{"gene":"LILRB1","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2003,"finding":"LILRB1 (ILT2) binds a broad range of classical and non-classical MHC class I molecules with 2- to 3-fold higher affinity than LILRB2 (ILT4), and binds HLA-G with 3- to 4-fold higher affinity than classical MHCIs; LILRB1 and LILRB2 compete with CD8 for MHC class I binding, raising the possibility that LILRB1 modulates CD8+ T cell activation by blocking CD8 binding in addition to recruiting inhibitory SHP-1 phosphatase via its ITIM motifs.","method":"Surface plasmon resonance (SPR) binding assays measuring Kd values for soluble ILT2/ILT4 vs. multiple MHC class I molecules; competition assays with CD8","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro binding assay (SPR) with quantitative Kd measurements, replicated across multiple ligands","pmids":["12853576"],"is_preprint":false},{"year":2000,"finding":"HLA-F directly interacts with LILRB1 (ILT2/LIR1) and LILRB2 (ILT4/LIR2); HLA-F tetramer binding to peripheral blood monocytes and B cells could be conferred on non-binding cells by transfection with ILT2 or ILT4, and a direct molecular interaction was confirmed by surface plasmon resonance.","method":"HLA-F tetramer staining, transfection of ILT2/ILT4 into non-binding cells, surface plasmon resonance","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — direct binding confirmed by SPR and functional cell transfection assays with orthogonal methods","pmids":["11169396"],"is_preprint":false},{"year":1999,"finding":"LILRB1 (ILT2/CD85j) is an inhibitory MHC class I receptor of the immunoglobulin superfamily expressed on B cells, monocytes, and subsets of T and NK cells; its cell signaling role involves inhibitory functions consistent with CD85 involvement in T cell activation, as confirmed by demonstrating that anti-CD85 mAbs stain ILT2 transfectants.","method":"Affinity purification, tryptic peptide sequencing, transfectant staining with anti-CD85 mAbs","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 — protein identity established by peptide sequencing and functional transfectant confirmation, single study","pmids":["10380908"],"is_preprint":false},{"year":2002,"finding":"LILRB1 (ILT2/CD85j) is functional on Sézary cell lines (CTCL): its triggering recruits SHP-1 (Src homology 2 domain-containing tyrosine phosphatase) and specifically inhibits CTCL cell proliferation induced by CD3/TCR stimulation; CD4+ILT2+ Sézary cells are less susceptible to anti-CD3-induced cell death than autologous CD4+ILT2- lymphocytes.","method":"ILT2 ligation on CTCL cell lines, SHP-1 recruitment assay, CD3/TCR stimulation proliferation assay, apoptosis comparison","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional assays showing SHP-1 recruitment and specific inhibition of TCR signaling, moderate evidence","pmids":["12130517"],"is_preprint":false},{"year":2007,"finding":"LILRB1 is selectively upregulated during DC differentiation from monocyte precursors; continuous ligation of LILRB1 modulates DC differentiation, confers resistance to CD95-mediated cell death, inhibits secretion of IL-10, IL-12p70, and TGF-beta, and results in poor stimulatory activity for T-cell proliferative responses that is reversed by CD80 blockade or depletion of CD4+CD25+CD127lo regulatory T cells.","method":"LILRB1 ligation during DC differentiation, cytokine ELISA, apoptosis assays, mixed lymphocyte reaction, antibody blockade experiments","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional readouts (differentiation, apoptosis resistance, cytokine suppression, T-cell stimulation) in a single controlled study","pmids":["18094328"],"is_preprint":false},{"year":2008,"finding":"LILRB1 (ILT2/CD85j) inhibits IFN-gamma production by NK cells and T cells via HLA class I recognition: ligation of ILT2/CD85j with HLA class I on target cells inhibits IFN-gamma mRNA expression, protein production, and secretion in NK-92 and primary ILT2+ NK cells, and inhibits IFN-gamma in response to poly(I:C); blocking ILT2-HLA class I interactions increases IFN-gamma secretion in NK/immature DC cocultures.","method":"NK cell stimulation assays with HLA class I-expressing targets, IFN-gamma mRNA and protein measurement, ILT2 blocking antibody experiments","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (mRNA, protein, secretion assays, blocking antibody), replicated in both cell line and primary NK cells","pmids":["18684926"],"is_preprint":false},{"year":2009,"finding":"Interaction of LILRB1 (ILT2) with HLA-G inhibits polarization of NK cell lytic granules and MTOC as well as F-actin accumulation at the NK/target-cell synapse, and inhibits intracellular calcium mobilization and IFN-gamma polarized production, without affecting recruitment of activatory receptor CD2 to the synapse—demonstrating differential effects on early vs. late NK activation synapse events.","method":"NK cell/target-cell synapse imaging, granule polarization assays, MTOC localization, F-actin staining, calcium mobilization, IFN-gamma secretion assays","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"High","confidence_rationale":"Tier 2 — multiple imaging and biochemical readouts showing mechanistic dissection of synapse events, single but rigorous study","pmids":["19841038"],"is_preprint":false},{"year":2005,"finding":"HLA-G upregulates expression of LILRB1 (ILT2) on antigen-presenting cells, NK cells, and T cells without requiring antigenic costimulation, suggesting that LILRB1 expression is itself regulated by its ligand HLA-G as part of an immune escape mechanism.","method":"Flow cytometry of ILT2 surface expression on immune cells after HLA-G exposure, analysis in multiple cell types","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 3 — single method (flow cytometry) in a single study, but across multiple cell types","pmids":["15670976"],"is_preprint":false},{"year":2017,"finding":"MHC class I (via its component β2-microglobulin) on cancer cells directly protects them from macrophage phagocytosis through the inhibitory receptor LILRB1, whose expression is upregulated on tumor-associated macrophages; disruption of either MHC class I or LILRB1 potentiates phagocytosis of tumor cells both in vitro and in vivo, defining MHC class I-LILRB1 as a phagocytosis checkpoint on macrophages.","method":"Phagocytosis assays in vitro and in vivo, LILRB1 knockdown/blockade, β2M manipulation on cancer cells, tumor-associated macrophage expression analysis","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — in vitro and in vivo phagocytosis assays with genetic and antibody-based disruption, replicated across multiple cancer cell types","pmids":["29180808"],"is_preprint":false},{"year":2019,"finding":"Crystal structure of four Ig-like domain LILRB2 and four-domain LILRB1 in complex with HLA-G1 reveals that D1D2 domains are responsible for HLA class I binding while D3D4 acts as a scaffold; the staggered assembly of four domains shows limited flexibility during ligand binding; dimeric HLA-G1 binding to LILRB1/2 suggests the dimeric receptor transduces stronger inhibitory signals.","method":"X-ray crystallography of LILRB1/2 four-domain constructs and LILRB1–HLA-G1 complex","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional domain mapping; directly validates binding model","pmids":["31273318"],"is_preprint":false},{"year":2020,"finding":"P. falciparum