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Showing LILRB1 — PIR-B is a alias.

LILRB1

Leukocyte immunoglobulin-like receptor subfamily B member 1 · UniProt Q8NHL6

Length
650 aa
Mass
70.8 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 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

LILRB1 (ILT2/LIR-1/CD85j) is an inhibitory immunoreceptor that restrains effector functions across T cells, NK cells, B cells, monocytes, dendritic cells, and macrophages following recognition of MHC class I (PMID:9842885, PMID:11034379). Its membrane-distal D1D2 Ig-like domains constitute the ligand-binding module, engaging classical HLA-A/B/C (PMID:9842885), non-classical HLA-G in a β2-microglobulin-dependent conformation (PMID:9933109, PMID:16210588), HLA-F (PMID:11169396), and the HCMV MHC-I homolog UL18 (PMID:11114384, PMID:15100307), while the membrane-proximal D3D4 domains form a structural scaffold and contribute a distinct binding surface exploited by Plasmodium falciparum RIFINs (PMID:31273318, PMID:33790470). Crystallographic, calorimetric, and NMR analyses show the receptor engages MHC-I through an entropically driven, fast-on/fast-off interaction accompanied by interdomain flexibility and conformational change (PMID:16305801, PMID:31273318). Upon ligand engagement, LILRB1 phosphorylation—dependent on Src kinase p56lck and the regulatory ITIM Y533—drives recruitment of SHP-1 to docking sites Y614 and Y644 and of Csk to Y562, which suppresses proximal activation cascades including TCRζ/ZAP70 coupling, ERK1/2 activation, calcium mobilization, and actin reorganization (PMID:11160312, PMID:11907092, PMID:15474475). Through these signals LILRB1 inhibits cytotoxicity and IFN-γ secretion by T and NK cells (PMID:15270723, PMID:18684926, PMID:31451484), antibody class switching and cytokine output by B cells (PMID:15939744), dendritic cell maturation and stimulatory capacity (PMID:15905516, PMID:18094328), and macrophage phagocytosis (PMID:36389667). Cell-type-specific surface density is set by dual promoter usage and a lymphocyte-specific 5'-UTR translational repressor element (PMID:20194892), and natural polymorphisms—including one controlling an N-linked glycan—tune ligand recognition (PMID:16014635, PMID:29528338). Beyond immune signaling, LILRB1 assembles with LDLR and LDLRAP1 to drive cholesterol uptake in multiple myeloma cells, protecting them from ferroptosis (PMID:38982045).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1998 High

    Established LILRB1 as an MHC class I-binding inhibitory receptor that recruits SHP-1 and dampens activating Fc receptor signaling, defining its core inhibitory logic.

    Evidence Co-ligation with FcγRI, SHP-1 co-IP, and calcium flux in primary monocytes

    PMID:9842885

    Open questions at the time
    • ITIM residues mediating SHP-1 docking not yet mapped
    • Kinase responsible for receptor phosphorylation not identified
  2. 1999 High

    Demonstrated direct recognition of the non-classical ligand HLA-G1, broadening the ligand repertoire beyond classical HLA.

    Evidence ILT2-Ig fusion binding to HLA-G1 transfectants with antibody blocking and leader-sequence mutagenesis

    PMID:9933109

    Open questions at the time
    • Conformational requirements of HLA-G not addressed
    • Downstream signaling in target cells not quantified
  3. 2000 High

    Solved the D1D2 structure and mapped the UL18-binding site, distinguishing LILRB1's engagement mode from KIRs.

    Evidence X-ray crystallography at 2.1 Å with binding-site localization

    PMID:11114384

    Open questions at the time
    • Full ectodomain (D3D4) architecture not resolved
    • MHC-bound complex geometry not yet determined
  4. 2000 High

    Extended ligand recognition to HLA-F and confirmed direct molecular binding, and showed LILRB1 inhibits TCR-driven T cell activation.

    Evidence HLA-F tetramer staining, transfection, SPR; cytolytic and Ca2+ assays in T cell clones

    PMID:11034379 PMID:11169396

    Open questions at the time
    • Physiological consequence of HLA-F engagement unclear
    • Signaling intermediates downstream of TCR inhibition not dissected
  5. 2001 High

    Defined the TCR-inhibitory mechanism: co-ligation recruits SHP-1, requires p56lck, and blocks TCRζ-ZAP70 coupling, ERK activation, and actin remodeling.

    Evidence Co-IP, phosphorylation, ERK and cytoskeleton imaging in CTLs and transfected T cells

    PMID:11160312

    Open questions at the time
    • Stoichiometry of receptor clustering at the synapse not resolved
    • Role of other ITIMs not yet tested
  6. 2002 High

    Assigned functional roles to individual ITIMs, identifying Y614/Y644 as SHP-1 docking sites and Y533 as a regulatory phosphorylation site.

    Evidence Systematic ITIM mutagenesis with SHP-1 binding and serotonin-release readouts in RBL and COS-7 cells

    PMID:11907092

    Open questions at the time
    • Y562 function unresolved at this stage
    • Kinetics of sequential ITIM phosphorylation not measured
  7. 2004 Medium

    Identified Csk as a second phosphotyrosine-dependent effector recruited to the LILRB1 tail, indicating a SHP-1-independent inhibitory arm.

    Evidence Yeast three-hybrid screen confirmed by mammalian co-IP and ITIM mutagenesis

    PMID:15474475

    Open questions at the time
    • Single lab; Csk/SHP-1 do not co-precipitate with LILRB1, leaving spatial coordination unclear
    • Functional weight of Csk arm in primary cells not established
  8. 2004 High

    Showed UL18-LILRB1 engagement can paradoxically trigger MHC-unrestricted lysis of HCMV-infected cells, and characterized viral exploitation of the receptor.

    Evidence Cytolysis assays, UL18-Fc co-IP, antibody blocking, UL18-null virus in CD8+ T and NK cells

    PMID:15100307 PMID:17372005

    Open questions at the time
    • Signaling switch between inhibition and activation not mechanistically resolved
    • In vivo relevance during HCMV infection not established
  9. 2005 High

    Characterized the biophysics of MHC-I recognition (entropy-driven, flexible, fast kinetics), conformational requirements (β2m-associated HLA-G), polymorphic control of expression, and functional cross-talk with KIRs.

