{"gene":"KIR2DL3","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1999,"finding":"Crystal structure of the extracellular region of KIR2DL3 (p58) was solved, revealing two tandem immunoglobulin-like domains with an unusually acute interdomain elbow angle of 23° different from KIR2DL1. The putative HLA-C binding site spans both domains on the outer surface of the elbow, and the relative domain orientation can modulate the binding site.","method":"X-ray crystallography","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure determination with direct structural comparison to KIR2DL1, establishing domain orientation and ligand-binding site geometry","pmids":["10196125"],"is_preprint":false},{"year":2008,"finding":"KIR2DL2 binds HLA-C ligands with higher avidity than KIR2DL3 due to synergistic polymorphism at two positions distal to the ligand-binding site: proline 16 in D1 and arginine 148 in D2. Site-directed mutagenesis showed that the combination (but not individual substitutions) of R16P and R148C converts KIR2DL3 into a stronger receptor comparable to KIR2DL2, likely by altering the hinge angle between the two Ig-like domains.","method":"Site-directed mutagenesis combined with functional binding assays to 93 HLA allotypes","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with mutagenesis and functional binding assays across broad panel of allotypes, mechanistic interpretation supported by structural rationale","pmids":["18322206"],"is_preprint":false},{"year":1999,"finding":"KIR2DL3 expressed as a transgene in mouse T cells can inhibit mixed lymphocyte reaction and anti-CD3-redirected cytotoxicity by freshly isolated splenocytes upon engagement with its ligand HLA-Cw3. However, antigen- or anti-CD3-induced cytotoxicity by activated alloreactive CTLs could NOT be inhibited by KIR2DL3 engagement, demonstrating that KIR2DL3's inhibitory effect on T cells is activation-stage dependent.","method":"Transgenic mouse model (Tg-KIR2DL3 and Tg-KIR2DL3 × Tg-HLA-Cw3 double transgenic), redirected killing assays, MLR, anti-CD3 stimulation","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic in vivo model with multiple functional readouts in single study, but limited to one lab","pmids":["10498612"],"is_preprint":false},{"year":2004,"finding":"A novel monoclonal antibody (ECM41) specific for KIR2DL3 was generated and used to show that KIR2DL3 and KIR2DL2 have distinct surface expression patterns and HLA-C specificities that were previously indistinguishable serologically. Simultaneous engagement of KIR2DL3 (inhibitory) and KIR2DS2 (activating) in NK cell clones co-expressing both receptors was functionally assessed using redirected killing assays.","method":"Monoclonal antibody generation, flow cytometry, redirected killing assays with NK cell clones","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — new specific reagent enabling discrimination of KIR2DL3 from KIR2DL2/S2, with functional validation in NK cell clones, single lab","pmids":["15314042"],"is_preprint":false},{"year":2010,"finding":"Site-directed mutagenesis of KIR2DL3 demonstrated that glutamine at position 35 is required for ECM41 mAb staining, and glutamic acid 35 plus arginine 50 are required for staining by EB6B/11PB6 mAbs. KIR2DL3*005 allele bearing these residues showed HLA-C specificity comparable to other KIR2DL2/L3 alleles despite its unusual antibody reactivity pattern.","method":"Site-directed mutagenesis, flow cytometry with multiple mAbs, functional analysis","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis identifying specific residues for antibody epitopes and functional validation, single lab","pmids":["20525888"],"is_preprint":false},{"year":2012,"finding":"Mutagenesis of six positively selected positions in the HLA class I binding site of KIR2DL3 showed that position 44 modulates specificity for HLA-C, positions 71 and 131 control cross-reactivity with HLA-A*11:02, and position 70 dominates avidity modulation (with lesser contributions from positions 68 and 182). KIR2DL3 has lower avidity and broader specificity than KIR2DL1, and unlike KIR2DL1 its avidity can be increased and specificity changed by mutation, demonstrating its greater adaptability.","method":"Site-directed mutagenesis generating 38 point mutants, binding assays to 95 HLA-A, -B, and -C allotypes","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — comprehensive mutagenesis of all six positively selected positions tested against broad HLA panel, multiple orthogonal functional readouts","pmids":["22772445"],"is_preprint":false},{"year":2013,"finding":"KIR2DL3*005 allele binds HLA-C with significantly higher affinity and avidity than KIR2DL3*001, producing stronger inhibition of NK cell IFN-γ production. Site-directed mutagenesis established that the combination of arginine at residue 11 and glutamic acid at residue 35 (both distal to the KIR/HLA-C interface) is critical to this increased affinity, likely by altering the interdomain hinge angle toward that of KIR2DL2.","method":"Surface plasmon resonance, flow cytometry, site-directed mutagenesis, NK cell functional assay (IFN-γ)","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — SPR quantitative binding, mutagenesis of specific residues, and NK functional validation in single study with multiple orthogonal methods","pmids":["23686481"],"is_preprint":false},{"year":2015,"finding":"HIV-1 mutation at p24 Gag position 303 (TGag303V) selected in individuals carrying both KIR2DL3 and HLA-C*03:04 enhanced KIR2DL3 binding to HLA-C*03:04-presenting cells and significantly reduced activation of primary KIR2DL3+ NK cells, demonstrating that peptide sequence variation within HLA-presented epitopes modulates KIR2DL3 inhibitory signaling and mediates viral immune escape.","method":"KIR2DL3 binding assay (flow cytometry with KIR2DL3-Fc fusion), primary NK cell activation assay, surface plasmon resonance, structural modeling","journal":"PLoS medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — SPR, direct binding assays, primary NK cell functional assay, and structural modeling as orthogonal methods in single cohort-based study","pmids":["26575988"],"is_preprint":false},{"year":2016,"finding":"An HCV core-derived peptide (YIPLVGAPL) bound to HLA-C*03:04 resulted in significantly higher KIR2DL3 binding and suppression of primary KIR2DL3+ NK cell function. Genotype-specific HCV peptide variants of this sequence showed lower HLA-C*03:04 stabilization, decreased KIR2DL3 binding, and lower NK cell inhibition, demonstrating sequence-dependent modulation of KIR2DL3 engagement by viral peptides.","method":"KIR2DL3-IgG fusion construct binding assay, HLA stabilization assay (722.221-HLA-C*03:04 transfectants), primary NK cell