RIFIN proteins mimic MHC class I in their LILRB1-binding mode: cryo-EM/crystal structure of RIFIN bound to LILRB1 shows structural mimicry; a single point mutation in RIFIN disrupts the complex, blocks LILRB1 binding of all tested RIFINs, and abolishes signaling in a reporter assay; in a supported lipid bilayer system, both RIFIN and MHC are recruited to the NK cell immunological synapse and suppress NK cell perforin mobilization.","method":"Cryo-EM/crystallography of RIFIN–LILRB1 complex, mutagenesis, reporter signaling assay, supported lipid bilayer NK cell activation assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — structure + mutagenesis + functional reporter + live-cell bilayer assay; multiple orthogonal methods in a single rigorous study","pmids":["32650338"],"is_preprint":false},{"year":2018,"finding":"LILRB1 polymorphisms in ligand-binding domains alter functional recognition of UL18 (HCMV MHC class I homolog) and classical MHC class I but not HLA-G; N-linked glycosylation controlled by one polymorphism alters binding to all ligands tested, including enhancing binding to UL18; specific LILRB1 alleles associated with superior HCMV immune evasion are restricted by mutations that limit LILRB1 expression selectively on NK cells.","method":"LILRB1 variant expression in NK cell models, functional binding assays with UL18/classical MHCI/HLA-G, glycosylation site mutagenesis, transplant patient cohort association","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of glycosylation site with quantitative binding assays, replicated in functional NK model, supported by patient association","pmids":["29528338"],"is_preprint":false},{"year":2021,"finding":"Crystal and cryo-EM structures of a RIFIN in complex with LILRB1 D3D4-containing antibody Fab reveal that RIFINs bind LILRB1 through its non-apical D3 domain; this interaction is similar in mode to RIFIN–LAIR1 binding; naturally occurring LILRB1 D3/D4 domain insertions in immunoglobulin VH-CH1 elbow generate RIFIN-specific antibodies in malaria-exposed donors.","method":"Cryo-EM and crystal structures of RIFIN–LILRB1 D3D4 Fab complexes, mass spectrometry, binding assays, B cell clone isolation","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — orthogonal structural methods (crystal + cryo-EM) plus binding assays and MS; single study but exceptionally rigorous","pmids":["33790470"],"is_preprint":false},{"year":2016,"finding":"HLA class Ia dimerization and the presence of intracellular Cys residues enhance LILRB1 recognition; type I interferon induces HLA class Ia dimer formation on primary monocytes that disproportionately increases LILRB1 interaction beyond the cytokine-induced increase in surface HLA-I expression, supporting regulated assembly of noncanonical HLA-I conformers as a mechanism to modulate LILRB1 avidity.","method":"Soluble LILRB1-Fc fusion protein binding, LILRB1-ζ chimera cellular reporter system, HLA-I transfectants in 721.221 cells, IFN treatment of primary monocytes","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay plus soluble protein binding across multiple HLA constructs, but single lab study","pmids":["27109306"],"is_preprint":false},{"year":2019,"finding":"LILRB1 functions as a negative regulator of human CD45RA+CCR7- CD8+ effector T cells; LILRB1 is expressed on distinct CD8+ T cell populations from PD1; engaging LILRB1 with HLA-G on tumor cells significantly inhibited BiTE molecule-induced CD8+ T cell activation; combined blockade of LILRB1 and PD1 induced greater CD8+ T cell activation than either alone.","method":"Flow cytometry of CD8+ T cell subsets, BiTE molecule stimulation assays, HLA-G engagement assays, dual blockade experiments","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 — functional assays with specific HLA-G engagement and antibody blockade, single study","pmids":["31253728"],"is_preprint":false},{"year":2024,"finding":"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 the anti-ferroptotic metabolite squalene and thereby enhancing ferroptosis of myeloma cells.","method":"Co-immunoprecipitation of LILRB1-LDLR-LDLRAP1 complex, LILRB1 knockout in vivo myeloma model, cholesterol uptake assays, squalene measurement, ferroptosis assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — Co-IP demonstrating complex, in vivo KO with defined metabolic phenotype, mechanistic readout of squalene and ferroptosis","pmids":["38982045"],"is_preprint":false},{"year":2020,"finding":"LILRB1 blockade on NK cells increases tumoricidal activity against multiple myeloma, leukemia, lymphoma and solid tumor cells both in vitro and in vivo, and the percentage of LILRB1+ NK cells is significantly higher in patients with persistent multiple myeloma or late-stage prostate cancer than in healthy donors.","method":"Antagonistic anti-LILRB1 monoclonal antibody treatment, in vitro cytotoxicity assays, NOD-SCID IL-2Rγ-null mouse xenograft model, flow cytometry of NK cells from cancer patients","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo functional assays with specific antibody blockade, single study","pmids":["32771992"],"is_preprint":false},{"year":2022,"finding":"Dual blockade of CD47 and LILRB1 significantly enhances antibody-dependent cellular phagocytosis (ADCP) of lymphoma cell lines and primary CLL/lymphoma cells by macrophages when combined with rituximab; LILRB1 blockade (but not LILRB2 blockade) promotes serial engulfment and potentiates ADCP by M0, M1, and M2 macrophages, but requires CD47 co-blockade and presence of CD20 antibody.","method":"ADCP phagocytosis assay with Fc-silent anti-LILRB1 antibody, lymphoma cell lines and primary patient cells, macrophage polarization experiments","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — functional phagocytosis assays with orthogonal macrophage polarization conditions and primary patient cells, single study","pmids":["36389667"],"is_preprint":false},{"year":2019,"finding":"CD8+ILT2+ tumor-infiltrating lymphocytes (TILs) are a late-differentiated cytotoxic CD27-CD28-CD57+ subset distinct from CD8+PD-1+ TILs; HLA-G expression on target cells specifically inhibits CD8+ILT2+ T cell cytotoxicity and IFNγ production, but not CD8+ILT2- or CD8+PD-1+ counterparts; blockade of HLA-G/ILT2 interaction restores cytotoxicity.","method":"Ex vivo flow cytometry, functional cytotoxicity assays with TILs and PBMCs, HLA-G blocking antibody experiments","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 — ex vivo functional assays with blocking antibody reversal in patient TILs, single study","pmids":["31451484"],"is_preprint":false}],"current_model":"LILRB1 (ILT2/CD85j/LIR1) is a transmembrane inhibitory receptor expressed on multiple immune cell lineages (NK cells, T cells, B cells, monocytes, macrophages, dendritic cells) that binds MHC class I molecules (classical HLA-A/B/C, non-classical HLA-E/F/G, and the HCMV homolog UL18) via its D1D2 extracellular domains with highest affinity for HLA-G dimers, recruits SHP-1 phosphatase through its cytoplasmic ITIM motifs to suppress TCR/NK-cell signaling, inhibits NK cell granule polarization and IFN-γ production, functions as a phagocytosis checkpoint on macrophages by recognizing MHC class I (β2M) on cancer cells, and additionally forms a complex with LDLR/LDLRAP1 to regulate cholesterol uptake and protect myeloma cells from ferroptosis; Plasmodium falciparum RIFINs structurally mimic MHC class I to exploit LILRB1 and suppress NK cell activation."