{"gene":"KIR2DL2","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1999,"finding":"Crystal structure of KIR2DL2 extracellular ligand-binding domains was determined at 2.9–3.0 Å resolution in two crystal forms, revealing K-type Ig topology with cis-proline residues in both domains, a hinge angle ~80° (14° larger than KIR2DL1), and a putative ligand-binding site formed by variable loops with charge distribution complementary to HLA-C. The interdomain hinge angle was found to vary by ~5° between crystal forms, suggesting it is not fixed.","method":"X-ray crystallography (two crystal forms: orthorhombic P212121 and trigonal P3221)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure determined at near-atomic resolution in two independent crystal forms with functional interpretation of binding site","pmids":["10097129"],"is_preprint":false},{"year":2008,"finding":"The higher HLA-C binding avidity of KIR2DL2*001 compared to KIR2DL3*001 was mapped by site-directed mutagenesis to a synergistic combination of arginine at position 16 (D1 domain) and cysteine at position 148 (D2 domain); neither residue individually conferred the avidity difference, and neither is at the ligand-binding site. Their juxtaposition near the D1–D2 hinge suggests they alter the interdomain hinge angle and relative domain orientation to strengthen ligand binding.","method":"Recombinant mutant protein generation, site-directed mutagenesis, binding assays to 93 HLA-A/B/C isoforms, functional analysis","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-directed mutagenesis combined with extensive binding assay panel and functional analysis in a single rigorous study","pmids":["18322206"],"is_preprint":false},{"year":2002,"finding":"KIR2DL2 (encoded by the cl43/KIR2DL2 gene) inhibits CD28-mediated natural cytotoxicity in the p56(lck)-negative NK cell line YT-Indy. Upon HLA-Cw3 engagement, KIR2DL2 becomes tyrosine-phosphorylated and recruits SHP1/SHP2 phosphatases, which dephosphorylate PLC-γ1, thereby suppressing CD28-triggered cytotoxic signaling. p56(lck) is not required for KIR2DL2-mediated inhibitory signaling.","method":"Stable transfection of KIR2DL2 into YT-Indy cells, pervanadate phosphorylation assay, SHP1/SHP2 co-immunoprecipitation, anti-KIR2DL2/anti-HLA class I antibody blocking, PLC-γ1 tyrosine phosphorylation assay, cytotoxicity assay","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution in transfected cells, multiple orthogonal biochemical assays (phosphorylation, co-IP, functional cytotoxicity), antibody blocking controls","pmids":["11750651"],"is_preprint":false},{"year":2021,"finding":"Crystal structures of KIR2DL2 and KIR2DL3 in complex with HLA-C*07:02 presenting a self-epitope revealed that KIR2DL2 adopts a different docking modality over HLA-C*07:02 compared to KIR2DL3. Mutagenesis assays demonstrated that these structural differences underlie differential recognition of HLA-C1 allotypes by the two receptors. HLA-C1 allotypes also differed markedly in their capacity to inhibit primary NK cell activation, and KIR2DS2 contributed to distinguishing KIR2DL2 and KIR2DL3 functional recognition.","method":"X-ray crystallography of KIR2DL2/HLA-C*07:02 and KIR2DL3/HLA-C*07:02 complexes, site-directed mutagenesis, primary NK cell functional assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of two receptor-ligand complexes with orthogonal mutagenesis and primary NK cell functional validation","pmids":["33846289"],"is_preprint":false},{"year":2012,"finding":"Peptide sequence variations within HLA-Cw*0102-restricted HIV-1 p24 Gag epitopes modulate binding of KIR2DL2 to HLA-Cw*0102. Only one of 11 HLA-Cw*0102-stabilizing peptides (p24 Gag209–218 AAEWDRLHPV) enabled KIR2DL2 binding, and this interaction caused significant inhibition of degranulation specifically in KIR2DL2+ primary NK cells. Sequence variations at position 7 of this epitope, observed in natural HIV-1 sequences, modulated KIR2DL2 binding affinity.","method":"KIR2DL2-IgG fusion protein binding assay, HLA-Cw*0102 stabilization assay on TAP-deficient T2 cells, primary NK cell degranulation assay by flow cytometry, 217-peptide panel screen","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — KIR2DL2-Fc binding assay with large peptide panel, primary NK cell functional readout, mechanistic link between peptide identity and KIR2DL2 engagement established","pmids":["22807681"],"is_preprint":false},{"year":2014,"finding":"Naturally occurring sequence variations within HLA-C*03:04-restricted HIV-1 p24 Gag epitopes (Gag144–152, Gag163–171, Gag295–304) enabled KIR2DL2 binding to HLA-C*03:04 and resulted in inhibition of KIR2DL2+ primary NK cells. Minor variants of Gag295–304 found in natural HIV-1 sequences enhanced KIR2DL2 binding to HLA-C*03:04 beyond consensus levels.","method":"KIR2DL2-Fc binding construct assay, HLA-C*03:04 stabilization assay on 721.220 tapasin-deficient cells, primary NK cell degranulation assay, HIV-1 p24 Gag overlapping peptide panel","journal":"AIDS (London, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KIR2DL2-Fc binding assay with systematic peptide panel, primary NK cell functional validation, two orthogonal methods in one study","pmids":["24785948"],"is_preprint":false},{"year":2013,"finding":"KIR2DL2+ and KIR2DL3+ NK cells exhibited a broader spectrum of HLA-C recognition than KIR2DL1+ NK cells, reacting against both C1 and C2 allele-expressing target cells. When KIR2DL2 and KIR2DS2 were co-expressed, KIR2DL2-mediated inhibition overrode KIR2DS2-mediated activation, whereas co-expression of KIR2DL1 and KIR2DS2 had an additive activating effect on NK responses against C1C1 targets.","method":"NK cell functional assays against HLA-C+ target cells from 159 KIR/HLA-genotyped individuals, NK cell clone analysis, KIR2DL2-/KIR2DS2-single vs. co-expressing NK cell comparison","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional NK cell assays in large cohort with NK cell clones, single lab but multiple genotype groups and functional readouts","pmids":["24078689"],"is_preprint":false},{"year":2013,"finding":"Allelic variation in KIR2DL3 at residues 11 (arginine) and 35 (glutamic acid) — both distal to the KIR/HLA-C interface — synergistically increases