    Evidence SPR, ITC, crystallography, NMR; LILRB1-Ig conformational binding; SNP/structure analysis; KIR mutant transfection in NK92

    PMID:16014635 PMID:16210588 PMID:16210603 PMID:16305801

    Open questions at the time
    • Functional impact of interdomain flexibility on signaling untested
    • Mechanism by which polymorphisms alter surface expression not defined
  10. 2005 Medium

    Extended inhibitory function to dendritic cells and B cells, showing LILRB1 suppresses cytokine production, class switching, and DC stimulatory activity.

    Evidence Cross-linking with Ca2+, cytokine ELISA, Bcl-2 blot, T cell proliferation and Ig switching assays in primary DCs and B cells

    PMID:15905516 PMID:15939744

    Open questions at the time
    • Single lab for each cell type
    • Physiological ligand driving these effects in vivo not identified
  11. 2006 Medium

    Provided in vivo evidence that LILRB1 engagement of MHC-I inhibits TCR signaling, shapes thymocyte development, and promotes allograft tolerance.

    Evidence ILT2-transgenic mice, H-2Db co-IP, thymocyte analysis, skin allograft model

    PMID:16897816

    Open questions at the time
    • Cross-species receptor-ligand pairing limits physiological interpretation
    • Cell-intrinsic vs systemic contributions to tolerance not separated
  12. 2008 Medium

    Revealed a contact-dependent, non-HLA-mediated CD85j role in NK suppression of HIV-1 replication in dendritic cells, pointing to an unidentified ligand.

    Evidence NK/DC coculture, CD85j subset sorting, recombinant CD85j and anti-HLA blocking

    PMID:18398485

    Open questions at the time
    • Non-HLA ligand identity unknown at this stage
    • Single lab
  13. 2008 High

    Established LILRB1 as a specific transcriptional and secretory regulator of IFN-γ in NK and T cells responding to HLA-I and dendritic cells.

    Evidence IFN-γ mRNA/protein assays, blocking antibodies in NK-92 and primary NK cells, NK/DC coculture

    PMID:18684926

    Open questions at the time
    • Transcriptional machinery linking LILRB1 signaling to IFN-γ mRNA not defined
  14. 2010 High

    Explained cell-type-specific receptor density via dual promoters and a lymphocyte-specific 5'-UTR translational repressor element.

    Evidence Promoter mapping, reporter and 5'-UTR deletion assays, ChIP, Western, flow across hematopoietic cells

    PMID:20194892

    Open questions at the time
    • Trans-acting factors binding the repressor element not identified
    • Signal-dependent regulation of promoter choice not addressed
  15. 2013 Medium

    Identified S100A9 as a non-HLA ligand linking LILRB1 to NK-mediated control of HIV infection.

    Evidence LILRB1-S100A9 co-IP, HIV replication assays, exogenous S100A9 stimulation of NK cells

    PMID:24156302

    Open questions at the time
    • Structural basis of S100A9 binding not determined
    • Single lab
  16. 2016 Medium

    Showed HLA-I dimerization and intracellular cysteines enhance LILRB1 recognition, with type I IFN boosting recognition beyond surface HLA increases.

    Evidence LILRB1-Fc and LILRB1-ζ chimera reporter binding, transfected 721.221 cells, IFN-α stimulation of monocytes

    PMID:27109306

    Open questions at the time
    • In vivo prevalence of HLA-I dimers uncertain
    • Single lab
  17. 2017 High

    Linked M2 macrophage HLA-G to LILRB1 upregulation on NK cells driving durable NK hyporesponsiveness.

    Evidence NK/macrophage coculture, degranulation and IFN-γ assays, TGF-β neutralization, anti-CD85j blocking

    PMID:29282306

    Open questions at the time
    • Mechanism of irreversibility of degranulation hyporesponsiveness unresolved
  18. 2018 High

    Demonstrated that natural LILRB1 polymorphisms, including a glycosylation-controlling variant, tune ligand recognition and correlate with HCMV outcomes.

    Evidence Clinical cohort, NK functional assays, SPR, glycosylation-site mutagenesis

    PMID:29528338

    Open questions at the time
    • Mechanism by which glycan alters binding geometry not structurally resolved
  19. 2019 High

    Established LILRB1/HLA-G as a tumor immune checkpoint on a distinct PD-1-negative CD8+ T cell subset, additive with PD-1 blockade and limiting BiTE efficacy.

    Evidence Transcriptomics, ex vivo TIL cytotoxicity/IFN-γ assays, BiTE stimulation, combined LILRB1/PD-1 blockade

    PMID:31253728 PMID:31451484

    Open questions at the time
    • Determinants of the LILRB1+ vs PD-1+ subset divergence unknown
    • In vivo efficacy of LILRB1 blockade not established
  20. 2019 High

    Resolved the full four-domain ectodomain bound to HLA-G1, assigning D1D2 as the ligand interface and D3D4 as a scaffold and supporting cis/trans and dimeric signaling models.

    Evidence X-ray crystallography of four-domain LILRB1 and LILRB1/HLA-G1 complex

    PMID:31273318

    Open questions at the time
    • Functional validation of dimeric signaling model lacking
    • Cis vs trans engagement in cells not directly demonstrated
  21. 2020 High

    Revealed molecular mimicry whereby P. falciparum RIFINs activate LILRB1 inhibitory signaling like MHC, suppressing NK perforin mobilization.

    Evidence RIFIN-LILRB1 crystal structure, reporter assay, RIFIN mutagenesis, supported lipid bilayer NK assay

    PMID:32650338

    Open questions at the time
    • In vivo contribution to malaria immune evasion not quantified
  22. 2021 High

    Showed a subset of RIFINs binds LILRB1 D3 (mimicking LAIR1 engagement) and that humans generate anti-RIFIN antibodies via genomic insertion of LILRB1 D3D4 into antibody elbows.