IFN-γ functional assay","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (binding assay, HLA stabilization, primary NK cell function) in single study, mechanistically defining peptide-dependent KIR2DL3 inhibitory signaling","pmids":["27057987"],"is_preprint":false},{"year":2017,"finding":"HLA-B*46:01 carries the C1 epitope introduced by intergenic mini-conversion from HLA-C*01:02 and is recognized by KIR2DL3. High-resolution mass spectrometry showed that only a minority (21%) of HLA-B*46:01 peptides with specific C-terminal characteristics form ligands for KIR2DL3, demonstrating that peptide composition of the HLA peptidome determines KIR2DL3 ligand formation.","method":"High-resolution mass spectrometry peptidome analysis, KIR2DL3 binding assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — mass spectrometry peptidome combined with KIR binding, single lab","pmids":["28514659"],"is_preprint":false},{"year":2014,"finding":"KIR2DL3-positive NK cells were more sensitive than KIR2DL2-positive NK cells to changes in the peptide content of MHC class I, with weakly inhibitory peptide VAPWNSRAL discriminating KIR2DL3 from KIR2DL2 donors. Mathematical modeling confirmed VAPWNSRAL dominance in distinguishing the two receptor populations, demonstrating peptide selectivity as a mechanistic basis for differential NK cell reactivity.","method":"Primary NK cell functional assays with defined peptide variants, mathematical modeling","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays with defined peptides in primary cells and mathematical modeling, single lab","pmids":["25359276"],"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 and KIR2DL3 differ in their docking geometry atop HLA-C*07:02. This structural plasticity correlates with differential recognition of HLA-C1 allotypes. Mutagenesis assays confirmed differences in the mechanism of HLA-C1 allotype recognition between KIR2DL2 and KIR2DL3, and primary NK cell inhibition by HLA-C1 allotypes differed markedly.","method":"X-ray crystallography of KIR2DL2/HLA-C*07:02 and KIR2DL3/HLA-C*07:02 complexes, mutagenesis assays, primary NK cell functional assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of both receptor complexes with functional mutagenesis and primary NK cell validation, multiple orthogonal methods","pmids":["33846289"],"is_preprint":false},{"year":2014,"finding":"KIR2DL3+NKG2A− NK cells were not inhibited by HLA-E ligation (unlike KIR2DL3−NKG2A+ NK cells), and this insensitivity to HLA-E-mediated inhibition was mechanistically linked to their ability to respond to HCV-infected cells. HLA-E upregulation in HCV-infected liver correlated with viral load and suppressed NK cell IFN-γ secretion specifically in NKG2A+ populations.","method":"Multicolor flow cytometry (phenotyping and functional assays), liver biopsy HLA-E expression analysis, primary NK cell IFN-γ assays","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional discrimination of KIR2DL3+NKG2A− vs KIR2DL3−NKG2A+ populations with mechanistic HLA-E inhibition assay, single lab","pmids":["24780303"],"is_preprint":false},{"year":2021,"finding":"KIR2DL3 expressed on T lymphocytes during immune reconstitution after haploidentical HSCT showed a higher inhibitory effect on CMV-specific T cell responses against allogeneic than autologous C1+ target cells, demonstrating that KIR2DL3-HLA interactions modulate T cell immune responses in an allogeneic setting.","method":"Functional T cell assays, flow cytometry, in vitro KIR2DL3 inhibition of CMV-specific T cell responses against allogeneic vs. autologous C1+ targets","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay with defined allogeneic vs. autologous controls establishing KIR2DL3 inhibitory mechanism on T cells, single lab","pmids":["34349169"],"is_preprint":false},{"year":2022,"finding":"Differential expression of KIR/NKAT2 (KIR2DL3) between NK cell subsets was documented: CD56dim peripheral blood NK cells express KIR/NKAT2 whereas CD56bright peripheral blood NK cells do not; however, both CD56bright and CD56dim decidual NK cell subsets express KIR/NKAT2 and CD94 in early pregnancy.","method":"Flow cytometry on peripheral blood and decidual tissue NK cells from pregnant and non-pregnant women","journal":"Fertility and sterility","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single flow cytometry study, no functional consequence directly tested for KIR2DL3 specifically","pmids":["15019821"],"is_preprint":false}],"current_model":"KIR2DL3 is an inhibitory NK cell receptor with two tandem Ig-like domains that dock onto HLA-C (and the exceptional HLA-B*46:01) via an acute interdomain elbow angle; its lower avidity and broader HLA-C specificity compared to the allotypically related KIR2DL2 are determined by residues distal to the binding site (positions 11, 16, 35, 148) that modulate the hinge angle between domains, while residues within the binding site (positions 44, 70, 71, 131) control specificity and avidity, and the precise peptide presented by HLA-C further tunes inhibitory signaling strength, enabling viral pathogens to escape KIR2DL3+ NK cell surveillance through mutations that enhance inhibitory receptor engagement."},"narrative":{"mechanistic_narrative":"KIR2DL3 is an inhibitory NK cell receptor whose two tandem Ig-like domains dock onto HLA-C (C1-epitope) allotypes to dampen NK cell effector responses, and whose engagement is exquisitely tuned by both receptor polymorphism and the peptide presented by the HLA-C ligand [PMID:10196125, PMID:33846289]. Its extracellular region adopts an acute interdomain elbow angle (~23°) that positions an HLA-C binding site spanning both domains, with the relative domain orientation itself shaping ligand binding [PMID:10196125]. Specificity and avidity are partitioned across two classes of residues: positions within the binding site (44, 70, 71, 131) govern HLA specificity, cross-reactivity, and avidity [PMID:22772445], whereas residues distal to the interface (11, 16, 35, 148) modulate the interdomain hinge angle and thereby set overall avidity—such that combining R16P+R148C, or R11+E35, raises KIR2DL3 affinity toward the stronger KIR2DL2-like state and increases inhibition of NK cell IFN-γ production [PMID:18322206, PMID:23686481]. Compared with the allotypically related KIR2DL2 and with KIR2DL1, KIR2DL3 has lower avidity, broader HLA-C specificity, and greater mutational adaptability, and the two C1 receptors achieve distinct docking geometries on HLA-C that translate into differential allotype recognition [PMID:22772445, PMID:33846289]. Engagement is further controlled by the specific peptide loaded onto HLA-C: peptide identity tunes inhibitory signaling strength, and HLA-presented peptide