{"gene":"KIR2DL2","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1999,"finding":"Crystal structure of KIR2DL2 extracellular ligand-binding domains determined at 2.9–3.0 Å resolution, revealing K-type Ig topology with cis-proline residues in both domains, a hinge angle of ~80° (14° larger than KIR2DL1), and a putative ligand-binding site formed by variable loop residues with charge distribution complementary to HLA-C.","method":"X-ray crystallography (orthorhombic and trigonal crystal forms)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — crystal structures in two independent crystal forms, foundational structural paper","pmids":["10097129"],"is_preprint":false},{"year":2008,"finding":"KIR2DL2 binds all C1 HLA-C allotypes and also cross-reacts with several C2 allotypes (e.g., Cw*0501, Cw*0202) and two HLA-B allotypes (B*4601, B*7301); it is a stronger receptor than KIR2DL3. Site-directed mutagenesis showed that the combination of arginine at position 16 (D1) and cysteine at position 148 (D2) — residues near the flexible D1–D2 hinge — is required for the higher avidity of KIR2DL2 over KIR2DL3, suggesting these polymorphisms alter the interdomain hinge angle and ligand-binding site orientation.","method":"Binding assays to 93 HLA isoforms, site-directed mutagenesis of recombinant KIR extracellular domains, functional analysis","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding assays combined with site-directed mutagenesis, multiple orthogonal methods","pmids":["18322206"],"is_preprint":false},{"year":2002,"finding":"KIR2DL2 inhibits CD28-mediated natural cytotoxicity in a p56(lck)-independent manner. Upon HLA-Cw3 engagement, KIR2DL2 undergoes phosphorylation, recruits SHP1/SHP2, and reduces CD28-induced tyrosine phosphorylation of PLC-γ1, indicating that PLC-γ1 dephosphorylation mediates KIR2DL2's inhibitory signal.","method":"Transfection of p56(lck)-negative YT-Indy cells with KIR2DL2, pervanadate-stimulated phosphorylation assays, co-immunoprecipitation of SHP1/SHP2, cytotoxicity assays with blocking antibodies, PLC-γ1 phosphorylation analysis","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1 — reconstitution in transfected cells, multiple biochemical readouts, mechanistic mutagenesis-level clarity","pmids":["11750651"],"is_preprint":false},{"year":2021,"finding":"Crystal structures of KIR2DL2 and KIR2DL3 in complex with HLA-C*07:02 reveal that KIR2DL2 adopts a different docking modality over HLA-C*07:02 compared to KIR2DL3. Mutagenesis confirmed differences in the mechanism of HLA-C1 allotype recognition, and KIR2DL2's binding geometry combines with KIR2DS2 activity to distinguish functional HLA-C1 recognition.","method":"X-ray crystallography of KIR/HLA complexes, site-directed mutagenesis, primary NK cell activation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — crystal structures with mutagenesis validation and functional NK cell assays, multiple orthogonal methods","pmids":["33846289"],"is_preprint":false},{"year":2013,"finding":"KIR2DL3*005, a KIR2DL3 allele bearing arginine at residue 11 and glutamic acid at residue 35, binds HLA-C with affinity and avidity comparable to KIR2DL2*001. Site-directed mutagenesis established that the combination of these two residues (distal to the KIR/HLA-C interface) is critical, likely by altering the interdomain hinge angle toward that of KIR2DL2*001.","method":"Surface plasmon resonance, KIR binding to HLA panel, flow cytometry, site-directed mutagenesis, molecular modeling, IFN-γ inhibition assay in KHYG-1 NK cells","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1 — SPR binding assay, mutagenesis, and functional NK cell assays in one study","pmids":["23686481"],"is_preprint":false},{"year":2012,"finding":"HIV-1 p24 Gag peptide Gag209-218 (AAEWDRLHPV) presented by HLA-Cw*0102 allows binding of KIR2DL2 and leads to significant inhibition of KIR2DL2+ primary