    Evidence Crystal and cryo-EM structures, SPR, B cell clone isolation and antibody sequencing

    PMID:33790470

    Open questions at the time
    • Signaling consequences of D3 engagement vs D1D2 engagement not compared
  23. 2022 Medium

    Demonstrated LILRB1 acts as a macrophage phagocytosis checkpoint whose blockade enhances antibody-dependent phagocytosis of lymphoma when combined with CD47 and CD20 antibodies.

    Evidence In vitro and patient-derived ADCP assays, Fc-silent anti-LILRB1, macrophage polarization, serial engulfment imaging

    PMID:36389667

    Open questions at the time
    • Dependence on CD47 co-blockade limits standalone utility
    • Single lab; in vivo efficacy untested
  24. 2024 High

    Uncovered a non-immune role: LILRB1 partners with LDLR and LDLRAP1 to drive cholesterol uptake and protect myeloma cells from ferroptosis.

    Evidence LILRB1-LDLR-LDLRAP1 co-IP, in vivo knockout, cholesterol/squalene/ferroptosis assays

    PMID:38982045

    Open questions at the time
    • Whether this complex functions outside myeloma not established
    • Relationship between immune and metabolic functions unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How LILRB1 toggles between inhibitory and activating outcomes, how its dimeric/cis-trans geometry is functionally deployed, and how its immune-signaling and cholesterol-uptake functions are integrated remain unresolved.
  • Structural model of signaling-competent receptor clusters not validated functionally
  • Spatial coordination of SHP-1 and Csk arms unresolved
  • Generality of the LDLR/LDLRAP1 complex beyond myeloma unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0060089 molecular transducer activity 5 GO:0001618 virus receptor activity 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 3
Pathway
R-HSA-168256 Immune System 6 R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 1
Partners
CSKHLA-GLCKLDLRLDLRAP1S100A9SHP-1UL18
Complex memberships
LILRB1–HLA-G1 receptor–ligand complexLILRB1–LDLR–LDLRAP1 complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 LILRB1 (LIR-1) binds HLA-A, -B, and -C alleles and, upon phosphorylation, recruits the tyrosine phosphatase SHP-1; coligation of LILRB1 with FcγRI inhibits tyrosine phosphorylation of the Fc receptor γ-chain and Syk, and blocks intracellular calcium mobilization in monocytes. Co-ligation assay, phosphorylation assay, SHP-1 co-immunoprecipitation, calcium flux measurement in primary monocytes European journal of immunology High 9842885
1999 ILT2/LILRB1 directly recognizes and binds HLA-G1 on target cells, as shown by ILT2-Ig fusion protein binding to HLA-G1-expressing (HLA-E-negative) transfectants and blocking with receptor- and ligand-specific antibodies. ILT2-Ig fusion protein binding assay, antibody blocking cytotoxicity assay, site-directed mutagenesis of HLA-G1 leader sequence to ablate HLA-E surface expression European journal of immunology High 9933109
2000 The crystal structure of LILRB1 D1D2 at 2.1 Å resolution reveals two immunoglobulin-like domains arranged at an acute angle; the UL18-binding site maps to a portion of D1 distant from the interdomain hinge, distinct from the KIR binding site. X-ray crystallography (2.1 Å), UL18 binding localization by structural analysis Immunity High 11114384
2000 HLA-F directly interacts with LILRB1 (ILT2) and ILT4; HLA-F tetramers stain monocytes and B cells, and this binding is conferred on non-binding cells by transfection with ILT2 or ILT4. Direct molecular interaction confirmed by surface plasmon resonance. HLA-F tetramer staining, cell transfection, surface plasmon resonance (SPR), immunoprecipitation European journal of immunology High 11169396
2000 LILRB1 (CD85j/ILT2) is present in the cytoplasm of all T lymphocytes and is tyrosine-phosphorylated; it inhibits CD3/TCR-mediated activation in CD4+ and CD8+ clones, down-regulates antigen recognition by CD8+ cells, reduces cytolytic activity, and inhibits intracellular Ca2+ mobilization. Flow cytometry, Western blot, biochemical phosphorylation analysis, RT-PCR, cytolytic assay, Ca2+ mobilization assay in T cell clones Journal of immunology High 11034379
2001 ILT2/LILRB1 inhibits TCR signaling by recruiting SHP-1 upon co-ligation with the TCR; this requires Src tyrosine kinase p56(lck) for ILT2 phosphorylation and results in reduced TCRζ phosphorylation, reduced TCRζ-ZAP70 complex formation, reduced ERK1/2 activation, and inhibition of actin cytoskeleton rearrangement. Both TCR and ILT2 polarize toward the APC upon engagement. Co-immunoprecipitation, phosphorylation assay, ERK activation assay, actin cytoskeleton imaging, confocal microscopy in primary CTLs and transfected T cell lines Journal of immunology High 11160312
2002 Mutational analysis of LILRB1 ITIMs identified Y644 (SIYATL) and Y614 (VTYAQL) as the SHP-1 docking sites required for inhibitory function; Y533 (NLYAAV) plays a regulatory role required for tyrosine phosphorylation of the receptor and subsequent SHP-1 recruitment; mutation of Y562 (VTYAEV) did not alter receptor function. Site-directed mutagenesis, SHP-1 binding assay (co-IP), FcεR-induced serotonin release inhibition assay in rat basophilic leukemia cells, transfection in COS-7 cells Journal of immunology High 11907092
2004 UL18 on HCMV-infected cells interacts with CD85j/LILRB1 on CD8+ T cells to trigger MHC-unrestricted lysis of infected cells; this activation is independent of CD3/TCR engagement. Soluble recombinant UL18-Fc immunoprecipitated CD85j from T cells, and lysis was specifically blocked by anti-CD85j and anti-UL18 antibodies. Cytolysis assay, co-immunoprecipitation with recombinant UL18-Fc, antibody blocking, UL18-deficient HCMV mutant comparison Journal of immunology High 15100307
2004 C-terminal Src kinase (Csk) is recruited to the LILRB1 cytoplasmic tail in a phosphotyrosine-dependent manner; yeast three-hybrid screening identified this interaction, confirmed by co-immunoprecipitation in mammalian cells. Mutational analysis suggests Csk SH2 domain preferentially binds ITIM Y562, though mutation of Y533, Y614, and Y644 also reduces Csk recruitment. Csk and SHP-1 do not co-precipitate together with LILRB1. Yeast three-hybrid screen, co-immunoprecipitation, Western blot, phospho-peptide mapping, site-directed mutagenesis Biochemical and biophysical research communications Medium 15474475