},"narrative":{"teleology":[{"year":1999,"claim":"Establishing the molecular identity of the CD85j antigen as LILRB1/ILT2, an inhibitory Ig-superfamily receptor on multiple immune lineages, provided the foundation for all subsequent mechanistic work on this receptor.","evidence":"Affinity purification, tryptic peptide sequencing, and transfectant staining with anti-CD85 mAbs","pmids":["10380908"],"confidence":"Medium","gaps":["Single-method identification without functional signaling readout","Expression pattern described by flow cytometry alone"]},{"year":2000,"claim":"Demonstrating that LILRB1 binds the non-classical molecule HLA-F expanded the receptor's ligand repertoire beyond classical MHC class I, raising the question of how broadly LILRB1 surveys MHC diversity.","evidence":"HLA-F tetramer staining, ILT2 transfection into non-binding cells, SPR confirmation","pmids":["11169396"],"confidence":"High","gaps":["Functional consequence of HLA-F engagement on immune cell signaling not tested","Affinity comparison with classical MHC I not performed"]},{"year":2003,"claim":"Quantitative SPR measurements established that LILRB1 binds a broad panel of classical and non-classical MHC class I molecules with systematically higher affinity than LILRB2, and preferentially recognizes HLA-G, while competing with CD8 for MHC binding—defining LILRB1's dual inhibitory mechanism (ITIM signaling plus CD8 displacement).","evidence":"Surface plasmon resonance Kd measurements across multiple MHC I ligands; competition assays with CD8","pmids":["12853576"],"confidence":"High","gaps":["CD8 competition demonstrated in vitro but not validated in T cell coculture","Contribution of CD8 displacement versus ITIM signaling to inhibition not quantified"]},{"year":2002,"claim":"Showing that LILRB1 ligation recruits SHP-1 and inhibits TCR/CD3-driven proliferation in Sézary cells provided the first direct evidence of the receptor's inhibitory signaling mechanism in T cells.","evidence":"SHP-1 recruitment assay, CD3/TCR stimulation proliferation assay, apoptosis comparison in CTCL cell lines","pmids":["12130517"],"confidence":"High","gaps":["Downstream substrates of SHP-1 in LILRB1 signaling not identified","Studied in malignant CTCL lines; relevance to normal T cells assumed but not shown"]},{"year":2005,"claim":"The finding that HLA-G upregulates LILRB1 surface expression on APCs, NK cells, and T cells revealed a positive feedback loop between ligand and receptor that could amplify immune suppression.","evidence":"Flow cytometry of ILT2 expression after HLA-G exposure across multiple cell types","pmids":["15670976"],"confidence":"Medium","gaps":["Single method (flow cytometry); transcriptional versus post-translational mechanism of upregulation not resolved","Functional consequence of upregulation on inhibitory signaling threshold not tested"]},{"year":2007,"claim":"Continuous LILRB1 ligation during DC differentiation was shown to modulate DC function—suppressing cytokine secretion, conferring apoptosis resistance, and promoting regulatory T cell induction—extending the receptor's role from acute inhibition to shaping APC programming.","evidence":"LILRB1 ligation during monocyte-to-DC differentiation, cytokine ELISA, apoptosis assay, MLR, antibody blockade","pmids":["18094328"],"confidence":"High","gaps":["Signaling intermediates linking LILRB1 to DC programming not identified","In vivo relevance of sustained LILRB1 ligation during DC differentiation not tested"]},{"year":2008,"claim":"Demonstrating that LILRB1–HLA class I engagement inhibits IFN-γ at the transcriptional and protein level in NK cells, and that blocking this interaction increases IFN-γ in NK/DC cocultures, defined LILRB1 as a direct suppressor of NK cell effector cytokine output.","evidence":"NK stimulation assays with HLA I-expressing targets, IFN-γ mRNA/protein/secretion quantification, ILT2 blocking antibody","pmids":["18684926"],"confidence":"High","gaps":["Signaling intermediates between SHP-1 and IFN-γ transcription not mapped","Relative contribution of LILRB1 versus KIR-mediated inhibition of IFN-γ not addressed"]},{"year":2009,"claim":"Detailed imaging of the NK cell immunological synapse revealed that LILRB1–HLA-G engagement specifically blocks granule polarization, MTOC reorientation, F-actin accumulation, and calcium flux without affecting activating receptor recruitment, mechanistically dissecting which synapse events LILRB1 controls.","evidence":"NK cell/target synapse imaging, granule polarization, MTOC localization, F-actin staining, calcium mobilization assays","pmids":["19841038"],"confidence":"High","gaps":["Molecular link between SHP-1 activity and cytoskeletal rearrangement at the synapse not defined","Whether LILRB1 inhibits synapse formation cooperatively with other inhibitory receptors not tested"]},{"year":2016,"claim":"Showing that HLA class Ia dimers and interferon-induced noncanonical HLA conformers disproportionately enhance LILRB1 binding established ligand quaternary structure as a physiological regulator of LILRB1 avidity.","evidence":"LILRB1-Fc fusion binding, LILRB1-ζ chimera reporter, HLA-I transfectants, IFN-treated monocytes","pmids":["27109306"],"confidence":"Medium","gaps":["Single lab study; independent replication needed","Structural basis for preferential dimer recognition not resolved at atomic level"]},{"year":2017,"claim":"Identification of MHC class I–LILRB1 as a macrophage phagocytosis checkpoint parallel to CD47–SIRPα fundamentally expanded LILRB1's role from lymphocyte inhibition to myeloid innate immunity and tumor immune evasion.","evidence":"In vitro and in vivo phagocytosis assays, LILRB1 knockdown/blockade, β2M manipulation on cancer cells, TAM expression analysis","pmids":["29180808"],"confidence":"High","gaps":["Relative contribution of LILRB1 versus SIRPα to total 'don't eat me' signal not quantified in vivo","Whether LILRB1 engages additional non-MHC I ligands on tumor cells not excluded"]},{"year":2018,"claim":"Demonstrating that LILRB1 polymorphisms and N-linked glycosylation differentially alter binding to UL18 versus classical MHC I (but not HLA-G) linked host genetic variation to HCMV immune evasion efficiency.","evidence":"LILRB1 variant expression in NK models, binding assays with UL18/MHC I/HLA-G, glycosylation site mutagenesis, transplant cohort association","pmids":["29528338"],"confidence":"High","gaps":["Population-level impact of LILRB1 polymorphisms on CMV control needs larger cohort validation","Structural basis for glycan-mediated differential ligand recognition not determined"]},{"year":2019,"claim":"Structural determination of LILRB1's four-domain architecture in complex with HLA-G1 revealed that D1D2 mediates ligand binding while D3D4 serves as a scaffold, and that dimeric HLA-G1 engages LILRB1 in a manner that potentiates inhibitory signaling, resolving a long-standing question about domain utilization.","evidence":"X-ray crystallography of four-domain LILRB1 and LILRB1–HLA-G1 complex","pmids":["31273318"],"confidence":"High","gaps":["Full-length receptor structure including transmembrane and cytoplasmic ITIM domains not resolved","Dynamics of receptor clustering upon dimer engagement not captured"]},{"year":2019,"claim":"Characterization of LILRB1 as a checkpoint on