NK cells; sequence variations at position 7 of this epitope modulate KIR2DL2 binding, identifying a peptide-dependent mechanism by which HIV-1 could escape NK cell surveillance.","method":"KIR2DL2-IgG fusion protein binding assays, flow cytometry-based HLA stabilization assay, NK cell degranulation assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (binding assay + functional NK degranulation), replicated concept across multiple peptide variants","pmids":["22807681"],"is_preprint":false},{"year":2013,"finding":"KIR2DL2+ NK cells recognize a broader spectrum of HLA-C allotypes (both C1 and C2) than KIR2DL1+ NK cells. When KIR2DL2 and KIR2DS2 are co-expressed, KIR2DL2-mediated inhibition overrides KIR2DS2-mediated activation, demonstrating a dominant inhibitory function of KIR2DL2 in the KIR2D repertoire.","method":"NK cell reactivity assays against HLA-C+ target cells, NK cell clone analysis, KIR co-expression functional assays","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 — clean functional dissection across large cohort and NK clones with multiple orthogonal readouts","pmids":["24078689"],"is_preprint":false},{"year":2004,"finding":"KIR2DL2 and KIR2DL3 can be distinguished at the serological and functional levels using novel mAb ECM41 (KIR2DL3-specific) in combination with GL183 (cross-reactive). NK cell clones expressing KIR2DL3 or KIR2DL2 (previously serologically indistinguishable) were shown to differ in HLA class I specificity. Simultaneous engagement of KIR2DL3 and KIR2DS2 in co-expressing NK clones was analyzed in redirected killing assays.","method":"Generation of KIR2DL3-specific monoclonal antibody ECM41, cell transfectants, flow cytometry, NK clone redirected killing assays","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 — new KIR2DL3-specific reagent enabling functional dissection, single lab","pmids":["15314042"],"is_preprint":false},{"year":2014,"finding":"HLA-C*03:04-restricted HIV-1 p24 Gag epitopes Gag144-152, Gag163-171, and Gag295-304 enable KIR2DL2 binding to HLA-C*03:04 and inhibit KIR2DL2+ primary NK cells; naturally occurring minor variants of Gag295-304 enhance KIR2DL2 binding, showing that peptide sequence variations modulate inhibitory KIR engagement.","method":"KIR2DL2-Fc construct binding assays, HLA stabilization assays, NK cell degranulation assays","journal":"AIDS (London, England)","confidence":"Medium","confidence_rationale":"Tier 2 — binding assay + functional NK degranulation, single lab, moderate evidence","pmids":["24785948"],"is_preprint":false},{"year":2016,"finding":"KIR2DL2+ NK cells suppress HIV-1 replication in HLA-C*14:03+ or HLA-C*12:02+ cells more effectively than KIR2DL2- NK cells. The mechanism involves reduced expression of peptide-HLA complexes on the cell surface (reduced KIR2DL2 ligand availability) rather than altered KIR2DL2 binding affinity to pHLA.","method":"In vitro viral suppression assays, KIR2DL2+ vs KIR2DL2- NK cell functional comparison, binding affinity measurements","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — functional in vitro assays distinguishing two mechanistic models (ligand availability vs. binding affinity), single lab","pmids":["27880898"],"is_preprint":false},{"year":2016,"finding":"KIR2DL2/L3 alleles with glutamic acid at position 35 (E35) are functionally stronger (greater NK cell cytotoxicity and licensing) than those with glutamine at the same position (Q35). Molecular modeling indicates E35 interacts with histidine at position 55, stabilizing the KIR2DL2/L3 dimer and reducing entropy loss upon HLA-C ligand binding.","method":"NK cell cytotoxicity assays, molecular modeling","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2+3 — functional cytotoxicity assay with allelic dissection, modeling without structural validation","pmids":["27030405"],"is_preprint":false},{"year":2014,"finding":"KIR2DL2+ NK cells are less sensitive