2004 ILT2/CD85j (LILRB1) is expressed on 40–55% of CMV-, EBV-, and HIV-specific CD8+ T cells on perforin+ CD27- effector cells; blocking ILT2 engagement increases antiviral IFN-γ production approximately threefold in both normal and HIV-infected donors, but does not appreciably affect cytotoxicity. Tetramer staining, antibody blocking, IFN-γ ELISPOT, cytotoxicity assay in primary human T cells Immunology Medium 15270723
2005 LILRB1 must engage β2m-associated (conformationally intact) HLA-G for inhibitory signaling; β2m-free HLA-G heavy chain complexes expressed on the cell surface are not recognized by CD85j/LILRB1 and may interfere with CD85j–HLA-G interaction. Flow cytometry with LILRB1-Ig fusion protein, anti-HLA-G antibodies distinguishing β2m-associated vs. free heavy chains, transfected cell lines Journal of immunology Medium 16210588
2005 LILRB1 (CD85j) cross-linking on immature dendritic cells abolishes Ca2+ flux and strongly reduces IL-8 and IL-12 production induced by hOSCAR (human osteoclast-associated receptor) activation; it counteracts the hOSCAR-dependent anti-apoptotic effect by reducing Bcl-2 expression, and impairs DC-enhanced antigen-specific T cell proliferation. Ca2+ flux assay, cytokine ELISA, apoptosis assay, Bcl-2 Western blot, T cell proliferation assay in monocyte-derived DCs Journal of immunology Medium 15905516
2005 LILRB1 cross-linking on B cells inhibits IgG and IgE class switching, reduces percentages of IgG- and IgE-expressing B cells, and down-regulates IL-8, IL-10, and TNF-α production across multiple stimulatory pathways (recall antigens, CD40L plus IL-4, LPS plus IL-4). Antibody cross-linking, flow cytometry, ELISA for cytokines and immunoglobulins, multiple B-cell stimulatory conditions Clinical and diagnostic laboratory immunology Medium 15939744
2005 LILRB1-MHC class I binding is entropically driven (−TΔS = −9.4 to −6.6 kcal/mol) with low heat capacity changes; kinetic studies show fast association and dissociation rates; crystal structures reveal elbow-angle variation between D1 and D2 domains indicating interdomain flexibility, and NMR directly demonstrates conformational changes in LILRB1 upon MHCI binding. Surface plasmon resonance (kinetics), isothermal titration calorimetry (thermodynamics), X-ray crystallography (multiple crystal forms), NMR spectroscopy Journal of molecular biology High 16305801
2005 LILRB1 polymorphisms in the ligand-binding domains alter surface expression on lymphocytes and monocytes; PE01 haplotype carriers show significantly decreased LILRB1 surface expression without gross differences in crystal structures, thermostability, or binding affinities to HLA class I ligands among PE01–03 haplotype products. SNP analysis, crystal structures of PE01–03 products, thermostability assay, binding affinity measurements (SPR), flow cytometry of primary cells Human molecular genetics High 16014635
2005 ILT2/LILRB1 signals in an inhibitory KIR-dependent manner in NK92 cells: mutant KIR lacking ITIM can inhibit via ILT2 engagement with the α3 domain of HLA class I, revealing functional cooperation between KIR and ILT2 signaling pathways. This KIR-dependent signaling requires catalytically active SHP-1. Transfection of KIR mutants into NK92 cells, antibody blocking of KIR–HLA-C and ILT2–HLA-I interactions, catalytically inactive SHP-1 overexpression assay Journal of immunology Medium 16210603
2006 Human ILT2/LILRB1 associates in vivo with murine MHC class I molecule H-2Db in ILT2-transgenic mice; this association inhibits TCR proximal signaling, affects thymocyte development, and results in long-term acceptance of skin allografts. Transgenic mouse model, co-immunoprecipitation (H-2Db with human ILT2), thymocyte development analysis, skin allograft model European journal of immunology Medium 16897816
2006 Spontaneous mutations in HCMV UL18 (clinical strains vs. AD169) in the α3 domain and α1 domain alter LIR-1/LILRB1 binding; α3 domain mutations are critical for LIR-1 binding; these two independent UL18 regions (α3 tip and α1 loops) contribute to LIR-1 recognition. Cytotoxicity assays, flow cytometry binding assays, Biacore (SPR), ELISA with soluble LIR-1 and UL18 variants from clinical strains European journal of immunology Medium 16479538
2007 HCMV UL18 inhibits cytotoxicity of LIR-1+ NKL cells and LIR-1+ primary NK cells through a direct LIR-1–UL18 interaction (demonstrated by antibody blocking); LIR-1- NK cells are activated by UL18 through a LIR-1-independent mechanism. Cytolysis assay with adenoviral UL18 transduction and UL18-null HCMV mutant, antibody blocking, CD107 mobilization assay, IFN-α-activated NK bulk cultures, single NK cell clones Journal of immunology High 17372005
2007 Continuous ligation of LILRB1 during monocyte-to-DC differentiation produces DCs with a unique phenotype, profound resistance to CD95-mediated death, inhibited secretion of IL-10, IL-12p70, and TGF-β, poor stimulatory activity for T-cell proliferation (reversed by CD80/CTLA-4 blockade or Treg depletion), and stable resistance to LPS activation. In vitro DC differentiation with continuous LILRB1 ligation, flow cytometry, cytokine ELISA, T-cell proliferation assay, CD95-mediated death assay, LPS stimulation Blood High 18094328
2008 CD85j+ NK cells (but not CD85j- NK cells) potently suppress HIV-1 replication in autologous monocyte-derived DCs in a cell-contact-dependent manner; this inhibition is abolished by blocking the CD85j receptor with recombinant CD85j protein, but only partially counteracted by anti-HLA class I antibodies, suggesting a non-HLA class I ligand on HIV-1-infected MDDCs mediates this interaction. NK/DC coculture, NK subset sorting (CD85j+ vs. CD85j-), HIV-1 replication assay, receptor blocking with recombinant CD85j and anti-HLA class I antibodies, recombinant CD85j staining of MDDCs PloS one Medium 18398485
2008 LILRB1/ILT2 (CD85j) inhibits IFN-γ mRNA expression and secretion by NK cells in response to HLA class I-expressing targets, poly(I:C), and immature dendritic cells, and inhibits IFN-γ by ILT2+ T cells in response to superantigen, establishing HLA class I–ILT2 interaction as a specific regulator of IFN-γ at the mRNA and protein levels. NK-92 line and primary NK cell functional assays, IFN-γ mRNA and protein measurement (ELISA, qPCR), blocking with anti-ILT2 and anti-HLA class I antibodies, NK/DC coculture Journal of immunology High 18684926