HLA-C binding affinity and avidity of KIR2DL3*005 to KIR2DL2-like levels. Site-directed mutagenesis confirmed that both substitutions together (not individually) are required. Molecular modeling suggested the mechanism involves alteration of the interdomain hinge angle toward that of KIR2DL2*001.","method":"Surface plasmon resonance, KIR binding to HLA allotype panel, flow cytometry (surface expression), IFN-γ inhibition assay in KHYG-1 NK cell line, site-directed mutagenesis, molecular modeling","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (SPR, functional assay, mutagenesis, structural modeling), rigorously replicated within one study","pmids":["23686481"],"is_preprint":false},{"year":2004,"finding":"KIR2DL2 and KIR2DL3 differ in HLA class I specificity at the NK clone level, revealed using a novel KIR2DL3-specific monoclonal antibody (ECM41) that distinguishes KIR2DL3 from KIR2DL2 and KIR2DS2 on cell transfectants. Simultaneous engagement of KIR2DL3 and KIR2DS2 in NK clones co-expressing both receptors was functionally assessed by redirected killing assays.","method":"Monoclonal antibody generation, cell transfectant surface expression analysis, NK clone HLA specificity analysis, redirected killing assay","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel discriminating antibody with transfectant validation, NK clone functional assays, single lab with multiple methods","pmids":["15314042"],"is_preprint":false},{"year":2016,"finding":"KIR2DL2+ NK cells suppressed HIV-1 replication in HLA-C*14:03+ or HLA-C*12:02+ cells to a significantly greater extent than KIR2DL2- NK cells in vitro. The mechanism involved reduced surface expression of peptide-HLA complexes (reduced KIR2DL2 ligand) on HIV-1-infected cells rather than altered binding affinity of KIR2DL2 to pHLA complexes, thereby disinhibiting KIR2DL2+ NK cells.","method":"In vitro viral suppression assay comparing KIR2DL2+ vs KIR2DL2- NK cells, KIR2DL2 binding affinity measurements, HLA-C surface expression analysis on HIV-infected cells","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional assay with mechanistic dissection (ligand expression vs. binding affinity), single lab","pmids":["27880898"],"is_preprint":false},{"year":2016,"finding":"KIR2DL2/L3 alleles carrying glutamic acid at position 35 (E35) are functionally stronger than those with glutamine (Q35). NK cells from HLA-C1+ donors with E35 alleles killed more target cells lacking HLA-C1 ligand, indicating better NK cell licensing. Molecular modeling showed that glutamic acid at position 35 interacts with histidine at position 55, stabilizing the KIR2DL2/L3 dimer and reducing entropy loss upon HLA-C ligand binding.","method":"NK cell cytotoxicity assay, allele genotyping, molecular modeling","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cytotoxicity assay with mechanistic modeling, single lab, modeling not experimentally validated by mutagenesis","pmids":["27030405"],"is_preprint":false},{"year":2018,"finding":"Decitabine (DAC) upregulated KIR2DL2/3 expression in KIR2DL2/3-negative γδ T cells by inhibiting methylation of the KIR2DL2/3 promoter, which enhanced binding of the transcription factor Sp-1 to the promoter and activated KIR2DL2/3 gene expression. KIR2DL2/3-positive γδ T cells were less cytotoxic than KIR2DL2/3-negative γδ T cells, and DAC treatment thereby reduced γδ T cell cytotoxicity.","method":"Flow cytometry (KIR2DL2/3 surface expression), promoter methylation analysis, Sp-1 binding assay (chromatin immunoprecipitation/EMSA-type), γδ T cell cytotoxicity assay","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter methylation and transcription factor binding assays with functional cytotoxicity readout, single lab","pmids":["29632540"],"is_preprint":false},{"year":2025,"finding":"A crystal structure of HLA-B*73:01 in complex with KIR2DL2 was determined, revealing differences from previously solved KIR2DL2/HLA-C structures. KIR2DL2 engagement of HLA-B*73:01 was described as 'skewed' relative to HLA-C complexes, providing a structural basis for KIR2DL2 recognition of an HLA-B allotype.","method":"X-ray crystallography of KIR2DL2/HLA-B*73:01 complex, mass spectrometry-based immunopeptidome profiling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with peptidome profiling, single lab, peer-reviewed","pmids":["40749828"],"is_preprint":false},{"year":2025,"finding":"Crystal structure of KIR2DL2 in complex with HLA-C*12:02 presenting an HIV-1 Pol escape mutant epitope was determined, providing the molecular basis for how the Pol mutant peptide-HLA complex is recognized by KIR2DL2. KIR2DL2+ NK cells showed enhanced ability to recognize HIV-1-infected cells after selection of the Pol mutant virus by T cells, demonstrating coordinated immune control by CD8+ T cells and KIR2DL2+ NK cells.","method":"Crystal structure determination (TCR- and KIR2DL2-HLA-C*12:02-peptide complexes), mass spectrometry immunopeptidome profiling, in vitro NK cell suppression assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mass spectrometry immunopeptidome profiling and functional NK cell assays in a single rigorous study","pmids":["41198628"],"is_preprint":false},{"year":2016,"finding":"KIR2DL2-positive MS patients exhibited increased susceptibility to HSV-1 infection, with decreased NK cell degranulation and cytotoxicity and upregulated KIR2DL2 surface expression after CpG treatment. Direct CpG treatment of purified NK cells modulated KIR2DL2 expression and NK cell activation, suggesting KIR2DL2 is directly regulatable on NK cells and functionally links to suppressed antiviral responses.","method":"In vitro PBMC infection with HSV-1, flow cytometry (NK cell activation markers and KIR2DL2 expression), NK cell cytotoxicity and degranulation assay, purified NK cell treatment with CpG","journal":"Journal of neuroimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct NK cell manipulation with CpG, KIR2DL2 expression modulation and cytotoxicity readout, single lab","pmids":["27138091"],"is_preprint":false},{"year":2014,"finding":"KIR2DL2-positive NK cells are more sensitive to changes in MHC class I peptide content (peptide selectivity) compared to KIR2DL3-positive NK cells. KIR2DL3+ NK cells were more