composition determines whether a given complex forms a KIR2DL3 ligand, including the exceptional HLA-B*46:01 that acquired the C1 epitope by mini-conversion [PMID:28514659, PMID:25359276]. This peptide sensitivity provides a route for viral immune escape, as HIV-1 Gag and HCV core peptide variants that enhance KIR2DL3/HLA-C engagement suppress primary KIR2DL3+ NK cell activation [PMID:26575988, PMID:27057987]. Beyond NK cells, transgenic and reconstitution-setting studies show KIR2DL3 can also deliver activation-stage-dependent inhibitory signals to T cells [PMID:10498612, PMID:34349169].","teleology":[{"year":1999,"claim":"Establishing the structural architecture of KIR2DL3 defined how a two-domain receptor presents its HLA-C binding surface, revealing that domain orientation is itself a tunable feature of ligand recognition.","evidence":"X-ray crystallography of the KIR2DL3 extracellular region with comparison to KIR2DL1","pmids":["10196125"],"confidence":"High","gaps":["No co-complex with HLA-C in this study","Functional consequence of the acute elbow angle not directly tested"]},{"year":1999,"claim":"Demonstrating that transgenic KIR2DL3 inhibits T cell cytotoxicity established its inhibitory function beyond NK cells and revealed dependence on the activation stage of the responding T cell.","evidence":"Tg-KIR2DL3 × Tg-HLA-Cw3 mouse model, MLR, and anti-CD3-redirected killing assays","pmids":["10498612"],"confidence":"Medium","gaps":["Single-lab transgenic system","Mechanism of activation-stage dependence unresolved","Human T cell relevance not addressed here"]},{"year":2004,"claim":"Generating a KIR2DL3-specific antibody enabled discrimination of KIR2DL3 from serologically indistinguishable KIR2DL2/S2, allowing receptor-resolved analysis of surface expression and signaling.","evidence":"Monoclonal antibody (ECM41) generation, flow cytometry, and redirected killing in NK cell clones","pmids":["15314042"],"confidence":"Medium","gaps":["Reagent specificity defined functionally but epitope not yet mapped","Single lab"]},{"year":2008,"claim":"Mapping the avidity difference between KIR2DL2 and KIR2DL3 to distal residues showed that ligand strength is encoded outside the binding site through interdomain hinge geometry.","evidence":"Site-directed mutagenesis (R16P, R148C) with functional binding across 93 HLA allotypes","pmids":["18322206"],"confidence":"High","gaps":["Hinge-angle change inferred, not structurally resolved here","Synergy mechanism between the two positions not visualized"]},{"year":2010,"claim":"Defining the residues controlling antibody reactivity clarified that unusual mAb staining of KIR2DL3*005 does not reflect altered HLA-C specificity, separating epitope variation from ligand function.","evidence":"Site-directed mutagenesis of positions 35/50 with multi-mAb flow cytometry and functional analysis","pmids":["20525888"],"confidence":"Medium","gaps":["Functional impact of residue 35 on ligand binding addressed only later","Single lab"]},{"year":2012,"claim":"Comprehensive mutagenesis of positively selected binding-site residues partitioned specificity, cross-reactivity, and avidity across discrete positions and established KIR2DL3 as more adaptable than KIR2DL1.","evidence":"38 point mutants assayed for binding against 95 HLA-A/-B/-C allotypes","pmids":["22772445"],"confidence":"High","gaps":["Structural basis of each residue contribution not directly visualized","Effect on downstream NK signaling not quantified"]},{"year":2013,"claim":"Linking the distal residues 11 and 35 to higher KIR2DL3*005 affinity connected hinge-angle modulation to a measurable increase in NK cell inhibition.","evidence":"Surface plasmon resonance, mutagenesis, and primary NK cell IFN-γ functional assay","pmids":["23686481"],"confidence":"High","gaps":["Hinge-angle change inferred rather than crystallographically confirmed","Allele-frequency/clinical consequence not assessed"]},{"year":2014,"claim":"Showing KIR2DL3+ NK cells are more peptide-sensitive than KIR2DL2+ cells established HLA-bound peptide selectivity as a basis for differential receptor reactivity.","evidence":"Primary NK cell functional assays with defined peptide variants and mathematical modeling","pmids":["25359276"],"confidence":"Medium","gaps":["Limited peptide panel","Structural basis of peptide discrimination not resolved","Single lab"]},{"year":2014,"claim":"Distinguishing KIR2DL3+NKG2A− from NKG2A+ NK cells in HCV infection linked receptor-defined subset identity to differential susceptibility to HLA-E-mediated inhibition and antiviral response.","evidence":"Multicolor flow cytometry, liver HLA-E expression analysis, and primary NK cell IFN-γ assays","pmids":["24780303"],"confidence":"Medium","gaps":["Correlative subset analysis","Direct causal role of KIR2DL3 vs. NKG2A absence not isolated","Single lab"]},{"year":2015,"claim":"Identifying an HIV-1 Gag escape mutation that strengthens KIR2DL3/HLA-C engagement demonstrated peptide-driven viral immune evasion through enhanced inhibitory receptor signaling.","evidence":"KIR2DL3-Fc binding, primary NK cell activation assay, SPR, and structural modeling in a genotyped cohort","pmids":["26575988"],"confidence":"High","gaps":["In vivo NK-mediated selection pressure inferred from cohort association","Structural model not experimentally resolved"]},{"year":2016,"claim":"Demonstrating that an HCV core peptide variant alters HLA-C stabilization and KIR2DL3 binding extended peptide-dependent immune escape to a second virus and tied epitope sequence to NK inhibition strength.","evidence":"KIR2DL3-IgG binding, HLA-C*03:04 stabilization assay, and primary NK cell IFN-γ functional assay","pmids":["27057987"],"confidence":"High","gaps":["No structural complex of the variant peptide","In vivo selection not directly demonstrated"]},{"year":2017,"claim":"Showing that HLA-B*46:01 acquired the C1 epitope and serves as a KIR2DL3 ligand for only a peptidome subset established that HLA peptide composition determines ligand formation beyond canonical HLA-C.","evidence":"High-resolution mass spectrometry peptidome analysis with KIR2DL3 binding assays","pmids":["28514659"],"confidence":"Medium","gaps":["Functional NK consequence of HLA-B*46:01 recognition not quantified","Single lab"]},{"year":2021,"claim":"Co-crystal structures of KIR2DL2 and KIR2DL3 with HLA-C*07:02 revealed distinct docking geometries, providing the structural basis for differential HLA-C1 allotype recognition by the two C1 receptors.","evidence":"X-ray crystallography of both receptor/HLA-C*07:02 complexes with mutagenesis and primary NK cell functional assays","pmids":["33846289"],"confidence":"High","gaps":["Single HLA-C allotype crystallized","Link between docking geometry