2010 Cell-type-specific surface density of CD85j/LILRB1 is controlled by two distinct promoters (lymphocyte promoter 13 kb upstream of monocyte promoter) and a translational repression element in the 5'-UTR exon unique to the lymphocyte transcript; this sequence reduces protein translation without affecting mRNA levels, explaining the lower surface expression in lymphocytes vs. monocytes. Promoter mapping, reporter assay, 5'-UTR deletion analysis, Western blot, flow cytometry, ChIP in multiple hematopoietic cell types Blood High 20194892
2013 S100A9 is a non-HLA class I ligand for CD85j/LILRB1; direct interaction was demonstrated by co-immunoprecipitation. HIV-1 infection of MDDCs induces surface modulation of S100A9, influencing CD85j+ NK cell anti-HIV activity. Exogenous S100A9 stimulation of NK cells via CD85j ligation enhances control of HIV-1 infection in CD4+ T cells. Co-immunoprecipitation of LILRB1 and S100A9, flow cytometry, HIV-1 replication assay, NK/MDDC coculture, exogenous S100A9 stimulation Retrovirology Medium 24156302
2016 Intracellular Cys residues and HLA-I dimerization enhance LILRB1 recognition; classical HLA class Ia dimers (detected in exosomes and after type I IFN treatment of monocytes) show increased LILRB1 binding compared to monomers. Type I IFN increases LILRB1 recognition of monocyte HLA-I disproportionate to the increase in HLA-I surface expression. LILRB1-Fc fusion protein binding assay, cellular reporter system (LILRB1-ζ chimera), transfected 721.221 cells, flow cytometry, IFN-α stimulation of primary monocytes European journal of immunology Medium 27109306
2017 M2 macrophages upregulate CD85j (ILT2/LILRB1) on NK cells through a mechanism involving HLA-G (expressed at higher levels on M2 than M1); CD85j upregulation on CD56dim NK cells accounts for hyporesponsive degranulation and cytotoxicity, while soluble TGF-β and CD85j upregulation together account for diminished IFN-γ by CD56bright NK cells. Hyporesponsiveness to degranulation was not reversed upon short-term removal of M2. NK/macrophage coculture, flow cytometry, IFN-γ intracellular staining, CD107a degranulation assay, TGF-β neutralization, anti-CD85j blocking antibody, HLA-G measurement by ELISA and flow cytometry Journal of immunology High 29282306
2018 LILRB1 polymorphisms in regulatory regions and ligand-binding domains affect functional recognition of HCMV UL18 and classical MHCI (but not HLA-G) by NK cells; four nonsynonymous substitutions in the first two Ig domains each contribute to differential binding. One polymorphism controls addition of an N-linked glycan whose removal enhances binding to UL18 and alters binding to all tested ligands. Clinical cohort HCMV outcome analysis, NK cell functional assays with LILRB1 variants, SPR binding assays, glycosylation site mutagenesis The Journal of clinical investigation High 29528338
2019 LILRB1 is expressed by a distinct CD8+PD-1- intratumoral T cell subset; HLA-G on tumor cells specifically inhibits CD8+ILT2+ (but not CD8+ILT2- or CD8+PD-1+) T cell cytotoxicity and IFN-γ production, and this inhibition is counteracted by blocking the HLA-G/ILT2 interaction. Transcriptomics, flow cytometry, ex vivo cytotoxicity assay with primary TILs and PBMCs, anti-ILT2/anti-HLA-G blocking experiments Cancer immunology research High 31451484
2019 LILRB1 engagement by HLA-G on tumor cells significantly inhibits BiTE molecule-induced CD8+ effector T cell activation; LILRB1 and PD-1 are expressed by distinct CD8+ T cell populations, and combined LILRB1 + PD-1 blockade induces greater activation than either alone. Flow cytometry, BiTE molecule stimulation assay, LILRB1/HLA-G blocking, anti-PD-1 blocking, T cell activation assays with primary human CD8+ T cells Journal of immunology Medium 31253728
2019 Crystal structure of four-domain LILRB1 in complex with HLA-G1 shows that D1D2 is responsible for HLA-I binding while D3D4 acts as a structural scaffold; staggered assembly of the four Ig-like domains shows limited flexibility. Structure supports models for both cis and trans HLA-I binding, and dimeric LILRB1 geometry suggests enhanced inhibitory signal transduction. X-ray crystallography of four-domain LILRB1 and LILRB1/HLA-G1 complex, structural analysis of domain angles and assembly Cellular & molecular immunology High 31273318
2020 A RIFIN from Plasmodium falciparum mimics the binding mode of MHC class I to activate LILRB1 signaling; the crystal structure of RIFIN bound to LILRB1 reveals this mimicry; a single mutation in the RIFIN disrupts the complex, blocks LILRB1 binding of all tested RIFINs, and abolishes signaling in a reporter assay. In a supported lipid bilayer NK cell system, RIFIN suppresses NK cell perforin mobilization similarly to MHC. X-ray crystallography of RIFIN–LILRB1 complex, LILRB1 reporter assay, site-directed mutagenesis of RIFIN, supported lipid bilayer NK cell assay (ADCC model), perforin mobilization measurement Nature High 32650338
2021 RIFIN proteins from Plasmodium falciparum bind to LILRB1 domain 3 (D3); crystal and cryo-EM structures of RIFIN in complex with LILRB1 D3D4 and a D3D4-containing antibody Fab reveal that RIFIN–LILRB1 D3 interaction is similar to RIFIN–LAIR1; DNA insertions encoding LILRB1 D3D4 or D3 into the VH-CH1 elbow of antibody genes generate RIFIN-specific antibodies in malaria-exposed donors. Cryo-EM and crystal structure determination, SPR/binding assays, mass spectrometry, B cell clone isolation, antibody gene sequencing Nature High 33790470
2022 LILRB1 blockade (Fc-silent anti-LILRB1 antibody LILRB1-IgGσ) significantly enhances antibody-dependent cellular phagocytosis (ADCP) of lymphoma cells by macrophages when combined with rituximab and CD47 blockade; LILRB1-IgGσ promotes serial engulfment and potentiates ADCP by M0, M1, and M2 macrophages, but requires CD47 co-blockade and CD20 antibody. LILRB2 blockade was not effective. In vitro ADCP assay, macrophage polarization, patient-derived CLL/lymphoma cell ADCP, antibody engineering (Fc-silent variants), serial engulfment imaging Frontiers in immunology Medium 36389667
2024 LILRB1 forms a complex with the low-density lipoprotein receptor (LDLR) and LDLR adapter protein 1 (LDLRAP1) to facilitate LDL/cholesterol uptake in multiple myeloma cells; loss of LILRB1 impairs cholesterol uptake but activates de novo cholesterol synthesis, decreasing anti-ferroptotic squalene and promoting ferroptosis. Co-immunoprecipitation (LILRB1–LDLR–LDLRAP1 complex), in vivo LILRB1 knockout (MM mouse model), cholesterol uptake assay, squalene measurement, ferroptosis assay, gene expression profiling Nature communications High 38982045