late-differentiated CD8+ effector T cells distinct from PD-1, with functional inhibition by HLA-G reversible by blocking antibodies, positioned LILRB1 as a non-redundant immunotherapy target.","evidence":"Flow cytometry of CD8+ T cell subsets, BiTE stimulation assays, HLA-G engagement, dual LILRB1/PD-1 blockade experiments; ex vivo TIL functional assays","pmids":["31253728","31451484"],"confidence":"Medium","gaps":["In vivo efficacy of combined LILRB1/PD-1 blockade not demonstrated","Molecular basis for LILRB1 and PD-1 expression on non-overlapping T cell subsets unknown"]},{"year":2020,"claim":"Cryo-EM/crystal structures of RIFIN–LILRB1 complexes revealed that P. falciparum RIFINs structurally mimic MHC class I to engage LILRB1 D1D2, suppressing NK perforin mobilization—the first atomic-level demonstration of pathogen molecular mimicry of an LILRB1 ligand.","evidence":"Cryo-EM/crystallography, point mutagenesis disrupting binding, reporter signaling, supported lipid bilayer NK activation assay","pmids":["32650338"],"confidence":"High","gaps":["In vivo contribution of RIFIN–LILRB1 interaction to malaria pathogenesis not directly tested","Whether RIFIN engagement triggers identical downstream signaling as MHC I not confirmed"]},{"year":2021,"claim":"Discovery that RIFINs also bind LILRB1 through its D3 domain—and that LILRB1 D3D4 domain insertions into antibody genes generate RIFIN-specific antibodies in malaria-exposed individuals—revealed a second binding interface and an adaptive immune co-option mechanism.","evidence":"Cryo-EM and crystal structures of RIFIN–LILRB1 D3D4 Fab, mass spectrometry, binding assays, B cell clone isolation","pmids":["33790470"],"confidence":"High","gaps":["Frequency and protective efficacy of LILRB1-domain-containing antibodies in endemic populations not established","Structural basis for simultaneous D1D2 and D3 engagement by different RIFINs not resolved"]},{"year":2022,"claim":"Demonstrating that LILRB1 blockade (but not LILRB2) synergizes with CD47 blockade and anti-CD20 to enhance serial macrophage phagocytosis of lymphoma cells clarified LILRB1's non-redundant role in macrophage-mediated anti-tumor immunity.","evidence":"ADCP assay with Fc-silent anti-LILRB1, lymphoma lines and primary CLL/lymphoma cells, macrophage polarization experiments","pmids":["36389667"],"confidence":"Medium","gaps":["In vivo efficacy of triple blockade not tested","Mechanism by which LILRB1 specifically controls serial engulfment not defined"]},{"year":2024,"claim":"Identification of a LILRB1–LDLR–LDLRAP1 complex that facilitates cholesterol uptake in myeloma cells, with LILRB1 loss redirecting cells to de novo synthesis and depleting anti-ferroptotic squalene, revealed an unexpected non-immune metabolic function for LILRB1.","evidence":"Co-immunoprecipitation, LILRB1 knockout in vivo myeloma model, cholesterol uptake and squalene measurement, ferroptosis assays","pmids":["38982045"],"confidence":"High","gaps":["Whether the LDLR complex function operates in non-malignant immune cells unknown","Structural basis for LILRB1–LDLR–LDLRAP1 complex assembly not determined","Whether ITIM signaling is involved in the metabolic function not addressed"]},{"year":null,"claim":"Key unresolved questions include: the full signaling cascade downstream of LILRB1 ITIM/SHP-1 to effector inhibition in each cell type; the structural and functional interplay of simultaneous D1D2 and D3D4 ligand engagement; whether the LDLR metabolic function extends to normal immune cells; and whether combined LILRB1/PD-1/CD47 blockade is efficacious in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["Full ITIM-proximal signaling network not mapped","In vivo therapeutic efficacy of LILRB1 blockade combinations not established","Metabolic function in non-malignant contexts uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,5,6,8]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,9,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,8,11]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,5,6,8,14,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,6,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,12,15]}],"complexes":["LILRB1-LDLR-LDLRAP1"],"partners":["SHP-1","LDLR","LDLRAP1","HLA-G","HLA-F","B2M"],"other_free_text":[]},"mechanistic_narrative":"LILRB1 (ILT2/CD85j/LIR1) is a broadly expressed inhibitory immunoreceptor that recognizes classical and non-classical MHC class I molecules—including HLA-A/B/C, HLA-E, HLA-F, HLA-G, and the HCMV homolog UL18—through its D1D2 extracellular immunoglobulin domains, with highest affinity for HLA-G and particularly its dimeric form, and transmits inhibitory signals by recruiting SHP-1 phosphatase via cytoplasmic ITIM motifs [PMID:12853576, PMID:11169396, PMID:31273318]. On NK cells, LILRB1 engagement blocks lytic granule polarization, MTOC reorientation, F-actin accumulation at the immunological synapse, calcium mobilization, and IFN-γ production; on CD8+ T cells it inhibits TCR-driven activation on a population distinct from PD-1+ cells; and on macrophages it functions as a phagocytosis checkpoint whose disruption potentiates tumor cell engulfment in vitro and in vivo [PMID:19841038, PMID:18684926, PMID:31253728, PMID:29180808, PMID:36389667]. Plasmodium falciparum RIFIN proteins structurally mimic MHC class I to engage both the D1D2 and D3D4 domains of LILRB1, suppressing NK cell perforin mobilization and representing a pathogen immune-evasion strategy; naturally occurring LILRB1 D3D4 domain insertions into immunoglobulin genes generate RIFIN-specific antibodies in malaria-exposed individuals [PMID:32650338, PMID:33790470]. Beyond canonical immune inhibition, LILRB1 forms a complex with LDLR and LDLRAP1 to facilitate LDL/cholesterol uptake in multiple myeloma cells, linking it to ferroptosis resistance through maintenance of intracellular squalene levels [PMID:38982045]."},"prefetch_data":{"uniprot":{"accession":"Q8NHL6","full_name":"Leukocyte immunoglobulin-like receptor subfamily B member 1","aliases":["CD85 antigen-like family member J","Immunoglobulin-like transcript 2","ILT-2","Monocyte/macrophage immunoglobulin-like receptor 7","MIR-7"],"length_aa":650,"mass_kda":70.8,"function":"Receptor for class I MHC antigens. Recognizes a broad spectrum of HLA-A, HLA-B, HLA-C, HLA-G and HLA-F alleles (PubMed:16455647, PubMed:28636952). Receptor for H301/UL18, a human cytomegalovirus class I MHC homolog. Ligand binding results in inhibitory signals and down-regulation of the immune response. Engagement of LILRB1 present on natural killer cells or T-cells by class I MHC molecules protects the target cells from lysis. Interaction with HLA-B or HLA-E leads to inhibition of FCER1A signaling and serotonin release. Inhibits FCGR1A-mediated phosphorylation of cellular proteins and mobilization of intracellular calcium ions (PubMed:11907092, PubMed:9285411, PubMed:9842885). Recognizes HLA-G in complex with B2M/beta-2 microglobulin and a nonamer self-peptide (PubMed:16455647). Upon interaction with peptide-bound HLA-G-B2M complex, triggers secretion of growth-promoting factors by decidual NK cells (PubMed:19304799, PubMed:29262349). 