and signaling magnitude not fully quantified"]},{"year":2021,"claim":"Demonstrating KIR2DL3 inhibition of CMV-specific T cell responses preferentially against allogeneic C1+ targets extended its inhibitory role to post-transplant T cell immunity.","evidence":"In vitro functional T cell assays comparing allogeneic vs. autologous C1+ targets after haploidentical HSCT","pmids":["34349169"],"confidence":"Medium","gaps":["Clinical outcome correlation not established","Single-lab in vitro setting"]},{"year":null,"claim":"How peptide-encoded differences in KIR2DL3 engagement quantitatively translate into NK/T cell activation thresholds in vivo, and whether they shape disease and transplant outcomes, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of peptide-variant complexes resolved at atomic resolution","Causal in vivo selection of escape variants by KIR2DL3+ NK cells not directly demonstrated","Clinical consequences of receptor polymorphism not established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,6,7,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,6,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,14]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,7,8,11]}],"complexes":[],"partners":["HLA-C","HLA-B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P43628","full_name":"Killer cell immunoglobulin-like receptor 2DL3","aliases":["CD158 antigen-like family member B2","KIR-023GB","Killer inhibitory receptor cl 2-3","NKAT2a","NKAT2b","Natural killer-associated transcript 2","NKAT-2","p58 natural killer cell receptor clone CL-6","p58 NK receptor CL-6","p58.2 MHC class-I-specific NK receptor"],"length_aa":341,"mass_kda":37.9,"function":"Receptor on natural killer (NK) cells for HLA-C alleles (HLA-Cw1, HLA-Cw3 and HLA-Cw7). Inhibits the activity of NK cells thus preventing cell lysis","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P43628/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KIR2DL3","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KIR2DL3","total_profiled":1310},"omim":[{"mim_id":"609532","title":"HEPATITIS C VIRUS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/609532"},{"mim_id":"609423","title":"HUMAN IMMUNODEFICIENCY VIRUS TYPE 1, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/609423"},{"mim_id":"604955","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, TWO DOMAINS, SHORT CYTOPLASMIC TAIL, 4; KIR2DS4","url":"https://www.omim.org/entry/604955"},{"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"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":1.4}],"url":"https://www.proteinatlas.org/search/KIR2DL3"},"hgnc":{"alias_symbol":["cl-6","nkat2","nkat2a","nkat2b","p58","CD158B2"],"prev_symbol":[]},"alphafold":{"accession":"P43628","domains":[{"cath_id":"2.60.40.10","chopping":"24-122","consensus_level":"high","plddt":93.3986,"start":24,"end":122},{"cath_id":"2.60.40.10","chopping":"127-220","consensus_level":"high","plddt":94.8754,"start":127,"end":220}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P43628","model_url":"https://alphafold.ebi.ac.uk/files/AF-P43628-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P43628-F1-predicted_aligned_error_v6.png","plddt_mean":76.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KIR2DL3","jax_strain_url":"https://www.jax.org/strain/search?query=KIR2DL3"},"sequence":{"accession":"P43628","fasta_url":"https://rest.uniprot.org/uniprotkb/P43628.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P43628/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P43628"}},"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":"19837691","id":"PMC_19837691","title":"Co-evolution of KIR2DL3 with HLA-C in a human population retaining minimal essential diversity of KIR and HLA class I ligands.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19837691","citation_count":100,"is_preprint":false},{"pmid":"23189078","id":"PMC_23189078","title":"Diverse functionality among human NK cell receptors for the C1 epitope of HLA-C: KIR2DS2, KIR2DL2, and KIR2DL3.","date":"2012","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23189078","citation_count":93,"is_preprint":false},{"pmid":"24078689","id":"PMC_24078689","title":"Large spectrum of HLA-C recognition by killer Ig-like receptor (KIR)2DL2 and KIR2DL3 and restricted C1 SPECIFICITY of KIR2DS2: dominant impact of KIR2DL2/KIR2DS2 on KIR2D NK cell repertoire formation.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24078689","citation_count":85,"is_preprint":false},{"pmid":"10196125","id":"PMC_10196125","title":"Crystal structure of the human p58 killer cell inhibitory receptor (KIR2DL3) specific for HLA-Cw3-related MHC class I.","date":"1999","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/10196125","citation_count":81,"is_preprint":false},{"pmid":"22772445","id":"PMC_22772445","title":"Mutation at positively selected positions in the binding site for HLA-C shows that KIR2DL1 is a more refined but less adaptable NK cell receptor than KIR2DL3.","date":"2012","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/22772445","citation_count":74,"is_preprint":false},{"pmid":"26575988","id":"PMC_26575988","title":"Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa.","date":"2015","source":"PLoS medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26575988","citation_count":71,"is_preprint":false},{"pmid":"23686481","id":"PMC_23686481","title":"Allelic variation in KIR2DL3 generates a KIR2DL2-like receptor with increased binding to its HLA-C ligand.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23686481","citation_count":61,"is_preprint":false},{"pmid":"17709553","id":"PMC_17709553","title":"Natural killer cells in perinatally HIV-1-infected children exhibit less degranulation compared to HIV-1-exposed uninfected children and their expression of KIR2DL3, NKG2C, and NKp46 correlates with disease severity.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17709553","citation_count":58,"is_preprint":false},{"pmid":"22412373","id":"PMC_22412373","title":"Significant association of KIR2DL3-HLA-C1 combination with cerebral malaria and implications for co-evolution of KIR and HLA.","date":"2012","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/22412373","citation_count":52,"is_preprint":false},{"pmid":"33846289","id":"PMC_33846289","title":"Structural plasticity of KIR2DL2 and KIR2DL3 enables altered docking geometries atop HLA-C.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33846289","citation_count":48,"is_preprint":false},{"pmid":"27057987","id":"PMC_27057987","title":"Sequence variations in HCV core-derived epitopes alter binding of KIR2DL3 to HLA-C∗03:04 and modulate NK cell function.","date":"2016","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/27057987","citation_count":40,"is_preprint":false},{"pmid":"28514659","id":"PMC_28514659","title":"The Intergenic Recombinant HLA-B∗46:01 Has a Distinctive Peptidome that Includes KIR2DL3 Ligands.