to changes in the peptide content of HLA-C class I than KIR2DL3+ NK cells. Specifically, KIR2DL3+ NK cells are more readily activated by weak inhibitory (VAPWNSRAL) and antagonist (VAPWNSDAL) peptides, indicating that stronger KIR2DL2 avidity for HLA-C/peptide complexes reduces NK cell sensitivity to peptide repertoire variation.","method":"NK cell degranulation assays with defined inhibitory, weak inhibitory, and antagonist peptides; mathematical modeling","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — clean functional dissection with defined peptides, multiple donor comparisons, mathematical modeling","pmids":["25359276"],"is_preprint":false},{"year":2018,"finding":"Decitabine (a DNA methyltransferase inhibitor) upregulates KIR2DL2/3 expression in KIR2DL2/3-negative γδ T cells by inhibiting KIR2DL2/3 promoter methylation, which enhances Sp-1 binding to the KIR2DL2/3 promoter and activates gene expression, resulting in reduced cytotoxicity of these cells.","method":"Flow cytometry, promoter methylation analysis, Sp-1 binding assay, cytotoxicity assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (methylation, transcription factor binding, functional cytotoxicity), single lab","pmids":["29632540"],"is_preprint":false},{"year":2025,"finding":"Crystal structure of KIR2DL2 in complex with HLA-B*73:01 (a non-HLA-C ligand) reveals differences in the binding interface compared to previously solved KIR2DL2/HLA-C complex structures. Mass spectrometry-based immunopeptidome profiling of HIV-1-infected cells and KIR2DL2-HLA-C*12:02-peptide crystal structures demonstrate the molecular basis for KIR2DL2 recognition of escape mutant epitopes selected by CD8+ T cells.","method":"X-ray crystallography (KIR2DL2/HLA-C*12:02-peptide and KIR2DL2/HLA-B*73:01), mass spectrometry immunopeptidomics, NK cell functional assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — crystal structures with MS immunopeptidomics and functional NK assays, multiple orthogonal methods","pmids":["41198628"],"is_preprint":false},{"year":2024,"finding":"Crystal structure of KIR2DL2 in complex with HLA-B*73:01 reveals that KIR2DL2 engages this non-HLA-C molecule with differences from previously solved HLA-C complexes, providing structural evidence that KIR2DL2 can recognize HLA-B allotypes in addition to HLA-C.","method":"X-ray crystallography","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure of KIR2DL2/HLA-B*73:01 complex","pmids":["40749828"],"is_preprint":false},{"year":2012,"finding":"In multiple sclerosis patients, CpG treatment caused NK cells to upregulate KIR2DL2 and show decreased degranulation and cytotoxicity in response to HSV-1 infection. Direct CpG treatment of purified NK cells reproduced KIR2DL2 upregulation, indicating a cell-autonomous mechanism linking TLR9 pathway activation to increased inhibitory KIR2DL2 expression and impaired NK cell function.","method":"In vitro viral infection assays, cytokine secretion, NK cell activation and degranulation assays, KIR expression measurement by flow cytometry on purified NK cells","journal":"Journal of neuroimmunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct NK cell CpG treatment linking TLR9 activation to KIR2DL2 upregulation and functional impairment, single lab","pmids":["22871633"],"is_preprint":false},{"year":2016,"finding":"MS patients with KIR2DL2+ NK cells that fail to control HSV-1 infection produce high levels of Th17 cytokines (rather than IFN-γ), while KIR2DL2- NK cells from MS patients release Th1 cytokines (IFN-γ). This demonstrates that KIR2DL2 inhibitory signaling skews NK cell cytokine secretion toward a Th17 profile during herpesvirus infection.","method":"In vitro HSV-1 infection assays, cytokine secretion analysis by flow cytometry/ELISA in KIR2DL2+ vs. KIR2DL2- NK cell subsets","journal":"Journal of neuroimmunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional comparison of KIR2DL2+ vs KIR2DL2- NK cells with defined viral challenge, single lab","pmids":["27138091"],"is_preprint":false},{"year":2019,"finding":"Lassa virus (LASV) NP and GP-derived peptides presented by HLA-C molecules (but not HLA-B or HLA-A) strongly inhibit degranulation of KIR2DL2+ NK cells. A specific variant of glycoprotein epitope vGP420 significantly increases this inhibitory effect, suggesting LASV exploits the HLA-C/KIR2DL2 axis to escape NK cell killing.","method":"In silico peptide screening, peptide-HLA stabilization assays, KIR2DL2 binding assays, NK cell degranulation polyfunction assays","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 — binding assays and functional NK degranulation assays, moderate evidence from single study","pmids":["30711514"],"is_preprint":false},{"year":2021,"finding":"HIV-1 clade C avoids acquiring a p24 Gag mutation that would abolish KIR2DL2 binding to HLA-C*03:04, demonstrating in vivo selection pressure to maintain KIR2DL2-mediated NK inhibition in individuals with the KIR2DL2+/HLA-C*03:04+ genotype.","method":"HIV-1 sequence analysis in KIR2DL2+/HLA-C*03:04+ individuals, KIR2DL2-Fc binding assays, NK cell disinhibition assays","journal":"AIDS (London, England)","confidence":"Medium","confidence_rationale":"Tier 2 — binding assays and NK cell functional assays combined with in vivo sequence data, single lab","pmids":["33273184"],"is_preprint":false}],"current_model":"KIR2DL2 is an inhibitory Ig-superfamily receptor on NK cells whose extracellular D1–D2 domains bind HLA-C (both C1 and C2 group allotypes, with broader specificity than KIR2DL1), as well as select HLA-B allotypes; upon ligand engagement it undergoes phosphorylation and recruits SHP1/SHP2, leading to dephosphorylation of PLC-γ1 and inhibition of NK cytotoxicity independently of p56(lck); the interdomain hinge angle determined by residues at positions 16 and 148 (and allele-specific contacts at positions 11, 35) modulates ligand-binding avidity; peptide cargo presented by HLA-C fine-tunes KIR2DL2 binding strength, enabling viral pathogens to evade NK killing by selecting epitopes that increase inhibitory KIR engagement; and KIR2DL2 inhibition dominates over co-expressed activating KIR2DS2 on the same NK cell."},"narrative":{"teleology":[{"year":1999,"claim":"Determining the three-dimensional structure of the KIR2DL2 extracellular domains established the K-type Ig fold topology, a distinctive ~80° interdomain hinge angle, and a putative ligand-binding site with charge complementarity to HLA-C, providing the first atomic framework for understanding inhibitory KIR recognition.","evidence":"X-ray crystallography of KIR2DL2 D1–D2 in two independent crystal forms at 2.9–3.0 Å","pmids":["10097129"],"confidence":"High","gaps":["No complex structure with HLA-C ligand at this stage","Role of individual residues in ligand contact not yet tested by mutagenesis"]},{"year":2002,"claim":"Reconstitution of KIR2DL2 signaling in lck-negative cells demonstrated that ligand engagement triggers receptor phosphorylation, SHP-1/SHP-2 recruitment, and PLCγ1 dephosphorylation, establishing the proximal inhibitory signaling cascade independently of Src-family kinase p56(lck).","evidence":"Transfection of KIR2DL2 into p56(lck)-negative YT-Indy cells; pervanadate-stimulated phosphorylation, co-immunoprecipitation of SHP-1/SHP-2, cytotoxicity and PLCγ1 phosphorylation assays","pmids":["11750651"],"confidence":"High","gaps":["Identity of the kinase that phosphorylates KIR2DL2 ITIMs in the absence of lck remains undefined","Downstream substrates beyond PLCγ1 not characterized"]},{"year":2008,"claim":"Systematic binding analysis across 93 HLA isoforms revealed that KIR2DL2 recognizes all C1-group and several C2-group HLA-C allotypes plus HLA-B*4601 and HLA-B*7301, and site-directed mutagenesis pinpointed residues Arg16 and Cys148 near the interdomain