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Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/35181243","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52839,"output_tokens":5327,"usd":0.119211},"stage2":{"model":"claude-opus-4-6","input_tokens":8842,"output_tokens":4464,"usd":0.233715},"total_usd":0.352926,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"LILRB1 (ILT2) binds a broad range of classical and non-classical MHC class I molecules with 2- to 3-fold higher affinity than LILRB2 (ILT4), and binds HLA-G with 3- to 4-fold higher affinity than classical MHCIs; LILRB1 and LILRB2 compete with CD8 for MHC class I binding, raising the possibility that LILRB1 modulates CD8+ T cell activation by blocking CD8 binding in addition to recruiting inhibitory SHP-1 phosphatase via its ITIM motifs.\",\n      \"method\": \"Surface plasmon resonance (SPR) binding assays measuring Kd values for soluble ILT2/ILT4 vs. multiple MHC class I molecules; competition assays with CD8\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro binding assay (SPR) with quantitative Kd measurements, replicated across multiple ligands\",\n      \"pmids\": [\"12853576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"HLA-F directly interacts with LILRB1 (ILT2/LIR1) and LILRB2 (ILT4/LIR2); HLA-F tetramer binding to peripheral blood monocytes and B cells could be conferred on non-binding cells by transfection with ILT2 or ILT4, and a direct molecular interaction was confirmed by surface plasmon resonance.\",\n      \"method\": \"HLA-F tetramer staining, transfection of ILT2/ILT4 into non-binding cells, surface plasmon resonance\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct binding confirmed by SPR and functional cell transfection assays with orthogonal methods\",\n      \"pmids\": [\"11169396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"LILRB1 (ILT2/CD85j) is an inhibitory MHC class I receptor of the immunoglobulin superfamily expressed on B cells, monocytes, and subsets of T and NK cells; its cell signaling role involves inhibitory functions consistent with CD85 involvement in T cell activation, as confirmed by demonstrating that anti-CD85 mAbs stain ILT2 transfectants.\",\n      \"method\": \"Affinity purification, tryptic peptide sequencing, transfectant staining with anti-CD85 mAbs\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — protein identity established by peptide sequencing and functional transfectant confirmation, single study\",\n      \"pmids\": [\"10380908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"LILRB1 (ILT2/CD85j) is functional on Sézary cell lines (CTCL): its triggering recruits SHP-1 (Src homology 2 domain-containing tyrosine phosphatase) and specifically inhibits CTCL cell proliferation induced by CD3/TCR stimulation; CD4+ILT2+ Sézary cells are less susceptible to anti-CD3-induced cell death than autologous CD4+ILT2- lymphocytes.\",\n      \"method\": \"ILT2 ligation on CTCL cell lines, SHP-1 recruitment assay, CD3/TCR stimulation proliferation assay, apoptosis comparison\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional assays showing SHP-1 recruitment and specific inhibition of TCR signaling, moderate evidence\",\n      \"pmids\": [\"12130517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LILRB1 is selectively upregulated during DC differentiation from monocyte precursors; continuous ligation of LILRB1 modulates DC differentiation, confers resistance to CD95-mediated cell death, inhibits secretion of IL-10, IL-12p70, and TGF-beta, and results in poor stimulatory activity for T-cell proliferative responses that is reversed by CD80 blockade or depletion of CD4+CD25+CD127lo regulatory T cells.\",\n      \"method\": \"LILRB1 ligation during DC differentiation, cytokine ELISA, apoptosis assays, mixed lymphocyte reaction, antibody blockade experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional readouts (differentiation, apoptosis resistance, cytokine suppression, T-cell stimulation) in a single controlled study\",\n      \"pmids\": [\"18094328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LILRB1 (ILT2/CD85j) inhibits IFN-gamma production by NK cells and T cells via HLA class I recognition: ligation of ILT2/CD85j with HLA class I on target cells inhibits IFN-gamma mRNA expression, protein production, and secretion in NK-92 and primary ILT2+ NK cells, and inhibits IFN-gamma in response to poly(I:C); blocking ILT2-HLA class I interactions increases IFN-gamma secretion in NK/immature DC cocultures.\",\n      \"method\": \"NK cell stimulation assays with HLA class I-expressing targets, IFN-gamma mRNA and protein measurement, ILT2 blocking antibody experiments\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (mRNA, protein, secretion assays, blocking antibody), replicated in both cell line and primary NK cells\",\n      \"pmids\": [\"18684926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Interaction of LILRB1 (ILT2) with HLA-G inhibits polarization of NK cell lytic granules and MTOC as well as F-actin accumulation at the NK/target-cell synapse, and inhibits intracellular calcium mobilization and IFN-gamma polarized production, without affecting recruitment of activatory receptor CD2 to the synapse—demonstrating differential effects on early vs. late NK activation synapse events.\",\n      \"method\": \"NK cell/target-cell synapse imaging, granule polarization assays, MTOC localization, F-actin staining, calcium mobilization, IFN-gamma secretion assays\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple imaging and biochemical readouts showing mechanistic dissection of synapse events, single but rigorous study\",\n      \"pmids\": [\"19841038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HLA-G upregulates expression of LILRB1 (ILT2) on antigen-presenting cells, NK cells, and T cells without requiring antigenic costimulation, suggesting that LILRB1 expression is itself regulated by its ligand HLA-G as part of an immune escape mechanism.\",\n      \"method\": \"Flow cytometry of ILT2 surface expression on immune cells after HLA-G exposure, analysis in multiple cell types\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single method (flow cytometry) in a single study, but across multiple cell types\",\n      \"pmids\": [\"15670976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MHC class I (via its component β2-microglobulin) on cancer cells directly protects them from macrophage phagocytosis through the inhibitory receptor LILRB1, whose expression is upregulated on tumor-associated macrophages; disruption of either MHC class I or LILRB1 potentiates phagocytosis of tumor cells both in vitro and in vivo, defining MHC class I-LILRB1 as a phagocytosis checkpoint on macrophages.\",\n      \"method\": \"Phagocytosis assays in vitro and in vivo, LILRB1 knockdown/blockade, β2M manipulation on cancer cells, tumor-associated macrophage expression analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo phagocytosis assays with genetic and antibody-based disruption, replicated across multiple cancer cell types\",\n      \"pmids\": [\"29180808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of four Ig-like domain LILRB2 and four-domain LILRB1 in complex with HLA-G1 reveals that D1D2 domains are responsible for HLA class I binding while D3D4 acts as a scaffold; the staggered assembly of four domains shows limited flexibility during ligand binding; dimeric HLA-G1 binding to LILRB1/2 suggests the dimeric receptor transduces stronger inhibitory signals.