responsive to a weakly inhibitory peptide (VAPWNSRAL) than KIR2DL2+ NK cells, demonstrating that the two closely related receptors confer qualitatively different responses to the peptide landscape presented by MHC class I.","method":"NK cell functional assays using defined inhibitory, weak inhibitory, and antagonist peptides; donors homozygous for KIR2DL2 or KIR2DL3; mathematical modeling of experimental data","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — controlled peptide panel with KIR-genotyped homozygous donors and mathematical modeling, single lab","pmids":["25359276"],"is_preprint":false},{"year":2019,"finding":"LASV nucleoprotein and glycoprotein epitopes presented by HLA-C molecules bound to KIR2DL2 and strongly inhibited degranulation of KIR2DL2+ NK cells. A viral glycoprotein variant (vGP420) detected in 28.1% of LASV sequences showed increased inhibition via KIR2DL2, consistent with a mechanism of NK cell escape through enhanced engagement of KIR2DL2 on the inhibitory receptor.","method":"In silico epitope screening of LASV NP and GP, peptide-HLA stabilization assay, KIR2DL2 binding assay, NK cell polyfunction assay (degranulation measurement)","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding and functional NK cell assays with defined peptides, single lab, in silico prediction validated by experiment","pmids":["30711514"],"is_preprint":false}],"current_model":"KIR2DL2 is an inhibitory NK cell receptor with a two-domain Ig-like extracellular structure whose interdomain hinge angle is flexible and critically determines HLA-C binding avidity; upon engagement of HLA-C (particularly C1-group allotypes, and some C2 and HLA-B allotypes), KIR2DL2 becomes tyrosine-phosphorylated and recruits SHP1/SHP2, which dephosphorylate PLC-γ1 to suppress downstream cytotoxic signaling, with peptide identity in the HLA-C groove serving as a key modulator of KIR2DL2 binding affinity and hence NK cell inhibition; allelic polymorphisms at sites distal to the ligand-binding site (positions 16, 35, 148) regulate binding strength through hinge angle effects, and KIR2DL2 promoter methylation controls its expression level, including upregulation by decitabine via Sp-1 binding."},"narrative":{"mechanistic_narrative":"KIR2DL2 is an inhibitory natural killer (NK) cell receptor that, upon engagement of HLA-C ligands, suppresses cytotoxic signaling and tunes NK cell self-tolerance and antiviral responsiveness [PMID:11750651, PMID:22807681]. Its extracellular region comprises two K-type Ig-like domains joined by a hinge whose angle is not fixed; this interdomain geometry, rather than the ligand-contacting loops alone, governs HLA-C binding avidity, as allelic residues distal to the interface (e.g. position 16 in D1 combined with position 148 in D2, and position 35) act synergistically through hinge-angle and dimer-stabilization effects to strengthen ligand binding [PMID:10097129, PMID:18322206, PMID:23686481, PMID:27030405]. Upon HLA-C engagement KIR2DL2 becomes tyrosine-phosphorylated and recruits the phosphatases SHP1 and SHP2, which dephosphorylate PLC-γ1 to abort activating signaling, independently of p56lck [PMID:11750651]. Recognition is exquisitely peptide-sensitive: the identity of the peptide presented in the HLA-C groove determines whether KIR2DL2 binds and inhibits, a property exploited and subverted during viral infection, where HIV-1, Lassa virus and other pathogens encode epitope variants that modulate KIR2DL2 engagement and thereby NK cell degranulation [PMID:22807681, PMID:24785948, PMID:25359276, PMID:30711514]. Structurally, KIR2DL2 adopts docking modalities over HLA-C that differ from its close relative KIR2DL3 and that are 'skewed' over the non-canonical ligand HLA-B*73:01, explaining its distinct and broader allotype recognition [PMID:33846289, PMID:40749828, PMID:41198628]. KIR2DL2 surface expression is controlled by promoter methylation, with decitabine de-repressing the gene through enhanced Sp-1 promoter binding [PMID:29632540].","teleology":[{"year":1999,"claim":"Established the structural architecture of KIR2DL2 and identified a flexible interdomain hinge and a charge-complementary ligand-binding surface, framing how the receptor could engage HLA-C.","evidence":"X-ray crystallography of the two-domain extracellular region in two crystal forms","pmids":["10097129"],"confidence":"High","gaps":["No bound HLA-C complex in this structure","Functional consequence of hinge flexibility not demonstrated"]},{"year":2002,"claim":"Defined the inhibitory signaling mechanism, showing KIR2DL2 engagement of HLA-C triggers phosphatase recruitment that shuts down activating signaling.","evidence":"Reconstitution in p56lck-negative YT-Indy NK cells with phosphorylation, SHP1/SHP2 co-IP, PLC-γ1 dephosphorylation, antibody blocking, and cytotoxicity assays","pmids":["11750651"],"confidence":"High","gaps":["Tested with HLA-Cw3 ligand only","Stoichiometry of SHP1 vs SHP2 recruitment not resolved"]},{"year":2004,"claim":"Demonstrated that KIR2DL2 and the closely related KIR2DL3 confer distinct HLA class I specificities at the NK clone level, motivating dissection of the allotype-specific basis of recognition.","evidence":"KIR2DL3-discriminating monoclonal antibody (ECM41), transfectant validation, NK clone specificity and redirected killing assays","pmids":["15314042"],"confidence":"Medium","gaps":["Molecular basis of specificity difference not defined here","Reliance on a single discriminating antibody"]},{"year":2008,"claim":"Mapped the higher HLA-C avidity of KIR2DL2 versus KIR2DL3 to allelic residues distant from the binding site, showing avidity is set allosterically through the D1–D2 hinge.","evidence":"Site-directed mutagenesis of positions 16 and 148 with binding assays across 93 HLA isoforms and functional analysis","pmids":["18322206"],"confidence":"High","gaps":["Hinge-angle change inferred, not directly structurally measured for the mutants","Effect on downstream signaling strength not quantified"]},{"year":2012,"claim":"Established that peptide identity in the HLA-C groove gates KIR2DL2 binding and inhibition, revealing a peptide-selectivity layer to NK self-recognition exploited by HIV-1.","evidence":"KIR2DL2-Fc binding to