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28514659","citation_count":39,"is_preprint":false},{"pmid":"24780303","id":"PMC_24780303","title":"KIR2DL3⁺NKG2A⁻ natural killer cells are associated with protection from productive hepatitis C virus infection in people who inject drugs.","date":"2014","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/24780303","citation_count":32,"is_preprint":false},{"pmid":"10498612","id":"PMC_10498612","title":"Modulation of T-cell functions in KIR2DL3 (CD158b) transgenic 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Counterparts.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27732638","citation_count":5,"is_preprint":false},{"pmid":"35537400","id":"PMC_35537400","title":"Clinical Impact of KIR2DS3 and KIR2DL3 Genes in Neuroblastoma Patients.","date":"2022","source":"Medical principles and practice : international journal of the Kuwait University, Health Science Centre","url":"https://pubmed.ncbi.nlm.nih.gov/35537400","citation_count":4,"is_preprint":false},{"pmid":"27506421","id":"PMC_27506421","title":"The differential impact of natural killer (NK) cell education via KIR2DL3 and KIR3DL1 on CCL4 secretion in the context of in-vitro HIV infection.","date":"2016","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27506421","citation_count":4,"is_preprint":false},{"pmid":"34349169","id":"PMC_34349169","title":"Deciphering the biology of KIR2DL3+ T lymphocytes that are associated to relapse in haploidentical 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25651940","citation_count":1,"is_preprint":false},{"pmid":"38837624","id":"PMC_38837624","title":"The novel KIR2DL3*037 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.","date":"2024","source":"HLA","url":"https://pubmed.ncbi.nlm.nih.gov/38837624","citation_count":1,"is_preprint":false},{"pmid":"19648663","id":"PMC_19648663","title":"[KIR-NKAT2 expression and monocytoid dendritic cells transformation in children diagnosed for immune deficiency: a pilot study].","date":"2009","source":"Medycyna wieku rozwojowego","url":"https://pubmed.ncbi.nlm.nih.gov/19648663","citation_count":0,"is_preprint":false},{"pmid":"38887878","id":"PMC_38887878","title":"Discovery of the novel KIR2DL3*00111 allele in a Chinese Han individual.","date":"2024","source":"HLA","url":"https://pubmed.ncbi.nlm.nih.gov/38887878","citation_count":0,"is_preprint":false},{"pmid":"38837671","id":"PMC_38837671","title":"A single nucleotide substitution in exon 5 generated the novel KIR2DL3*00112 allele.","date":"2024","source":"HLA","url":"https://pubmed.ncbi.nlm.nih.gov/38837671","citation_count":0,"is_preprint":false},{"pmid":"25626612","id":"PMC_25626612","title":"A novel KIR2DL3 variant allele, KIR2DL3*032, which has arisen by a missense mutation in codon 231.","date":"2015","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/25626612","citation_count":0,"is_preprint":false},{"pmid":"25346343","id":"PMC_25346343","title":"A novel KIR2DL3 allele, KIR2DL3*026, found in an individual from a southern Chinese Han population.","date":"2014","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/25346343","citation_count":0,"is_preprint":false},{"pmid":"25113143","id":"PMC_25113143","title":"A novel KIR2DL3 variant allele, KIR2DL3*031, identified from a southern Chinese Han individual.","date":"2014","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/25113143","citation_count":0,"is_preprint":false},{"pmid":"24849728","id":"PMC_24849728","title":"Characterization of the novel KIR2DL3*029 allele identified in a southern Chinese Han individual.","date":"2014","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/24849728","citation_count":0,"is_preprint":false},{"pmid":"25352250","id":"PMC_25352250","title":"A novel KIR2DL3 allele, KIR2DL3*027, identified in an individual from a southern Chinese Han population.","date":"2014","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/25352250","citation_count":0,"is_preprint":false},{"pmid":"24903265","id":"PMC_24903265","title":"A novel KIR2DL3*00110 allele identified in a southern Chinese Han individual.","date":"2014","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/24903265","citation_count":0,"is_preprint":false},{"pmid":"25131705","id":"PMC_25131705","title":"Identification of the novel 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The putative HLA-C binding site spans both domains on the outer surface of the elbow, and the relative domain orientation can modulate the binding site.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure determination with direct structural comparison to KIR2DL1, establishing domain orientation and ligand-binding site geometry\",\n      \"pmids\": [\"10196125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KIR2DL2 binds HLA-C ligands with higher avidity than KIR2DL3 due to synergistic polymorphism at two positions distal to the ligand-binding site: proline 16 in D1 and arginine 148 in D2. Site-directed mutagenesis showed that the combination (but not individual substitutions) of R16P and R148C converts KIR2DL3 into a stronger receptor comparable to KIR2DL2, likely by altering the hinge angle between the two Ig-like domains.\",\n      \"method\": \"Site-directed mutagenesis combined with functional binding assays to 93 HLA allotypes\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with mutagenesis and functional binding assays across broad panel of allotypes, mechanistic interpretation supported by structural rationale\",\n      \"pmids\": [\"18322206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"KIR2DL3 expressed as a transgene in mouse T cells can inhibit mixed lymphocyte reaction and anti-CD3-redirected cytotoxicity by freshly isolated splenocytes upon engagement with its ligand HLA-Cw3. However, antigen- or anti-CD3-induced cytotoxicity by activated alloreactive CTLs could NOT be inhibited by KIR2DL3 engagement, demonstrating that KIR2DL3's inhibitory effect on T cells is activation-stage dependent.\",\n      \"method\": \"Transgenic mouse model (Tg-KIR2DL3 and Tg-KIR2DL3 × Tg-HLA-Cw3 double transgenic), redirected killing assays, MLR, anti-CD3 stimulation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic in vivo model with multiple functional readouts in single study, but limited to one lab\",\n      \"pmids\": [\"10498612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A novel monoclonal antibody (ECM41) specific for KIR2DL3 was generated and used to show that KIR2DL3 and KIR2DL2 have distinct surface expression patterns and HLA-C specificities that were previously indistinguishable serologically. Simultaneous engagement of KIR2DL3 (inhibitory) and KIR2DS2 (activating) in NK cell clones co-expressing both receptors was functionally assessed using redirected killing assays.