions at the time

   • How LILRB3 distinguishes normal from elevated MHC-I levels to trigger extrusion not defined
   • Whether this mechanism operates in vivo in human tissues not shown
   • Contribution of other LILRB family members to cell competition not excluded
6. 2023 High

   Structural elucidation of isoform-specific APOE4 recognition: crystal structures revealed that two LILRB3 molecules form a heterotetrameric complex with two APOE4 molecules via a positively charged patch on the APOE4 N-terminal domain, and this interaction activates pro-inflammatory microglia, linking LILRB3 to neuroinflammation.

   Evidence X-ray crystallography, biochemical binding assays, microglial activation assays with LILRB3 knockdown/knockout

   PMID:36588123

   Open questions at the time

   • Whether LILRB3-APOE4 interaction drives neurodegeneration in Alzheimer's disease models not tested
   • Signaling pathway downstream of LILRB3 activation in microglia (SHP vs. NF-κB) not resolved
   • Whether APOE4-LILRB3 engagement occurs in vivo in human brain not demonstrated
7. 2023 Medium

   Mapping downstream transcriptional and metabolic consequences: LILRB3 blockade in AML cells upregulated myeloid differentiation transcription factors (PU.1, C/EBP, IRF) and suppressed AKT/cyclin D1/Rb phosphorylation, while agonist activation induced cholesterol metabolism pathways promoting leukemia survival.

   Evidence Antagonistic and agonistic antibody treatment, transcriptomic profiling, Western blotting, in vivo AML models, CAR T cell co-culture assays

   PMID:38098451

   Open questions at the time

   • Whether cholesterol metabolic reprogramming is a direct LILRB3 signaling output or secondary effect unknown
   • Whether differentiation induction by LILRB3 blockade generalizes beyond AML not tested
   • Direct transcription factor regulation versus indirect pathway effects not distinguished
8. 2024 Medium

   Identification of galectins as tumor-associated LILRB3 ligands: galectin-4 and galectin-7 were found to activate LILRB3 on immunosuppressive myeloid cells (MDSCs), and LILRB3 blockade impeded tumor growth in a T cell-dependent manner in myeloid-specific transgenic mice.

   Evidence Ligand-receptor binding assays, antagonistic antibody blockade, LILRB3 myeloid transgenic mouse tumor model, T cell depletion experiments

   PMID:38113030

   Open questions at the time

   • Binding site of galectins on LILRB3 extracellular domain not structurally resolved
   • Glycan dependence of galectin-LILRB3 interaction not tested
   • Relative importance of galectin-4 vs. galectin-7 in tumor microenvironment not distinguished
9. 2024 Medium

   Post-transcriptional regulation of LILRB3 identified: miR-103a-2-5p directly targets the LILRB3 3′-UTR, reducing LILRB3 protein and thereby inhibiting AML proliferation and promoting apoptosis via increased ROS and suppressed Nrf2/HO-1, while rescuing CD8+ T cell viability.

   Evidence Dual luciferase reporter assay, qRT-PCR, colony formation, flow cytometry, AML mouse model with liposomal miRNA delivery

   PMID:38486250

   Open questions at the time

   • Whether Nrf2/HO-1 axis is directly regulated by LILRB3 signaling or an indirect consequence of LILRB3 loss not resolved
   • Specificity of miR-103a-2-5p for LILRB3 versus other targets not controlled
   • In vivo pharmacokinetics and off-target effects of liposomal miRNA delivery not characterized
10. 2025 Medium

    Genetic variants near the ITIM link LILRB3 to transplant outcome: a cluster of four missense SNPs proximal to the SHP-1/2-binding ITIM motif was associated with kidney transplant failure in African Americans, correlated with enhanced monocyte inflammation and ferroptosis.

    Evidence Whole-blood RNA sequencing, SNP genotyping, multiomics analysis of blood and biopsies, Biobank association studies

    PMID:40065170

    Open questions at the time

    • Direct demonstration that these SNPs impair ITIM phosphorylation or SHP recruitment not performed
    • Causal relationship between LILRB3 variants and ferroptosis not mechanistically validated
    • Whether these variants affect other LILRB3 functions (e.g., TRAF2 binding) not tested

• Major open question: how LILRB3 integrates signals from its diverse extracellular ligands (MHC-I, APOE4, cytokeratins, galectins) to select between ITIM/SHP-mediated inhibition and TRAF2/NF-κB-mediated survival in different myeloid cell contexts remains unresolved.
• No unified model of how ligand identity determines intracellular pathway choice
• Structural basis for simultaneous or competitive ligand engagement across domains not known
• In vivo relevance of LILRB3-APOE4 axis in Alzheimer's disease not established