HLA-Cw*0102 stabilized with a 217-peptide panel and primary NK cell degranulation readout","pmids":["22807681"],"confidence":"High","gaps":["Single HLA-C allotype context","Structural basis of peptide-dependent binding not yet solved at this stage"]},{"year":2013,"claim":"Showed allelic residues distal to the interface (positions 11 and 35) jointly raise affinity toward KIR2DL2-like levels and that KIR2DL2/L3 recognize a broader C1/C2 spectrum, with KIR2DL2 inhibition dominating over KIR2DS2 activation.","evidence":"SPR, HLA panel binding, mutagenesis, molecular modeling, IFN-γ inhibition in KHYG-1; and functional NK assays in 159 genotyped donors with co-expression comparisons","pmids":["23686481","24078689"],"confidence":"High","gaps":["Hinge-angle mechanism from modeling not experimentally validated by structure","Dominance of inhibition over activation tested in limited target contexts"]},{"year":2014,"claim":"Refined peptide selectivity by showing KIR2DL2 is more sensitive than KIR2DL3 to MHC peptide content, and extended peptide-gated recognition to additional HLA-C allotypes and HIV epitopes.","evidence":"Defined inhibitory/weak/antagonist peptide panels in KIR-homozygous donors with mathematical modeling; KIR2DL2-Fc binding and NK degranulation on HLA-C*03:04","pmids":["25359276","24785948"],"confidence":"Medium","gaps":["Mechanistic basis of differential peptide sensitivity between L2 and L3 not structurally resolved","Single-lab functional datasets"]},{"year":2016,"claim":"Connected KIR2DL2 ligand levels to antiviral control and identified expression as a CpG-responsive, functionally relevant variable on NK cells.","evidence":"In vitro HIV suppression by KIR2DL2+ vs KIR2DL2- NK cells with ligand-expression vs affinity dissection; allele functional strength assays; CpG modulation of KIR2DL2 in HSV-1 infection","pmids":["27880898","27030405","27138091"],"confidence":"Medium","gaps":["Mechanisms inferred largely from in vitro systems","Position-35 dimer-stabilization model not validated by mutagenesis"]},{"year":2018,"claim":"Identified epigenetic control of KIR2DL2 expression, showing promoter demethylation by decitabine de-represses the gene via Sp-1.","evidence":"Promoter methylation analysis, Sp-1 binding assay, and γδ T cell surface expression and cytotoxicity readouts after decitabine","pmids":["29632540"],"confidence":"Medium","gaps":["Direct Sp-1 occupancy at endogenous promoter not fully resolved","Studied in γδ T cells rather than NK cells"]},{"year":2021,"claim":"Provided the structural basis for KIR2DL2 versus KIR2DL3 differential HLA-C1 recognition through distinct docking modalities over HLA-C*07:02.","evidence":"Crystal structures of both receptor/HLA-C*07:02 complexes with mutagenesis and primary NK cell functional validation","pmids":["33846289"],"confidence":"High","gaps":["Single HLA-C1 allotype crystallized","Hinge-angle predictions from earlier work not directly correlated to these structures"]},{"year":2025,"claim":"Extended structural understanding to non-canonical and infection-relevant ligands, defining skewed KIR2DL2 docking on HLA-B*73:01 and recognition of an HIV-1 Pol escape peptide, linking T cell and NK cell immune control.","evidence":"Crystal structures of KIR2DL2/HLA-B*73:01 and KIR2DL2/HLA-C*12:02-Pol-mutant complexes with immunopeptidome profiling and NK suppression assays","pmids":["40749828","41198628"],"confidence":"High","gaps":["Functional significance of HLA-B*73:01 recognition in vivo not established","Breadth of HLA-B allotypes recognized unknown"]},{"year":null,"claim":"How the allelic hinge-angle modulations, peptide identity, and receptor expression level integrate quantitatively to set the NK cell inhibitory threshold in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structure-function model spanning hinge geometry, peptide gating, and expression","In vivo physiological thresholds for inhibition not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,11,14]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,4,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]}],"complexes":[],"partners":["SHP1","SHP2","PLCG1","HLA-C","KIR2DS2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P43627","full_name":"Killer cell immunoglobulin-like receptor 2DL2","aliases":["CD158 antigen-like family member B1","Natural killer-associated transcript 6","NKAT-6","p58 natural killer cell receptor clone CL-43","p58 NK receptor CL-43"],"length_aa":348,"mass_kda":38.5,"function":"Receptor on natural killer (NK) cells for HLA-Cw1, 3, 7, and 8 allotypes. Inhibits the activity of NK cells thus preventing cell lysis","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P43627/entry"},"depmap":{"release":"DepMap","has_data":false,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KIR2DL2"},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KIR2DL2","total_profiled":1310},"omim":[{"mim_id":"609423","title":"HUMAN IMMUNODEFICIENCY VIRUS TYPE 1, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/609423"},{"mim_id":"606021","title":"PRAME NUCLEAR RECEPTOR TRANSCRIPTIONAL REGULATOR; PRAME","url":"https://www.omim.org/entry/606021"},{"mim_id":"604953","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, TWO DOMAINS, SHORT CYTOPLASMIC TAIL, 2; KIR2DS2","url":"https://www.omim.org/entry/604953"},{"mim_id":"604938","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, TWO DOMAINS, LONG CYTOPLASMIC TAIL, 3; KIR2DL3","url":"https://www.omim.org/entry/604938"},{"mim_id":"604937","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, TWO DOMAINS, LONG CYTOPLASMIC TAIL, 2; KIR2DL2","url":"https://www.omim.org/entry/604937"}],"hpa":{"profiled":false,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"","tissue_distribution":"","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KIR2DL2"},"hgnc":{"alias_symbol":["cl-43","nkat6","CD158B1","CD158k"],"prev_symbol":[]},"alphafold":{"accession":"P43627","domains":[{"cath_id":"2.60.40.10","chopping":"24-123","consensus_level":"high","plddt":93.0276,"start":24,"end":123},{"cath_id":"2.60.40.10","chopping":"127-220","consensus_level":"high","plddt":93.9104,"start":127,"end":220}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P43627","model_url":"https://alphafold.ebi.ac.uk/files/AF-P43627-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P43627-F1-predicted_aligned_error_v6.png","plddt_mean":74.