\",\n      \"method\": \"Monoclonal antibody generation, flow cytometry, redirected killing assays with NK cell clones\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — new specific reagent enabling discrimination of KIR2DL3 from KIR2DL2/S2, with functional validation in NK cell clones, single lab\",\n      \"pmids\": [\"15314042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Site-directed mutagenesis of KIR2DL3 demonstrated that glutamine at position 35 is required for ECM41 mAb staining, and glutamic acid 35 plus arginine 50 are required for staining by EB6B/11PB6 mAbs. KIR2DL3*005 allele bearing these residues showed HLA-C specificity comparable to other KIR2DL2/L3 alleles despite its unusual antibody reactivity pattern.\",\n      \"method\": \"Site-directed mutagenesis, flow cytometry with multiple mAbs, functional analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis identifying specific residues for antibody epitopes and functional validation, single lab\",\n      \"pmids\": [\"20525888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mutagenesis of six positively selected positions in the HLA class I binding site of KIR2DL3 showed that position 44 modulates specificity for HLA-C, positions 71 and 131 control cross-reactivity with HLA-A*11:02, and position 70 dominates avidity modulation (with lesser contributions from positions 68 and 182). KIR2DL3 has lower avidity and broader specificity than KIR2DL1, and unlike KIR2DL1 its avidity can be increased and specificity changed by mutation, demonstrating its greater adaptability.\",\n      \"method\": \"Site-directed mutagenesis generating 38 point mutants, binding assays to 95 HLA-A, -B, and -C allotypes\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — comprehensive mutagenesis of all six positively selected positions tested against broad HLA panel, multiple orthogonal functional readouts\",\n      \"pmids\": [\"22772445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KIR2DL3*005 allele binds HLA-C with significantly higher affinity and avidity than KIR2DL3*001, producing stronger inhibition of NK cell IFN-γ production. Site-directed mutagenesis established that the combination of arginine at residue 11 and glutamic acid at residue 35 (both distal to the KIR/HLA-C interface) is critical to this increased affinity, likely by altering the interdomain hinge angle toward that of KIR2DL2.\",\n      \"method\": \"Surface plasmon resonance, flow cytometry, site-directed mutagenesis, NK cell functional assay (IFN-γ)\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — SPR quantitative binding, mutagenesis of specific residues, and NK functional validation in single study with multiple orthogonal methods\",\n      \"pmids\": [\"23686481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HIV-1 mutation at p24 Gag position 303 (TGag303V) selected in individuals carrying both KIR2DL3 and HLA-C*03:04 enhanced KIR2DL3 binding to HLA-C*03:04-presenting cells and significantly reduced activation of primary KIR2DL3+ NK cells, demonstrating that peptide sequence variation within HLA-presented epitopes modulates KIR2DL3 inhibitory signaling and mediates viral immune escape.\",\n      \"method\": \"KIR2DL3 binding assay (flow cytometry with KIR2DL3-Fc fusion), primary NK cell activation assay, surface plasmon resonance, structural modeling\",\n      \"journal\": \"PLoS medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — SPR, direct binding assays, primary NK cell functional assay, and structural modeling as orthogonal methods in single cohort-based study\",\n      \"pmids\": [\"26575988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"An HCV core-derived peptide (YIPLVGAPL) bound to HLA-C*03:04 resulted in significantly higher KIR2DL3 binding and suppression of primary KIR2DL3+ NK cell function. Genotype-specific HCV peptide variants of this sequence showed lower HLA-C*03:04 stabilization, decreased KIR2DL3 binding, and lower NK cell inhibition, demonstrating sequence-dependent modulation of KIR2DL3 engagement by viral peptides.\",\n      \"method\": \"KIR2DL3-IgG fusion construct binding assay, HLA stabilization assay (722.221-HLA-C*03:04 transfectants), primary NK cell IFN-γ functional assay\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (binding assay, HLA stabilization, primary NK cell function) in single study, mechanistically defining peptide-dependent KIR2DL3 inhibitory signaling\",\n      \"pmids\": [\"27057987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HLA-B*46:01 carries the C1 epitope introduced by intergenic mini-conversion from HLA-C*01:02 and is recognized by KIR2DL3. High-resolution mass spectrometry showed that only a minority (21%) of HLA-B*46:01 peptides with specific C-terminal characteristics form ligands for KIR2DL3, demonstrating that peptide composition of the HLA peptidome determines KIR2DL3 ligand formation.\",\n      \"method\": \"High-resolution mass spectrometry peptidome analysis, KIR2DL3 binding assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mass spectrometry peptidome combined with KIR binding, single lab\",\n      \"pmids\": [\"28514659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIR2DL3-positive NK cells were more sensitive than KIR2DL2-positive NK cells to changes in the peptide content of MHC class I, with weakly inhibitory peptide VAPWNSRAL discriminating KIR2DL3 from KIR2DL2 donors. Mathematical modeling confirmed VAPWNSRAL dominance in distinguishing the two receptor populations, demonstrating peptide selectivity as a mechanistic basis for differential NK cell reactivity.\",\n      \"method\": \"Primary NK cell functional assays with defined peptide variants, mathematical modeling\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays with defined peptides in primary cells and mathematical modeling, single lab\",\n      \"pmids\": [\"25359276\"],\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 and KIR2DL3 differ in their docking geometry atop HLA-C*07:02. This structural plasticity correlates with differential recognition of HLA-C1 allotypes. Mutagenesis assays confirmed differences in the mechanism of HLA-C1 allotype recognition between KIR2DL2 and KIR2DL3, and primary NK cell inhibition by HLA-C1 allotypes differed markedly.