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Circular RNA and miR-7 in cancer. Cancer research 799 24014594
2018 CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7. Cell death & disease 500 29549306
1999 The ILT2(LIR1) and CD94/NKG2A NK cell receptors respectively recognize HLA-G1 and HLA-E molecules co-expressed on target cells. European journal of immunology 300 9933109
1998 The MHC class I binding proteins LIR-1 and LIR-2 inhibit Fc receptor-mediated signaling in monocytes. European journal of immunology 173 9842885
2000 Functional characterization of HLA-F and binding of HLA-F tetramers to ILT2 and ILT4 receptors. European journal of immunology 159 11169396
2019 MiR-7-5p suppresses tumor metastasis of non-small cell lung cancer by targeting NOVA2. Cellular & molecular biology letters 126 31832068
2014 miR-7-5p suppresses cell proliferation and induces apoptosis of breast cancer cells mainly by targeting REGγ. Cancer letters 125 25511742
2000 Crystal structure and ligand binding properties of the D1D2 region of the inhibitory receptor LIR-1 (ILT2). Immunity 118 11114384
2007 The human cytomegalovirus MHC class I homolog UL18 inhibits LIR-1+ but activates LIR-1- NK cells. Journal of immunology (Baltimore, Md. : 1950) 115 17372005
2000 The CD85/LIR-1/ILT2 inhibitory receptor is expressed by all human T lymphocytes and down-regulates their functions. Journal of immunology (Baltimore, Md. : 1950) 115 11034379
2001 Ig-like transcript 2 (ILT2)/leukocyte Ig-like receptor 1 (LIR1) inhibits TCR signaling and actin cytoskeleton reorganization. Journal of immunology (Baltimore, Md. : 1950) 110 11160312
2021 METTL14 promotes doxorubicin-induced cardiomyocyte ferroptosis by regulating the KCNQ1OT1-miR-7-5p-TFRC axis. Cell biology and toxicology 96 34648132
2005 The CD85J/leukocyte inhibitory receptor-1 distinguishes between conformed and beta 2-microglobulin-free HLA-G molecules. Journal of immunology (Baltimore, Md. : 1950) 94 16210588
2007 The inhibitory receptor LILRB1 modulates the differentiation and regulatory potential of human dendritic cells. Blood 84 18094328
2017 Human M2 Macrophages Limit NK Cell Effector Functions through Secretion of TGF-β and Engagement of CD85j. Journal of immunology (Baltimore, Md. : 1950) 79 29282306
2013 Identification of miR-7 as an oncogene in renal cell carcinoma. Journal of molecular histology 78 23793934
2018 miR-7 Replacement Therapy in Parkinson's Disease. Current gene therapy 75 29714132
2005 Inhibitory receptors CD85j, LAIR-1, and CD152 down-regulate immunoglobulin and cytokine production by human B lymphocytes. Clinical and diagnostic laboratory immunology 73 15939744
2014 miR-7 inhibits colorectal cancer cell proliferation and induces apoptosis by targeting XRCC2. OncoTargets and therapy 68 24570594
2020 Long non-coding RNA LPP-AS2 promotes glioma tumorigenesis via miR-7-5p/EGFR/PI3K/AKT/c-MYC feedback loop. Journal of experimental & clinical cancer research : CR 67 32962742
2004 Immunoglobulin-like transcripts ILT2, ILT3 and ILT7 are expressed by human dendritic cells and down-regulated following activation. Gene 67 15094202
2005 Extensive polymorphisms of LILRB1 (ILT2, LIR1) and their association with HLA-DRB1 shared epitope negative rheumatoid arthritis. Human molecular genetics 65 16014635
2019 CD8+PD-1-ILT2+ T Cells Are an Intratumoral Cytotoxic Population Selectively Inhibited by the Immune-Checkpoint HLA-G. Cancer immunology research 63 31451484
2005 Does memory improve with age? CD85j (ILT-2/LIR-1) expression on CD8 T cells correlates with 'memory inflation' in human cytomegalovirus infection. Immunology and cell biology 60 15748215
2019 Dihydroartemisinin inhibits prostate cancer via JARID2/miR-7/miR-34a-dependent downregulation of Axl. Oncogenesis 59 30783079
2014 MiR-7 promotes epithelial cell transformation by targeting the tumor suppressor KLF4. PloS one 52 25181544
2020 Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells. Journal for immunotherapy of cancer 51 32771992
2019 The MHC class I-LILRB1 signalling axis as a promising target in cancer therapy. Scandinavian journal of immunology 51 31267559
2019 HIV-1 Tat-Induced Astrocytic Extracellular Vesicle miR-7 Impairs Synaptic Architecture. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 50 31401755
2012 Dynamic shift from CD85j/ILT-2 to NKG2D NK receptor expression pattern on human decidual NK during the first trimester of pregnancy. PloS one 50 22242197
2003 LIR-1 expression on lymphocytes, and cytomegalovirus disease in lung-transplant recipients. Lancet (London, England) 49 12672315
2017 MicroRNAs miR-7 and miR-340 predict response to neoadjuvant chemotherapy in breast cancer. Breast cancer research and treatment 48 28181130
2002 Mutational analysis of immunoreceptor tyrosine-based inhibition motifs of the Ig-like transcript 2 (CD85j) leukocyte receptor. Journal of immunology (Baltimore, Md. : 1950) 48 11907092