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KIR2DL2","jax_strain_url":"https://www.jax.org/strain/search?query=KIR2DL2"},"sequence":{"accession":"P43627","fasta_url":"https://rest.uniprot.org/uniprotkb/P43627.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P43627/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P43627"}},"corpus_meta":[{"pmid":"18322206","id":"PMC_18322206","title":"Synergistic polymorphism at two positions distal to the ligand-binding site makes KIR2DL2 a stronger receptor for HLA-C than KIR2DL3.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18322206","citation_count":324,"is_preprint":false},{"pmid":"11468170","id":"PMC_11468170","title":"Human natural killer cells with polyclonal lectin and immunoglobulinlike receptors develop from single hematopoietic stem cells with preferential expression of NKG2A and KIR2DL2/L3/S2.","date":"2001","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11468170","citation_count":164,"is_preprint":false},{"pmid":"10097129","id":"PMC_10097129","title":"Crystal structure of the HLA-Cw3 allotype-specific killer cell inhibitory receptor KIR2DL2.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of 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complementary to HLA-C. The interdomain hinge angle was found to vary by ~5° between crystal forms, suggesting it is not fixed.\",\n      \"method\": \"X-ray crystallography (two crystal forms: orthorhombic P212121 and trigonal P3221)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure determined at near-atomic resolution in two independent crystal forms with functional interpretation of binding site\",\n      \"pmids\": [\"10097129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The higher HLA-C binding avidity of KIR2DL2*001 compared to KIR2DL3*001 was mapped by site-directed mutagenesis to a synergistic combination of arginine at position 16 (D1 domain) and cysteine at position 148 (D2 domain); neither residue individually conferred the avidity difference, and neither is at the ligand-binding site. Their juxtaposition near the D1–D2 hinge suggests they alter the interdomain hinge angle and relative domain orientation to strengthen ligand binding.\",\n      \"method\": \"Recombinant mutant protein generation, site-directed mutagenesis, binding assays to 93 HLA-A/B/C isoforms, functional analysis\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-directed mutagenesis combined with extensive binding assay panel and functional analysis in a single rigorous study\",\n      \"pmids\": [\"18322206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"KIR2DL2 (encoded by the cl43/KIR2DL2 gene) inhibits CD28-mediated natural cytotoxicity in the p56(lck)-negative NK cell line YT-Indy. Upon HLA-Cw3 engagement, KIR2DL2 becomes tyrosine-phosphorylated and recruits SHP1/SHP2 phosphatases, which dephosphorylate PLC-γ1, thereby suppressing CD28-triggered cytotoxic signaling. p56(lck) is not required for KIR2DL2-mediated inhibitory signaling.\",\n      \"method\": \"Stable transfection of KIR2DL2 into YT-Indy cells, pervanadate phosphorylation assay, SHP1/SHP2 co-immunoprecipitation, anti-KIR2DL2/anti-HLA class I antibody blocking, PLC-γ1 tyrosine phosphorylation assay, cytotoxicity assay\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution in transfected cells, multiple orthogonal biochemical assays (phosphorylation, co-IP, functional cytotoxicity), antibody blocking controls\",\n      \"pmids\": [\"11750651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structures of KIR2DL2 and KIR2DL3 in complex with HLA-C*07:02 presenting a self-epitope revealed that KIR2DL2 adopts a different docking modality over HLA-C*07:02 compared to KIR2DL3. Mutagenesis assays demonstrated that these structural differences underlie differential recognition of HLA-C1 allotypes by the two receptors. HLA-C1 allotypes also differed markedly in their capacity to inhibit primary NK cell activation, and KIR2DS2 contributed to distinguishing KIR2DL2 and KIR2DL3 functional recognition.\",\n      \"method\": \"X-ray crystallography of KIR2DL2/HLA-C*07:02 and KIR2DL3/HLA-C*07:02 complexes, site-directed mutagenesis, primary NK cell functional assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of two receptor-ligand complexes with orthogonal mutagenesis and primary NK cell functional validation\",\n      \"pmids\": [\"33846289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Peptide sequence variations within HLA-Cw*0102-restricted HIV-1 p24 Gag epitopes modulate binding of KIR2DL2 to HLA-Cw*0102. Only one of 11 HLA-Cw*0102-stabilizing peptides (p24 Gag209–218 AAEWDRLHPV) enabled KIR2DL2 binding, and this interaction caused significant inhibition of degranulation specifically in KIR2DL2+ primary NK cells. Sequence variations at position 7 of this epitope, observed in natural HIV-1 sequences, modulated KIR2DL2 binding affinity.\",\n      \"method\": \"KIR2DL2-IgG fusion protein binding assay, HLA-Cw*0102 stabilization assay on TAP-deficient T2 cells, primary NK cell degranulation assay by flow cytometry, 217-peptide panel screen\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KIR2DL2-Fc binding assay with large peptide panel, primary NK cell functional readout, mechanistic link between peptide identity and KIR2DL2 engagement established\",\n      \"pmids\": [\"22807681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Naturally occurring sequence variations within HLA-C*03:04-restricted HIV-1 p24 Gag epitopes (Gag144–152, Gag163–171, Gag295–304) enabled KIR2DL2 binding to HLA-C*03:04 and resulted in inhibition of KIR2DL2+ primary NK cells. Minor variants of Gag295–304 found in natural HIV-1 sequences enhanced KIR2DL2 binding to HLA-C*03:04 beyond consensus levels.