\",\n      \"method\": \"X-ray crystallography of KIR2DL2/HLA-C*07:02 and KIR2DL3/HLA-C*07:02 complexes, mutagenesis assays, primary NK cell functional assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of both receptor complexes with functional mutagenesis and primary NK cell validation, multiple orthogonal methods\",\n      \"pmids\": [\"33846289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIR2DL3+NKG2A− NK cells were not inhibited by HLA-E ligation (unlike KIR2DL3−NKG2A+ NK cells), and this insensitivity to HLA-E-mediated inhibition was mechanistically linked to their ability to respond to HCV-infected cells. HLA-E upregulation in HCV-infected liver correlated with viral load and suppressed NK cell IFN-γ secretion specifically in NKG2A+ populations.\",\n      \"method\": \"Multicolor flow cytometry (phenotyping and functional assays), liver biopsy HLA-E expression analysis, primary NK cell IFN-γ assays\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional discrimination of KIR2DL3+NKG2A− vs KIR2DL3−NKG2A+ populations with mechanistic HLA-E inhibition assay, single lab\",\n      \"pmids\": [\"24780303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KIR2DL3 expressed on T lymphocytes during immune reconstitution after haploidentical HSCT showed a higher inhibitory effect on CMV-specific T cell responses against allogeneic than autologous C1+ target cells, demonstrating that KIR2DL3-HLA interactions modulate T cell immune responses in an allogeneic setting.\",\n      \"method\": \"Functional T cell assays, flow cytometry, in vitro KIR2DL3 inhibition of CMV-specific T cell responses against allogeneic vs. autologous C1+ targets\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay with defined allogeneic vs. autologous controls establishing KIR2DL3 inhibitory mechanism on T cells, single lab\",\n      \"pmids\": [\"34349169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Differential expression of KIR/NKAT2 (KIR2DL3) between NK cell subsets was documented: CD56dim peripheral blood NK cells express KIR/NKAT2 whereas CD56bright peripheral blood NK cells do not; however, both CD56bright and CD56dim decidual NK cell subsets express KIR/NKAT2 and CD94 in early pregnancy.\",\n      \"method\": \"Flow cytometry on peripheral blood and decidual tissue NK cells from pregnant and non-pregnant women\",\n      \"journal\": \"Fertility and sterility\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single flow cytometry study, no functional consequence directly tested for KIR2DL3 specifically\",\n      \"pmids\": [\"15019821\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIR2DL3 is an inhibitory NK cell receptor with two tandem Ig-like domains that dock onto HLA-C (and the exceptional HLA-B*46:01) via an acute interdomain elbow angle; its lower avidity and broader HLA-C specificity compared to the allotypically related KIR2DL2 are determined by residues distal to the binding site (positions 11, 16, 35, 148) that modulate the hinge angle between domains, while residues within the binding site (positions 44, 70, 71, 131) control specificity and avidity, and the precise peptide presented by HLA-C further tunes inhibitory signaling strength, enabling viral pathogens to escape KIR2DL3+ NK cell surveillance through mutations that enhance inhibitory receptor engagement.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIR2DL3 is an inhibitory NK cell receptor whose two tandem Ig-like domains dock onto HLA-C (C1-epitope) allotypes to dampen NK cell effector responses, and whose engagement is exquisitely tuned by both receptor polymorphism and the peptide presented by the HLA-C ligand [#0, #11]. Its extracellular region adopts an acute interdomain elbow angle (~23\\u00b0) that positions an HLA-C binding site spanning both domains, with the relative domain orientation itself shaping ligand binding [#0]. Specificity and avidity are partitioned across two classes of residues: positions within the binding site (44, 70, 71, 131) govern HLA specificity, cross-reactivity, and avidity [#5], whereas residues distal to the interface (11, 16, 35, 148) modulate the interdomain hinge angle and thereby set overall avidity\\u2014such that combining R16P+R148C, or R11+E35, raises KIR2DL3 affinity toward the stronger KIR2DL2-like state and increases inhibition of NK cell IFN-\\u03b3 production [#1, #6]. Compared with the allotypically related KIR2DL2 and with KIR2DL1, KIR2DL3 has lower avidity, broader HLA-C specificity, and greater mutational adaptability, and the two C1 receptors achieve distinct docking geometries on HLA-C that translate into differential allotype recognition [#5, #11]. Engagement is further controlled by the specific peptide loaded onto HLA-C: peptide identity tunes inhibitory signaling strength, and HLA-presented peptide composition determines whether a given complex forms a KIR2DL3 ligand, including the exceptional HLA-B*46:01 that acquired the C1 epitope by mini-conversion [#9, #10]. This peptide sensitivity provides a route for viral immune escape, as HIV-1 Gag and HCV core peptide variants that enhance KIR2DL3/HLA-C engagement suppress primary KIR2DL3+ NK cell activation [#7, #8]. Beyond NK cells, transgenic and reconstitution-setting studies show KIR2DL3 can also deliver activation-stage-dependent inhibitory signals to T cells [#2, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing the structural architecture of KIR2DL3 defined how a two-domain receptor presents its HLA-C binding surface, revealing that domain orientation is itself a tunable feature of ligand recognition.\",\n      \"evidence\": \"X-ray crystallography of the KIR2DL3 extracellular region with comparison to KIR2DL1\",\n      \"pmids\": [\"10196125\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-complex with HLA-C in this study\", \"Functional consequence of the acute elbow angle not directly tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating that transgenic KIR2DL3 inhibits T cell cytotoxicity established its inhibitory function beyond NK cells and revealed dependence on the activation stage of the responding T cell.\",\n      \"evidence\": \"Tg-KIR2DL3 \\u00d7 Tg-HLA-Cw3 mouse model, MLR, and anti-CD3-redirected killing assays\",\n      \"pmids\": [\"10498612\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab transgenic system\", \"Mechanism of activation-stage dependence unresolved\", \"Human T cell relevance not addressed here\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Generating a KIR2DL3-specific antibody enabled discrimination of KIR2DL3 from serologically indistinguishable KIR2DL2/S2, allowing receptor-resolved analysis of surface expression and signaling.