2021 MiR-7 in Cancer Development. Biomedicines 47 33806891
2004 Increased expression of the natural killer cell inhibitory receptor CD85j/ILT2 on antigen-specific effector CD8 T cells and its impact on CD8 T-cell function. Immunology 47 15270723
2021 Exosomes-transmitted miR-7 reverses gefitinib resistance by targeting YAP in non-small-cell lung cancer. Pharmacological research 45 33497805
2013 S100A9 protein is a novel ligand for the CD85j receptor and its interaction is implicated in the control of HIV-1 replication by NK cells. Retrovirology 45 24156302
2004 Specific recognition of the viral protein UL18 by CD85j/LIR-1/ILT2 on CD8+ T cells mediates the non-MHC-restricted lysis of human cytomegalovirus-infected cells. Journal of immunology (Baltimore, Md. : 1950) 45 15100307
2019 Structures of the four Ig-like domain LILRB2 and the four-domain LILRB1 and HLA-G1 complex. Cellular & molecular immunology 44 31273318
2015 Overexpression of CD85j in TNBC patients inhibits Cetuximab-mediated NK-cell ADCC but can be restored with CD85j functional blockade. European journal of immunology 44 25726929
2020 Structural basis for RIFIN-mediated activation of LILRB1 in malaria. Nature 43 32650338
2019 LILRB1 Blockade Enhances Bispecific T Cell Engager Antibody-Induced Tumor Cell Killing by Effector CD8+ T Cells. Journal of immunology (Baltimore, Md. : 1950) 43 31253728
2019 miR-7 Reverses Breast Cancer Resistance To Chemotherapy By Targeting MRP1 And BCL2. OncoTargets and therapy 43 31908478
2020 Combinatory Treatment with miR-7-5p and Drug-Loaded Cubosomes Effectively Impairs Cancer Cells. International journal of molecular sciences 42 32708846
2018 Ig-Like Transcript 2 (ILT2) Blockade and Lenalidomide Restore NK Cell Function in Chronic Lymphocytic Leukemia. Frontiers in immunology 42 30619281
2022 BND-22, a first-in-class humanized ILT2-blocking antibody, promotes antitumor immunity and tumor regression. Journal for immunotherapy of cancer 41 36096532
2008 HLA class I molecules regulate IFN-gamma production induced in NK cells by target cells, viral products, or immature dendritic cells through the inhibitory receptor ILT2/CD85j. Journal of immunology (Baltimore, Md. : 1950) 41 18684926
2021 miR-7/TGF-β2 axis sustains acidic tumor microenvironment-induced lung cancer metastasis. Acta pharmaceutica Sinica. B 40 35251919
2010 Promoter choice and translational repression determine cell type-specific cell surface density of the inhibitory receptor CD85j expressed on different hematopoietic lineages. Blood 40 20194892
2022 Dual checkpoint blockade of CD47 and LILRB1 enhances CD20 antibody-dependent phagocytosis of lymphoma cells by macrophages. Frontiers in immunology 39 36389667
2020 miR-7 Regulates GLP-1-Mediated Insulin Release by Targeting β-Arrestin 1. Cells 39 32640511
2005 CD85j (leukocyte Ig-like receptor-1/Ig-like transcript 2) inhibits human osteoclast-associated receptor-mediated activation of human dendritic cells. Journal of immunology (Baltimore, Md. : 1950) 39 15905516
2018 miR-7-5p inhibits cell migration and invasion in glioblastoma through targeting SATB1. Oncology letters 38 30675243
2007 Analysis of expression and function of the inhibitory receptor ILT2 (CD85j/LILRB1/LIR-1) in peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE). Journal of autoimmunity 38 17601702
2004 Recruitment of C-terminal Src kinase by the leukocyte inhibitory receptor CD85j. Biochemical and biophysical research communications 37 15474475
2023 Perspectives of targeting LILRB1 in innate and adaptive immune checkpoint therapy of cancer. Frontiers in immunology 36 37781391
2020 Simultaneous downregulation of miR-21 and upregulation of miR-7 has anti-tumor efficacy. Scientific reports 36 32019988
2008 The CD85j+ NK cell subset potently controls HIV-1 replication in autologous dendritic cells. PloS one 36 18398485
2006 Spontaneous mutations in the human CMV HLA class I homologue UL18 affect its binding to the inhibitory receptor LIR-1/ILT2/CD85j. European journal of immunology 35 16479538
2006 Human ILT2 receptor associates with murine MHC class I molecules in vivo and impairs T cell function. European journal of immunology 35 16897816
2021 C/EBPα/miR-7 Controls CD4+ T-Cell Activation and Function and Orchestrates Experimental Autoimmune Hepatitis in Mice. Hepatology (Baltimore, Md.) 34 33125780
2020 lncRNA Neat1 Stimulates Osteoclastogenesis Via Sponging miR-7. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 34 32353178
2017 Immune Checkpoint Function of CD85j in CD8 T Cell Differentiation and Aging. Frontiers in immunology 34 28659925
2022 Role of MicroRNA-7 (MiR-7) in Cancer Physiopathology. International journal of molecular sciences 33 36012357
2020 MiR-7 mediates mitochondrial impairment to trigger apoptosis and necroptosis in Rhabdomyosarcoma. Biochimica et biophysica acta. Molecular cell research 32 32810522
2010 LILRB1 polymorphism and surface phenotypes of natural killer cells. Human immunology 32 20600445