hinge as determinants of higher avidity relative to KIR2DL3.","evidence":"Recombinant KIR extracellular domain binding assays to 93 HLA isoforms; site-directed mutagenesis of positions 16 and 148","pmids":["18322206"],"confidence":"High","gaps":["Structural basis for cross-reactivity with HLA-B allotypes not resolved","How hinge angle change translates to altered binding kinetics not quantified by SPR in this study"]},{"year":2012,"claim":"Discovery that HLA-C-presented HIV-1 Gag peptides modulate KIR2DL2 binding and NK cell inhibition established a peptide-dependent mechanism of viral immune evasion, showing that the peptide cargo is not merely a passenger but an active determinant of inhibitory KIR engagement.","evidence":"KIR2DL2-Fc binding assays, HLA stabilization assays, and primary NK cell degranulation assays with variant Gag peptides","pmids":["22807681"],"confidence":"High","gaps":["Structural basis for peptide discrimination not yet determined at atomic resolution","In vivo selection pressure on viral peptides not demonstrated"]},{"year":2013,"claim":"Functional and mutagenesis studies showed that allele-specific residues at positions 11 and 35 (distal to the HLA-C contact surface) modulate KIR2DL2/L3 binding avidity by altering the interdomain hinge angle, and that KIR2DL2-mediated inhibition dominates over co-expressed KIR2DS2 activation, establishing KIR2DL2 as the functionally dominant receptor in NK cells bearing both.","evidence":"SPR binding, flow cytometry, mutagenesis, IFN-γ inhibition in KHYG-1 cells; NK clone reactivity assays across HLA-C panels","pmids":["23686481","24078689"],"confidence":"High","gaps":["Crystal structure confirming hinge angle change from positions 11/35 not available at this time","Mechanism by which inhibitory signal overrides activating KIR2DS2 at the signalosome level is undefined"]},{"year":2014,"claim":"Extending the peptide-dependent evasion paradigm, additional HIV-1 Gag epitopes presented by HLA-C*03:04 were shown to promote KIR2DL2 binding and NK inhibition, and KIR2DL2+ NK cells were found to be less sensitive than KIR2DL3+ cells to peptide repertoire changes owing to their higher avidity, linking receptor strength to functional tuning of peptide discrimination.","evidence":"KIR2DL2-Fc binding and NK degranulation assays with defined peptides; mathematical modeling of inhibitory thresholds","pmids":["24785948","25359276"],"confidence":"Medium","gaps":["Whether higher avidity uniformly reduces sensitivity to all peptide variants or is context-dependent remains untested","No in vivo data confirming differential peptide sensitivity between KIR2DL2 and KIR2DL3"]},{"year":2016,"claim":"Position-35 polymorphism (E35 vs Q35) was shown to modulate NK cytotoxicity and licensing strength, and KIR2DL2 expression was linked to skewing of NK cytokine secretion toward a Th17 profile during herpesvirus infection, expanding the functional consequences of KIR2DL2 signaling beyond degranulation.","evidence":"NK cytotoxicity assays with allelic dissection and molecular modeling; in vitro HSV-1 infection with cytokine profiling of KIR2DL2+ vs KIR2DL2− NK subsets","pmids":["27030405","27138091"],"confidence":"Medium","gaps":["E35-H55 interaction predicted by modeling lacks crystallographic validation","Th17 skewing mechanism downstream of ITIM signaling is uncharacterized"]},{"year":2018,"claim":"Demonstration that decitabine upregulates KIR2DL2/3 transcription by demethylating the promoter and enabling Sp-1 binding revealed an epigenetic mechanism controlling KIR2DL2 expression and consequent inhibition of γδ T cell cytotoxicity.","evidence":"Flow cytometry, promoter methylation analysis, Sp-1 binding assay, and cytotoxicity assays in γδ T cells treated with decitabine","pmids":["29632540"],"confidence":"Medium","gaps":["Whether this epigenetic regulation operates identically in conventional NK cells is