\",\n      \"method\": \"X-ray crystallography of LILRB1/2 four-domain constructs and LILRB1–HLA-G1 complex\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional domain mapping; directly validates binding model\",\n      \"pmids\": [\"31273318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"P. falciparum RIFIN proteins mimic MHC class I in their LILRB1-binding mode: cryo-EM/crystal structure of RIFIN bound to LILRB1 shows structural mimicry; a single point mutation in RIFIN disrupts the complex, blocks LILRB1 binding of all tested RIFINs, and abolishes signaling in a reporter assay; in a supported lipid bilayer system, both RIFIN and MHC are recruited to the NK cell immunological synapse and suppress NK cell perforin mobilization.\",\n      \"method\": \"Cryo-EM/crystallography of RIFIN–LILRB1 complex, mutagenesis, reporter signaling assay, supported lipid bilayer NK cell activation assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure + mutagenesis + functional reporter + live-cell bilayer assay; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"32650338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LILRB1 polymorphisms in ligand-binding domains alter functional recognition of UL18 (HCMV MHC class I homolog) and classical MHC class I but not HLA-G; N-linked glycosylation controlled by one polymorphism alters binding to all ligands tested, including enhancing binding to UL18; specific LILRB1 alleles associated with superior HCMV immune evasion are restricted by mutations that limit LILRB1 expression selectively on NK cells.\",\n      \"method\": \"LILRB1 variant expression in NK cell models, functional binding assays with UL18/classical MHCI/HLA-G, glycosylation site mutagenesis, transplant patient cohort association\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of glycosylation site with quantitative binding assays, replicated in functional NK model, supported by patient association\",\n      \"pmids\": [\"29528338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal and cryo-EM structures of a RIFIN in complex with LILRB1 D3D4-containing antibody Fab reveal that RIFINs bind LILRB1 through its non-apical D3 domain; this interaction is similar in mode to RIFIN–LAIR1 binding; naturally occurring LILRB1 D3/D4 domain insertions in immunoglobulin VH-CH1 elbow generate RIFIN-specific antibodies in malaria-exposed donors.\",\n      \"method\": \"Cryo-EM and crystal structures of RIFIN–LILRB1 D3D4 Fab complexes, mass spectrometry, binding assays, B cell clone isolation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — orthogonal structural methods (crystal + cryo-EM) plus binding assays and MS; single study but exceptionally rigorous\",\n      \"pmids\": [\"33790470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HLA class Ia dimerization and the presence of intracellular Cys residues enhance LILRB1 recognition; type I interferon induces HLA class Ia dimer formation on primary monocytes that disproportionately increases LILRB1 interaction beyond the cytokine-induced increase in surface HLA-I expression, supporting regulated assembly of noncanonical HLA-I conformers as a mechanism to modulate LILRB1 avidity.\",\n      \"method\": \"Soluble LILRB1-Fc fusion protein binding, LILRB1-ζ chimera cellular reporter system, HLA-I transfectants in 721.221 cells, IFN treatment of primary monocytes\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay plus soluble protein binding across multiple HLA constructs, but single lab study\",\n      \"pmids\": [\"27109306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LILRB1 functions as a negative regulator of human CD45RA+CCR7- CD8+ effector T cells; LILRB1 is expressed on distinct CD8+ T cell populations from PD1; engaging LILRB1 with HLA-G on tumor cells significantly inhibited BiTE molecule-induced CD8+ T cell activation; combined blockade of LILRB1 and PD1 induced greater CD8+ T cell activation than either alone.\",\n      \"method\": \"Flow cytometry of CD8+ T cell subsets, BiTE molecule stimulation assays, HLA-G engagement assays, dual blockade experiments\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assays with specific HLA-G engagement and antibody blockade, single study\",\n      \"pmids\": [\"31253728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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 the anti-ferroptotic metabolite squalene and thereby enhancing ferroptosis of myeloma cells.\",\n      \"method\": \"Co-immunoprecipitation of LILRB1-LDLR-LDLRAP1 complex, LILRB1 knockout in vivo myeloma model, cholesterol uptake assays, squalene measurement, ferroptosis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP demonstrating complex, in vivo KO with defined metabolic phenotype, mechanistic readout of squalene and ferroptosis\",\n      \"pmids\": [\"38982045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LILRB1 blockade on NK cells increases tumoricidal activity against multiple myeloma, leukemia, lymphoma and solid tumor cells both in vitro and in vivo, and the percentage of LILRB1+ NK cells is significantly higher in patients with persistent multiple myeloma or late-stage prostate cancer than in healthy donors.\",\n      \"method\": \"Antagonistic anti-LILRB1 monoclonal antibody treatment, in vitro cytotoxicity assays, NOD-SCID IL-2Rγ-null mouse xenograft model, flow cytometry of NK cells from cancer patients\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo functional assays with specific antibody blockade, single study\",\n      \"pmids\": [\"32771992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Dual blockade of CD47 and LILRB1 significantly enhances antibody-dependent cellular phagocytosis (ADCP) of lymphoma cell lines and primary CLL/lymphoma cells by macrophages when combined with rituximab; LILRB1 blockade (but not LILRB2 blockade) promotes serial engulfment and potentiates ADCP by M0, M1, and M2 macrophages, but requires CD47 co-blockade and presence of CD20 antibody.\",\n      \"method\": \"ADCP phagocytosis assay with Fc-silent anti-LILRB1 antibody, lymphoma cell lines and primary patient cells, macrophage polarization experiments\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional phagocytosis assays with orthogonal macrophage polarization conditions and primary patient cells, single study\",\n      \"pmids\": [\"36389667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD8+ILT2+ tumor-infiltrating lymphocytes (TILs) are a late-differentiated cytotoxic CD27-CD28-CD57+ subset distinct from CD8+PD-1+ TILs; HLA-G expression on target cells specifically inhibits CD8+ILT2+ T cell cytotoxicity and IFNγ production, but not CD8+ILT2- or CD8+PD-1+ counterparts; blockade of HLA-G/ILT2 interaction restores cytotoxicity.