2024 Leukocyte immunoglobulin-like receptor B1 (LILRB1) protects human multiple myeloma cells from ferroptosis by maintaining cholesterol homeostasis. Nature communications 31 38982045
2001 CD85/LIR-1/ILT2 and CD152 (cytotoxic T lymphocyte antigen 4) inhibitory molecules down-regulate the cytolytic activity of human CD4+ T-cell clones specific for Mycobacterium tuberculosis. Infection and immunity 31 11553539
2020 Antagonizing miR-7 suppresses B cell hyperresponsiveness and inhibits lupus development. Journal of autoimmunity 30 32201226
2018 LILRB1 polymorphisms influence posttransplant HCMV susceptibility and ligand interactions. The Journal of clinical investigation 29 29528338
2005 Killer cell Ig-like receptor-dependent signaling by Ig-like transcript 2 (ILT2/CD85j/LILRB1/LIR-1). Journal of immunology (Baltimore, Md. : 1950) 29 16210603
2023 MiR-7-5p/KLF4 signaling inhibits stemness and radioresistance in colorectal cancer. Cell death discovery 28 36732504
2023 Serum and Exosomal miR-7-1-5p and miR-223-3p as Possible Biomarkers for Parkinson's Disease. Biomolecules 28 37238734
2013 Decreased miR-7 expression in the skin and sera of patients with dermatomyositis. Acta dermato-venereologica 28 23007163
2020 miR-7 Reduces Breast Cancer Stem Cell Metastasis via Inhibiting RELA to Decrease ESAM Expression. Molecular therapy oncolytics 27 32637582
2014 Regulation of Human PAX6 Expression by miR-7. Evolutionary bioinformatics online 27 25089088
2005 Entropically driven MHC class I recognition by human inhibitory receptor leukocyte Ig-like receptor B1 (LILRB1/ILT2/CD85j). Journal of molecular biology 27 16305801
2021 Circulating and Tumor-Infiltrating NK Cells From Clear Cell Renal Cell Carcinoma Patients Exhibit a Predominantly Inhibitory Phenotype Characterized by Overexpression of CD85j, CD45, CD48 and PD-1. Frontiers in immunology 25 34149719
2021 miR-7/EGFR/MEGF9 axis regulates cartilage degradation in osteoarthritis via PI3K/AKT/mTOR signaling pathway. Bioengineered 25 34629037
2017 miR-7 Buffers Differentiation in the Developing Drosophila Visual System. Cell reports 25 28793250
2012 Impact of the NK cell receptor LIR-1 (ILT-2/CD85j/LILRB1) on cytotoxicity against multiple myeloma. Clinical & developmental immunology 25 22844324
2023 The miR-7/EGFR axis controls the epithelial cell immunomodulation and regeneration and orchestrates the pathology in inflammatory bowel disease. Journal of advanced research 23 37094666
2020 miR-7 Controls the Dopaminergic/Oligodendroglial Fate through Wnt/β-catenin Signaling Regulation. Cells 23 32183236
2020 miR-7-5p Affects Brain Edema After Intracerebral Hemorrhage and Its Possible Mechanism. Frontiers in cell and developmental biology 23 33392188
2019 MicroRNA miR-7 and miR-17-92 in the Arcuate Nucleus of Mouse Hypothalamus Regulate Sex-Specific Diet-Induced Obesity. Molecular neurobiology 23 31044367
2022 Low shear stress inhibits endothelial mitophagy via caveolin-1/miR-7-5p/SQSTM1 signaling pathway. Atherosclerosis 22 35952464
2021 Structural basis of malaria RIFIN binding by LILRB1-containing antibodies. Nature 22 33790470
2018 Loss of the Immune Checkpoint CD85j/LILRB1 on Malignant Plasma Cells Contributes to Immune Escape in Multiple Myeloma. Journal of immunology (Baltimore, Md. : 1950) 22 29531171
2002 Engagement of ILT2/CD85j in Sézary syndrome cells inhibits their CD3/TCR signaling. Blood 22 12130517
2022 LncRNA OIP5-AS1-directed miR-7 degradation promotes MYMX production during human myogenesis. Nucleic acids research 21 35736212
2020 Long noncoding RNA LINC00115 promotes breast cancer metastasis by inhibiting miR-7. FEBS open bio 21 32175684
2019 High-throughput screening identified miR-7-2-3p and miR-29c-3p as metastasis suppressors in gallbladder carcinoma. Journal of gastroenterology 21 31562534
2024 miR-7 controls glutamatergic transmission and neuronal connectivity in a Cdr1as-dependent manner. EMBO reports 20 38831125
2021 circHIPK3 regulates proliferation and differentiation of myoblast through the miR-7/TCF12 pathway. Journal of cellular physiology 20 33748999
2016 Possible Role of HLA-G, LILRB1 and KIR2DL4 Gene Polymorphisms in Spontaneous Miscarriage. Archivum immunologiae et therapiae experimentalis 20 26973020
2016 Interaction of the LILRB1 inhibitory receptor with HLA class Ia dimers. European journal of immunology 20 27109306
2021 Circular RNA WHSC1 exerts oncogenic properties by regulating miR-7/TAB2 in lung cancer. Journal of cellular and molecular medicine 19 34551195
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
2017 Oleic Acid Induces MiR-7 Processing through Remodeling of Pri-MiR-7/Protein Complex. Journal of molecular biology 19 28483648
2013 MiR-7-1 potentiated estrogen receptor agonists for functional neuroprotection in VSC4.1 motoneurons. Neuroscience 19 24157932

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