\",\n      \"method\": \"KIR2DL2-Fc binding construct assay, HLA-C*03:04 stabilization assay on 721.220 tapasin-deficient cells, primary NK cell degranulation assay, HIV-1 p24 Gag overlapping peptide panel\",\n      \"journal\": \"AIDS (London, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KIR2DL2-Fc binding assay with systematic peptide panel, primary NK cell functional validation, two orthogonal methods in one study\",\n      \"pmids\": [\"24785948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KIR2DL2+ and KIR2DL3+ NK cells exhibited a broader spectrum of HLA-C recognition than KIR2DL1+ NK cells, reacting against both C1 and C2 allele-expressing target cells. When KIR2DL2 and KIR2DS2 were co-expressed, KIR2DL2-mediated inhibition overrode KIR2DS2-mediated activation, whereas co-expression of KIR2DL1 and KIR2DS2 had an additive activating effect on NK responses against C1C1 targets.\",\n      \"method\": \"NK cell functional assays against HLA-C+ target cells from 159 KIR/HLA-genotyped individuals, NK cell clone analysis, KIR2DL2-/KIR2DS2-single vs. co-expressing NK cell comparison\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional NK cell assays in large cohort with NK cell clones, single lab but multiple genotype groups and functional readouts\",\n      \"pmids\": [\"24078689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Allelic variation in KIR2DL3 at residues 11 (arginine) and 35 (glutamic acid) — both distal to the KIR/HLA-C interface — synergistically increases HLA-C binding affinity and avidity of KIR2DL3*005 to KIR2DL2-like levels. Site-directed mutagenesis confirmed that both substitutions together (not individually) are required. Molecular modeling suggested the mechanism involves alteration of the interdomain hinge angle toward that of KIR2DL2*001.\",\n      \"method\": \"Surface plasmon resonance, KIR binding to HLA allotype panel, flow cytometry (surface expression), IFN-γ inhibition assay in KHYG-1 NK cell line, site-directed mutagenesis, molecular modeling\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (SPR, functional assay, mutagenesis, structural modeling), rigorously replicated within one study\",\n      \"pmids\": [\"23686481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KIR2DL2 and KIR2DL3 differ in HLA class I specificity at the NK clone level, revealed using a novel KIR2DL3-specific monoclonal antibody (ECM41) that distinguishes KIR2DL3 from KIR2DL2 and KIR2DS2 on cell transfectants. Simultaneous engagement of KIR2DL3 and KIR2DS2 in NK clones co-expressing both receptors was functionally assessed by redirected killing assays.\",\n      \"method\": \"Monoclonal antibody generation, cell transfectant surface expression analysis, NK clone HLA specificity analysis, redirected killing assay\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel discriminating antibody with transfectant validation, NK clone functional assays, single lab with multiple methods\",\n      \"pmids\": [\"15314042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIR2DL2+ NK cells suppressed HIV-1 replication in HLA-C*14:03+ or HLA-C*12:02+ cells to a significantly greater extent than KIR2DL2- NK cells in vitro. The mechanism involved reduced surface expression of peptide-HLA complexes (reduced KIR2DL2 ligand) on HIV-1-infected cells rather than altered binding affinity of KIR2DL2 to pHLA complexes, thereby disinhibiting KIR2DL2+ NK cells.\",\n      \"method\": \"In vitro viral suppression assay comparing KIR2DL2+ vs KIR2DL2- NK cells, KIR2DL2 binding affinity measurements, HLA-C surface expression analysis on HIV-infected cells\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional assay with mechanistic dissection (ligand expression vs. binding affinity), single lab\",\n      \"pmids\": [\"27880898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIR2DL2/L3 alleles carrying glutamic acid at position 35 (E35) are functionally stronger than those with glutamine (Q35). NK cells from HLA-C1+ donors with E35 alleles killed more target cells lacking HLA-C1 ligand, indicating better NK cell licensing. Molecular modeling showed that glutamic acid at position 35 interacts with histidine at position 55, stabilizing the KIR2DL2/L3 dimer and reducing entropy loss upon HLA-C ligand binding.\",\n      \"method\": \"NK cell cytotoxicity assay, allele genotyping, molecular modeling\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cytotoxicity assay with mechanistic modeling, single lab, modeling not experimentally validated by mutagenesis\",\n      \"pmids\": [\"27030405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Decitabine (DAC) upregulated KIR2DL2/3 expression in KIR2DL2/3-negative γδ T cells by inhibiting methylation of the KIR2DL2/3 promoter, which enhanced binding of the transcription factor Sp-1 to the promoter and activated KIR2DL2/3 gene expression. KIR2DL2/3-positive γδ T cells were less cytotoxic than KIR2DL2/3-negative γδ T cells, and DAC treatment thereby reduced γδ T cell cytotoxicity.\",\n      \"method\": \"Flow cytometry (KIR2DL2/3 surface expression), promoter methylation analysis, Sp-1 binding assay (chromatin immunoprecipitation/EMSA-type), γδ T cell cytotoxicity assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter methylation and transcription factor binding assays with functional cytotoxicity readout, single lab\",\n      \"pmids\": [\"29632540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A crystal structure of HLA-B*73:01 in complex with KIR2DL2 was determined, revealing differences from previously solved KIR2DL2/HLA-C structures. KIR2DL2 engagement of HLA-B*73:01 was described as 'skewed' relative to HLA-C complexes, providing a structural basis for KIR2DL2 recognition of an HLA-B allotype.\",\n      \"method\": \"X-ray crystallography of KIR2DL2/HLA-B*73:01 complex, mass spectrometry-based immunopeptidome profiling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with peptidome profiling, single lab, peer-reviewed\",\n      \"pmids\": [\"40749828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Crystal structure of KIR2DL2 in complex with HLA-C*12:02 presenting an HIV-1 Pol escape mutant epitope was determined, providing the molecular basis for how the Pol mutant peptide-HLA complex is recognized by KIR2DL2. KIR2DL2+ NK cells showed enhanced ability to recognize HIV-1-infected cells after selection of the Pol mutant virus by T cells, demonstrating coordinated immune control by CD8+ T cells and KIR2DL2+ NK cells.