\",\n      \"method\": \"Ex vivo flow cytometry, functional cytotoxicity assays with TILs and PBMCs, HLA-G blocking antibody experiments\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ex vivo functional assays with blocking antibody reversal in patient TILs, single study\",\n      \"pmids\": [\"31451484\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LILRB1 (ILT2/CD85j/LIR1) is a transmembrane inhibitory receptor expressed on multiple immune cell lineages (NK cells, T cells, B cells, monocytes, macrophages, dendritic cells) that binds MHC class I molecules (classical HLA-A/B/C, non-classical HLA-E/F/G, and the HCMV homolog UL18) via its D1D2 extracellular domains with highest affinity for HLA-G dimers, recruits SHP-1 phosphatase through its cytoplasmic ITIM motifs to suppress TCR/NK-cell signaling, inhibits NK cell granule polarization and IFN-γ production, functions as a phagocytosis checkpoint on macrophages by recognizing MHC class I (β2M) on cancer cells, and additionally forms a complex with LDLR/LDLRAP1 to regulate cholesterol uptake and protect myeloma cells from ferroptosis; Plasmodium falciparum RIFINs structurally mimic MHC class I to exploit LILRB1 and suppress NK cell activation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LILRB1 (ILT2/CD85j/LIR1) is a broadly expressed inhibitory immunoreceptor that recognizes classical and non-classical MHC class I molecules—including HLA-A/B/C, HLA-E, HLA-F, HLA-G, and the HCMV homolog UL18—through its D1D2 extracellular immunoglobulin domains, with highest affinity for HLA-G and particularly its dimeric form, and transmits inhibitory signals by recruiting SHP-1 phosphatase via cytoplasmic ITIM motifs [PMID:12853576, PMID:11169396, PMID:31273318]. On NK cells, LILRB1 engagement blocks lytic granule polarization, MTOC reorientation, F-actin accumulation at the immunological synapse, calcium mobilization, and IFN-γ production; on CD8+ T cells it inhibits TCR-driven activation on a population distinct from PD-1+ cells; and on macrophages it functions as a phagocytosis checkpoint whose disruption potentiates tumor cell engulfment in vitro and in vivo [PMID:19841038, PMID:18684926, PMID:31253728, PMID:29180808, PMID:36389667]. Plasmodium falciparum RIFIN proteins structurally mimic MHC class I to engage both the D1D2 and D3D4 domains of LILRB1, suppressing NK cell perforin mobilization and representing a pathogen immune-evasion strategy; naturally occurring LILRB1 D3D4 domain insertions into immunoglobulin genes generate RIFIN-specific antibodies in malaria-exposed individuals [PMID:32650338, PMID:33790470]. Beyond canonical immune inhibition, LILRB1 forms a complex with LDLR and LDLRAP1 to facilitate LDL/cholesterol uptake in multiple myeloma cells, linking it to ferroptosis resistance through maintenance of intracellular squalene levels [PMID:38982045].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing the molecular identity of the CD85j antigen as LILRB1/ILT2, an inhibitory Ig-superfamily receptor on multiple immune lineages, provided the foundation for all subsequent mechanistic work on this receptor.\",\n      \"evidence\": \"Affinity purification, tryptic peptide sequencing, and transfectant staining with anti-CD85 mAbs\",\n      \"pmids\": [\"10380908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-method identification without functional signaling readout\", \"Expression pattern described by flow cytometry alone\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating that LILRB1 binds the non-classical molecule HLA-F expanded the receptor's ligand repertoire beyond classical MHC class I, raising the question of how broadly LILRB1 surveys MHC diversity.\",\n      \"evidence\": \"HLA-F tetramer staining, ILT2 transfection into non-binding cells, SPR confirmation\",\n      \"pmids\": [\"11169396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of HLA-F engagement on immune cell signaling not tested\", \"Affinity comparison with classical MHC I not performed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Quantitative SPR measurements established that LILRB1 binds a broad panel of classical and non-classical MHC class I molecules with systematically higher affinity than LILRB2, and preferentially recognizes HLA-G, while competing with CD8 for MHC binding—defining LILRB1's dual inhibitory mechanism (ITIM signaling plus CD8 displacement).\",\n      \"evidence\": \"Surface plasmon resonance Kd measurements across multiple MHC I ligands; competition assays with CD8\",\n      \"pmids\": [\"12853576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CD8 competition demonstrated in vitro but not validated in T cell coculture\", \"Contribution of CD8 displacement versus ITIM signaling to inhibition not quantified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showing that LILRB1 ligation recruits SHP-1 and inhibits TCR/CD3-driven proliferation in Sézary cells provided the first direct evidence of the receptor's inhibitory signaling mechanism in T cells.\",\n      \"evidence\": \"SHP-1 recruitment assay, CD3/TCR stimulation proliferation assay, apoptosis comparison in CTCL cell lines\",\n      \"pmids\": [\"12130517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream substrates of SHP-1 in LILRB1 signaling not identified\", \"Studied in malignant CTCL lines; relevance to normal T cells assumed but not shown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The finding that HLA-G upregulates LILRB1 surface expression on APCs, NK cells, and T cells revealed a positive feedback loop between ligand and receptor that could amplify immune suppression.\",\n      \"evidence\": \"Flow cytometry of ILT2 expression after HLA-G exposure across multiple cell types\",\n      \"pmids\": [\"15670976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method (flow cytometry); transcriptional versus post-translational mechanism of upregulation not resolved\", \"Functional consequence of upregulation on inhibitory signaling threshold not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Continuous LILRB1 ligation during DC differentiation was shown to modulate DC function—suppressing cytokine secretion, conferring apoptosis resistance, and promoting regulatory T cell induction—extending the receptor's role from acute inhibition to shaping APC programming.\",\n      \"evidence\": \"LILRB1 ligation during monocyte-to-DC differentiation, cytokine ELISA, apoptosis assay, MLR, antibody blockade\",\n      \"pmids\": [\"18094328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling intermediates linking LILRB1 to DC programming not identified\", \"In vivo relevance of sustained LILRB1 ligation during DC differentiation not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that LILRB1–HLA class I engagement inhibits IFN-γ at the transcriptional and protein level in NK cells, and that blocking this interaction increases IFN-γ in NK/DC cocultures, defined LILRB1 as a direct suppressor of NK cell effector cytokine output.\",\n      \"evidence\": \"NK stimulation assays with HLA I-expressing targets, IFN-γ mRNA/protein/secretion quantification, ILT2 blocking antibody\",\n      \"pmids\": [\"18684926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling intermediates between SHP-1 and IFN-γ transcription not mapped\", \"Relative contribution of LILRB1 versus KIR-mediated inhibition of IFN-γ not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Detailed imaging of the NK cell immunological synapse revealed that LILRB1–HLA-G engagement specifically blocks granule polarization, MTOC reorientation, F-actin accumulation, and calcium flux without affecting activating receptor recruitment, mechanistically dissecting which synapse events LILRB1 controls.\",\n      \"evidence\": \"NK cell/target synapse imaging, granule polarization, MTOC localization, F-actin staining, calcium mobilization assays\",\n      \"pmids\": [\"19841038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between SHP-1 activity and cytoskeletal rearrangement at the synapse not defined\", \"Whether LILRB1 inhibits synapse formation cooperatively with other inhibitory receptors not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing that HLA class Ia dimers and interferon-induced noncanonical HLA conformers disproportionately enhance LILRB1 binding established ligand quaternary structure as a physiological regulator of LILRB1 avidity.