\",\n      \"evidence\": \"Monoclonal antibody (ECM41) generation, flow cytometry, and redirected killing in NK cell clones\",\n      \"pmids\": [\"15314042\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reagent specificity defined functionally but epitope not yet mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapping the avidity difference between KIR2DL2 and KIR2DL3 to distal residues showed that ligand strength is encoded outside the binding site through interdomain hinge geometry.\",\n      \"evidence\": \"Site-directed mutagenesis (R16P, R148C) with functional binding across 93 HLA allotypes\",\n      \"pmids\": [\"18322206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hinge-angle change inferred, not structurally resolved here\", \"Synergy mechanism between the two positions not visualized\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defining the residues controlling antibody reactivity clarified that unusual mAb staining of KIR2DL3*005 does not reflect altered HLA-C specificity, separating epitope variation from ligand function.\",\n      \"evidence\": \"Site-directed mutagenesis of positions 35/50 with multi-mAb flow cytometry and functional analysis\",\n      \"pmids\": [\"20525888\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional impact of residue 35 on ligand binding addressed only later\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Comprehensive mutagenesis of positively selected binding-site residues partitioned specificity, cross-reactivity, and avidity across discrete positions and established KIR2DL3 as more adaptable than KIR2DL1.\",\n      \"evidence\": \"38 point mutants assayed for binding against 95 HLA-A/-B/-C allotypes\",\n      \"pmids\": [\"22772445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of each residue contribution not directly visualized\", \"Effect on downstream NK signaling not quantified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linking the distal residues 11 and 35 to higher KIR2DL3*005 affinity connected hinge-angle modulation to a measurable increase in NK cell inhibition.\",\n      \"evidence\": \"Surface plasmon resonance, mutagenesis, and primary NK cell IFN-\\u03b3 functional assay\",\n      \"pmids\": [\"23686481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hinge-angle change inferred rather than crystallographically confirmed\", \"Allele-frequency/clinical consequence not assessed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing KIR2DL3+ NK cells are more peptide-sensitive than KIR2DL2+ cells established HLA-bound peptide selectivity as a basis for differential receptor reactivity.\",\n      \"evidence\": \"Primary NK cell functional assays with defined peptide variants and mathematical modeling\",\n      \"pmids\": [\"25359276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited peptide panel\", \"Structural basis of peptide discrimination not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Distinguishing KIR2DL3+NKG2A\\u2212 from NKG2A+ NK cells in HCV infection linked receptor-defined subset identity to differential susceptibility to HLA-E-mediated inhibition and antiviral response.\",\n      \"evidence\": \"Multicolor flow cytometry, liver HLA-E expression analysis, and primary NK cell IFN-\\u03b3 assays\",\n      \"pmids\": [\"24780303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative subset analysis\", \"Direct causal role of KIR2DL3 vs. NKG2A absence not isolated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying an HIV-1 Gag escape mutation that strengthens KIR2DL3/HLA-C engagement demonstrated peptide-driven viral immune evasion through enhanced inhibitory receptor signaling.\",\n      \"evidence\": \"KIR2DL3-Fc binding, primary NK cell activation assay, SPR, and structural modeling in a genotyped cohort\",\n      \"pmids\": [\"26575988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo NK-mediated selection pressure inferred from cohort association\", \"Structural model not experimentally resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating that an HCV core peptide variant alters HLA-C stabilization and KIR2DL3 binding extended peptide-dependent immune escape to a second virus and tied epitope sequence to NK inhibition strength.\",\n      \"evidence\": \"KIR2DL3-IgG binding, HLA-C*03:04 stabilization assay, and primary NK cell IFN-\\u03b3 functional assay\",\n      \"pmids\": [\"27057987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural complex of the variant peptide\", \"In vivo selection not directly demonstrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showing that HLA-B*46:01 acquired the C1 epitope and serves as a KIR2DL3 ligand for only a peptidome subset established that HLA peptide composition determines ligand formation beyond canonical HLA-C.\",\n      \"evidence\": \"High-resolution mass spectrometry peptidome analysis with KIR2DL3 binding assays\",\n      \"pmids\": [\"28514659\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional NK consequence of HLA-B*46:01 recognition not quantified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Co-crystal structures of KIR2DL2 and KIR2DL3 with HLA-C*07:02 revealed distinct docking geometries, providing the structural basis for differential HLA-C1 allotype recognition by the two C1 receptors.\",\n      \"evidence\": \"X-ray crystallography of both receptor/HLA-C*07:02 complexes with mutagenesis and primary NK cell functional assays\",\n      \"pmids\": [\"33846289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single HLA-C allotype crystallized\", \"Link between docking geometry and signaling magnitude not fully quantified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating KIR2DL3 inhibition of CMV-specific T cell responses preferentially against allogeneic C1+ targets extended its inhibitory role to post-transplant T cell immunity.\",\n      \"evidence\": \"In vitro functional T cell assays comparing allogeneic vs. autologous C1+ targets after haploidentical HSCT\",\n      \"pmids\": [\"34349169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Clinical outcome correlation not established\", \"Single-lab in vitro setting\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How peptide-encoded differences in KIR2DL3 engagement quantitatively translate into NK/T cell activation thresholds in vivo, and whether they shape disease and transplant outcomes, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of peptide-variant complexes resolved at atomic resolution\", \"Causal in vivo selection of escape variants by KIR2DL3+ NK cells not directly demonstrated\", \"Clinical consequences of receptor polymorphism not established in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 6, 7, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 6, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 7, 8, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HLA-C\", \"HLA-B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}