\",\n      \"method\": \"Crystal structure determination (TCR- and KIR2DL2-HLA-C*12:02-peptide complexes), mass spectrometry immunopeptidome profiling, in vitro NK cell suppression assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mass spectrometry immunopeptidome profiling and functional NK cell assays in a single rigorous study\",\n      \"pmids\": [\"41198628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIR2DL2-positive MS patients exhibited increased susceptibility to HSV-1 infection, with decreased NK cell degranulation and cytotoxicity and upregulated KIR2DL2 surface expression after CpG treatment. Direct CpG treatment of purified NK cells modulated KIR2DL2 expression and NK cell activation, suggesting KIR2DL2 is directly regulatable on NK cells and functionally links to suppressed antiviral responses.\",\n      \"method\": \"In vitro PBMC infection with HSV-1, flow cytometry (NK cell activation markers and KIR2DL2 expression), NK cell cytotoxicity and degranulation assay, purified NK cell treatment with CpG\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct NK cell manipulation with CpG, KIR2DL2 expression modulation and cytotoxicity readout, single lab\",\n      \"pmids\": [\"27138091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIR2DL2-positive NK cells are more sensitive to changes in MHC class I peptide content (peptide selectivity) compared to KIR2DL3-positive NK cells. KIR2DL3+ NK cells were more responsive to a weakly inhibitory peptide (VAPWNSRAL) than KIR2DL2+ NK cells, demonstrating that the two closely related receptors confer qualitatively different responses to the peptide landscape presented by MHC class I.\",\n      \"method\": \"NK cell functional assays using defined inhibitory, weak inhibitory, and antagonist peptides; donors homozygous for KIR2DL2 or KIR2DL3; mathematical modeling of experimental data\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — controlled peptide panel with KIR-genotyped homozygous donors and mathematical modeling, single lab\",\n      \"pmids\": [\"25359276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LASV nucleoprotein and glycoprotein epitopes presented by HLA-C molecules bound to KIR2DL2 and strongly inhibited degranulation of KIR2DL2+ NK cells. A viral glycoprotein variant (vGP420) detected in 28.1% of LASV sequences showed increased inhibition via KIR2DL2, consistent with a mechanism of NK cell escape through enhanced engagement of KIR2DL2 on the inhibitory receptor.\",\n      \"method\": \"In silico epitope screening of LASV NP and GP, peptide-HLA stabilization assay, KIR2DL2 binding assay, NK cell polyfunction assay (degranulation measurement)\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding and functional NK cell assays with defined peptides, single lab, in silico prediction validated by experiment\",\n      \"pmids\": [\"30711514\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIR2DL2 is an inhibitory NK cell receptor with a two-domain Ig-like extracellular structure whose interdomain hinge angle is flexible and critically determines HLA-C binding avidity; upon engagement of HLA-C (particularly C1-group allotypes, and some C2 and HLA-B allotypes), KIR2DL2 becomes tyrosine-phosphorylated and recruits SHP1/SHP2, which dephosphorylate PLC-γ1 to suppress downstream cytotoxic signaling, with peptide identity in the HLA-C groove serving as a key modulator of KIR2DL2 binding affinity and hence NK cell inhibition; allelic polymorphisms at sites distal to the ligand-binding site (positions 16, 35, 148) regulate binding strength through hinge angle effects, and KIR2DL2 promoter methylation controls its expression level, including upregulation by decitabine via Sp-1 binding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIR2DL2 is an inhibitory natural killer (NK) cell receptor that, upon engagement of HLA-C ligands, suppresses cytotoxic signaling and tunes NK cell self-tolerance and antiviral responsiveness [#2, #4]. Its extracellular region comprises two K-type Ig-like domains joined by a hinge whose angle is not fixed; this interdomain geometry, rather than the ligand-contacting loops alone, governs HLA-C binding avidity, as allelic residues distal to the interface (e.g. position 16 in D1 combined with position 148 in D2, and position 35) act synergistically through hinge-angle and dimer-stabilization effects to strengthen ligand binding [#0, #1, #7, #10]. Upon HLA-C engagement KIR2DL2 becomes tyrosine-phosphorylated and recruits the phosphatases SHP1 and SHP2, which dephosphorylate PLC-\\u03b31 to abort activating signaling, independently of p56lck [#2]. Recognition is exquisitely peptide-sensitive: the identity of the peptide presented in the HLA-C groove determines whether KIR2DL2 binds and inhibits, a property exploited and subverted during viral infection, where HIV-1, Lassa virus and other pathogens encode epitope variants that modulate KIR2DL2 engagement and thereby NK cell degranulation [#4, #5, #15, #16]. Structurally, KIR2DL2 adopts docking modalities over HLA-C that differ from its close relative KIR2DL3 and that are 'skewed' over the non-canonical ligand HLA-B*73:01, explaining its distinct and broader allotype recognition [#3, #12, #13]. KIR2DL2 surface expression is controlled by promoter methylation, with decitabine de-repressing the gene through enhanced Sp-1 promoter binding [#11].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the structural architecture of KIR2DL2 and identified a flexible interdomain hinge and a charge-complementary ligand-binding surface, framing how the receptor could engage HLA-C.\",\n      \"evidence\": \"X-ray crystallography of the two-domain extracellular region in two crystal forms\",\n      \"pmids\": [\"10097129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No bound HLA-C complex in this structure\", \"Functional consequence of hinge flexibility not demonstrated\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the inhibitory signaling mechanism, showing KIR2DL2 engagement of HLA-C triggers phosphatase recruitment that shuts down activating signaling.