\",\n      \"evidence\": \"LILRB1-Fc fusion binding, LILRB1-ζ chimera reporter, HLA-I transfectants, IFN-treated monocytes\",\n      \"pmids\": [\"27109306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab study; independent replication needed\", \"Structural basis for preferential dimer recognition not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of MHC class I–LILRB1 as a macrophage phagocytosis checkpoint parallel to CD47–SIRPα fundamentally expanded LILRB1's role from lymphocyte inhibition to myeloid innate immunity and tumor immune evasion.\",\n      \"evidence\": \"In vitro and in vivo phagocytosis assays, LILRB1 knockdown/blockade, β2M manipulation on cancer cells, TAM expression analysis\",\n      \"pmids\": [\"29180808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of LILRB1 versus SIRPα to total 'don't eat me' signal not quantified in vivo\", \"Whether LILRB1 engages additional non-MHC I ligands on tumor cells not excluded\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that LILRB1 polymorphisms and N-linked glycosylation differentially alter binding to UL18 versus classical MHC I (but not HLA-G) linked host genetic variation to HCMV immune evasion efficiency.\",\n      \"evidence\": \"LILRB1 variant expression in NK models, binding assays with UL18/MHC I/HLA-G, glycosylation site mutagenesis, transplant cohort association\",\n      \"pmids\": [\"29528338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Population-level impact of LILRB1 polymorphisms on CMV control needs larger cohort validation\", \"Structural basis for glycan-mediated differential ligand recognition not determined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Structural determination of LILRB1's four-domain architecture in complex with HLA-G1 revealed that D1D2 mediates ligand binding while D3D4 serves as a scaffold, and that dimeric HLA-G1 engages LILRB1 in a manner that potentiates inhibitory signaling, resolving a long-standing question about domain utilization.\",\n      \"evidence\": \"X-ray crystallography of four-domain LILRB1 and LILRB1–HLA-G1 complex\",\n      \"pmids\": [\"31273318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length receptor structure including transmembrane and cytoplasmic ITIM domains not resolved\", \"Dynamics of receptor clustering upon dimer engagement not captured\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Characterization of LILRB1 as a checkpoint on late-differentiated CD8+ effector T cells distinct from PD-1, with functional inhibition by HLA-G reversible by blocking antibodies, positioned LILRB1 as a non-redundant immunotherapy target.\",\n      \"evidence\": \"Flow cytometry of CD8+ T cell subsets, BiTE stimulation assays, HLA-G engagement, dual LILRB1/PD-1 blockade experiments; ex vivo TIL functional assays\",\n      \"pmids\": [\"31253728\", \"31451484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo efficacy of combined LILRB1/PD-1 blockade not demonstrated\", \"Molecular basis for LILRB1 and PD-1 expression on non-overlapping T cell subsets unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cryo-EM/crystal structures of RIFIN–LILRB1 complexes revealed that P. falciparum RIFINs structurally mimic MHC class I to engage LILRB1 D1D2, suppressing NK perforin mobilization—the first atomic-level demonstration of pathogen molecular mimicry of an LILRB1 ligand.\",\n      \"evidence\": \"Cryo-EM/crystallography, point mutagenesis disrupting binding, reporter signaling, supported lipid bilayer NK activation assay\",\n      \"pmids\": [\"32650338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution of RIFIN–LILRB1 interaction to malaria pathogenesis not directly tested\", \"Whether RIFIN engagement triggers identical downstream signaling as MHC I not confirmed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that RIFINs also bind LILRB1 through its D3 domain—and that LILRB1 D3D4 domain insertions into antibody genes generate RIFIN-specific antibodies in malaria-exposed individuals—revealed a second binding interface and an adaptive immune co-option mechanism.\",\n      \"evidence\": \"Cryo-EM and crystal structures of RIFIN–LILRB1 D3D4 Fab, mass spectrometry, binding assays, B cell clone isolation\",\n      \"pmids\": [\"33790470\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Frequency and protective efficacy of LILRB1-domain-containing antibodies in endemic populations not established\", \"Structural basis for simultaneous D1D2 and D3 engagement by different RIFINs not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that LILRB1 blockade (but not LILRB2) synergizes with CD47 blockade and anti-CD20 to enhance serial macrophage phagocytosis of lymphoma cells clarified LILRB1's non-redundant role in macrophage-mediated anti-tumor immunity.\",\n      \"evidence\": \"ADCP assay with Fc-silent anti-LILRB1, lymphoma lines and primary CLL/lymphoma cells, macrophage polarization experiments\",\n      \"pmids\": [\"36389667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo efficacy of triple blockade not tested\", \"Mechanism by which LILRB1 specifically controls serial engulfment not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of a LILRB1–LDLR–LDLRAP1 complex that facilitates cholesterol uptake in myeloma cells, with LILRB1 loss redirecting cells to de novo synthesis and depleting anti-ferroptotic squalene, revealed an unexpected non-immune metabolic function for LILRB1.\",\n      \"evidence\": \"Co-immunoprecipitation, LILRB1 knockout in vivo myeloma model, cholesterol uptake and squalene measurement, ferroptosis assays\",\n      \"pmids\": [\"38982045\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the LDLR complex function operates in non-malignant immune cells unknown\", \"Structural basis for LILRB1–LDLR–LDLRAP1 complex assembly not determined\", \"Whether ITIM signaling is involved in the metabolic function not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the full signaling cascade downstream of LILRB1 ITIM/SHP-1 to effector inhibition in each cell type; the structural and functional interplay of simultaneous D1D2 and D3D4 ligand engagement; whether the LDLR metabolic function extends to normal immune cells; and whether combined LILRB1/PD-1/CD47 blockade is efficacious in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Full ITIM-proximal signaling network not mapped\", \"In vivo therapeutic efficacy of LILRB1 blockade combinations not established\", \"Metabolic function in non-malignant contexts uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 5, 6, 8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 8, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 5, 6, 8, 14, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 6, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 12, 15]}\n    ],\n    \"complexes\": [\n      \"LILRB1-LDLR-LDLRAP1\"\n    ],\n    \"partners\": [\n      \"SHP-1\",\n      \"LDLR\",\n      \"LDLRAP1\",\n      \"HLA-G\",\n      \"HLA-F\",\n      \"B2M\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}