\",\n      \"evidence\": \"Reconstitution in p56lck-negative YT-Indy NK cells with phosphorylation, SHP1/SHP2 co-IP, PLC-\\u03b31 dephosphorylation, antibody blocking, and cytotoxicity assays\",\n      \"pmids\": [\"11750651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tested with HLA-Cw3 ligand only\", \"Stoichiometry of SHP1 vs SHP2 recruitment not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated that KIR2DL2 and the closely related KIR2DL3 confer distinct HLA class I specificities at the NK clone level, motivating dissection of the allotype-specific basis of recognition.\",\n      \"evidence\": \"KIR2DL3-discriminating monoclonal antibody (ECM41), transfectant validation, NK clone specificity and redirected killing assays\",\n      \"pmids\": [\"15314042\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of specificity difference not defined here\", \"Reliance on a single discriminating antibody\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped the higher HLA-C avidity of KIR2DL2 versus KIR2DL3 to allelic residues distant from the binding site, showing avidity is set allosterically through the D1\\u2013D2 hinge.\",\n      \"evidence\": \"Site-directed mutagenesis of positions 16 and 148 with binding assays across 93 HLA isoforms and functional analysis\",\n      \"pmids\": [\"18322206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hinge-angle change inferred, not directly structurally measured for the mutants\", \"Effect on downstream signaling strength not quantified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that peptide identity in the HLA-C groove gates KIR2DL2 binding and inhibition, revealing a peptide-selectivity layer to NK self-recognition exploited by HIV-1.\",\n      \"evidence\": \"KIR2DL2-Fc binding to HLA-Cw*0102 stabilized with a 217-peptide panel and primary NK cell degranulation readout\",\n      \"pmids\": [\"22807681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single HLA-C allotype context\", \"Structural basis of peptide-dependent binding not yet solved at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed allelic residues distal to the interface (positions 11 and 35) jointly raise affinity toward KIR2DL2-like levels and that KIR2DL2/L3 recognize a broader C1/C2 spectrum, with KIR2DL2 inhibition dominating over KIR2DS2 activation.\",\n      \"evidence\": \"SPR, HLA panel binding, mutagenesis, molecular modeling, IFN-\\u03b3 inhibition in KHYG-1; and functional NK assays in 159 genotyped donors with co-expression comparisons\",\n      \"pmids\": [\"23686481\", \"24078689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hinge-angle mechanism from modeling not experimentally validated by structure\", \"Dominance of inhibition over activation tested in limited target contexts\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Refined peptide selectivity by showing KIR2DL2 is more sensitive than KIR2DL3 to MHC peptide content, and extended peptide-gated recognition to additional HLA-C allotypes and HIV epitopes.\",\n      \"evidence\": \"Defined inhibitory/weak/antagonist peptide panels in KIR-homozygous donors with mathematical modeling; KIR2DL2-Fc binding and NK degranulation on HLA-C*03:04\",\n      \"pmids\": [\"25359276\", \"24785948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis of differential peptide sensitivity between L2 and L3 not structurally resolved\", \"Single-lab functional datasets\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected KIR2DL2 ligand levels to antiviral control and identified expression as a CpG-responsive, functionally relevant variable on NK cells.\",\n      \"evidence\": \"In vitro HIV suppression by KIR2DL2+ vs KIR2DL2- NK cells with ligand-expression vs affinity dissection; allele functional strength assays; CpG modulation of KIR2DL2 in HSV-1 infection\",\n      \"pmids\": [\"27880898\", \"27030405\", \"27138091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanisms inferred largely from in vitro systems\", \"Position-35 dimer-stabilization model not validated by mutagenesis\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified epigenetic control of KIR2DL2 expression, showing promoter demethylation by decitabine de-represses the gene via Sp-1.\",\n      \"evidence\": \"Promoter methylation analysis, Sp-1 binding assay, and \\u03b3\\u03b4 T cell surface expression and cytotoxicity readouts after decitabine\",\n      \"pmids\": [\"29632540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Sp-1 occupancy at endogenous promoter not fully resolved\", \"Studied in \\u03b3\\u03b4 T cells rather than NK cells\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the structural basis for KIR2DL2 versus KIR2DL3 differential HLA-C1 recognition through distinct docking modalities over HLA-C*07:02.\",\n      \"evidence\": \"Crystal structures of both receptor/HLA-C*07:02 complexes with mutagenesis and primary NK cell functional validation\",\n      \"pmids\": [\"33846289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single HLA-C1 allotype crystallized\", \"Hinge-angle predictions from earlier work not directly correlated to these structures\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended structural understanding to non-canonical and infection-relevant ligands, defining skewed KIR2DL2 docking on HLA-B*73:01 and recognition of an HIV-1 Pol escape peptide, linking T cell and NK cell immune control.\",\n      \"evidence\": \"Crystal structures of KIR2DL2/HLA-B*73:01 and KIR2DL2/HLA-C*12:02-Pol-mutant complexes with immunopeptidome profiling and NK suppression assays\",\n      \"pmids\": [\"40749828\", \"41198628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of HLA-B*73:01 recognition in vivo not established\", \"Breadth of HLA-B allotypes recognized unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the allelic hinge-angle modulations, peptide identity, and receptor expression level integrate quantitatively to set the NK cell inhibitory threshold in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structure-function model spanning hinge geometry, peptide gating, and expression\", \"In vivo physiological thresholds for inhibition not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 11, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 4, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SHP1\", \"SHP2\", \"PLCG1\", \"HLA-C\", \"KIR2DS2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}