untested","Chromatin accessibility or histone modification data not provided"]},{"year":2019,"claim":"Lassa virus-derived peptides presented by HLA-C were shown to strongly inhibit KIR2DL2+ NK degranulation, extending the peptide-dependent evasion mechanism beyond HIV-1 and indicating it is a general viral strategy exploiting the HLA-C/KIR2DL2 axis.","evidence":"Peptide-HLA stabilization, KIR2DL2 binding, and NK polyfunction degranulation assays with LASV NP and GP peptides","pmids":["30711514"],"confidence":"Medium","gaps":["No crystal structure of KIR2DL2 with LASV peptide-HLA complex","In vivo relevance in Lassa fever patients not examined"]},{"year":2021,"claim":"Crystal structures of KIR2DL2 and KIR2DL3 bound to HLA-C*07:02 revealed distinct docking modalities, explaining their differential recognition of C1 allotypes at atomic resolution, and in vivo HIV-1 sequence data showed that clade C virus avoids mutations that would abolish KIR2DL2 binding, confirming peptide-dependent NK evasion under physiological selection pressure.","evidence":"X-ray crystallography of KIR2DL2/HLA-C*07:02 complex with mutagenesis and primary NK assays; HIV-1 clade C sequence analysis combined with KIR2DL2-Fc binding and disinhibition assays","pmids":["33846289","33273184"],"confidence":"High","gaps":["Full energetic decomposition of docking modality differences not performed","Whether KIR2DL2 docking differences extend to all C1 allotypes or are HLA-C*07:02-specific is not resolved"]},{"year":2025,"claim":"Crystal structures of KIR2DL2 with HLA-B*73:01 and with HLA-C*12:02 presenting HIV-derived escape-mutant peptides provided the structural basis for KIR2DL2 cross-reactivity with non-HLA-C ligands and for peptide-dependent modulation of inhibitory engagement, unifying the molecular mechanism of viral immune evasion at atomic resolution.","evidence":"X-ray crystallography of KIR2DL2/HLA-B*73:01 and KIR2DL2/HLA-C*12:02-peptide complexes; mass spectrometry immunopeptidomics of HIV-1-infected cells; NK functional assays","pmids":["41198628","40749828"],"confidence":"High","gaps":["Whether KIR2DL2 engages other HLA-B allotypes (e.g., B*46:01) with the same docking mode is untested","Immunopeptidome data are from cell lines and may not fully recapitulate in vivo peptide presentation"]},{"year":null,"claim":"Key unresolved questions include the identity of the kinase(s) that phosphorylate KIR2DL2 ITIMs, the structural basis for dominance of KIR2DL2 inhibition over KIR2DS2 activation at the signalosome level, and whether peptide-dependent evasion by non-HIV/non-LASV viruses and tumors is a general phenomenon.","evidence":"","pmids":[],"confidence":"Low","gaps":["ITIM kinase identity unknown","Signalosome-level mechanism of inhibitory dominance over KIR2DS2 not resolved","Breadth of peptide-dependent evasion across diverse pathogens and cancer untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,6]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,6,7]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,5,6,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,6]}],"complexes":[],"partners":["PTPN6","PTPN11","PLCG1","HLA-C","KIR2DS2"],"other_free_text":[]},"mechanistic_narrative":"KIR2DL2 is an inhibitory killer-cell immunoglobulin-like receptor on NK cells that suppresses cytotoxicity upon engagement of HLA class I ligands, functioning as a key checkpoint in innate immune surveillance of virally infected and transformed cells. Its extracellular D1–D2 domains adopt a K-type Ig fold with a characteristic ~80° interdomain hinge angle; polymorphic residues at positions 16, 148, 11, and 35 tune this hinge geometry and confer higher binding avidity than the related KIR2DL3, enabling recognition of all C1-group HLA-C allotypes plus cross-reactivity with several C2-group HLA-C and HLA-B allotypes [PMID:10097129, PMID:18322206, PMID:23686481, PMID:40749828]. Upon HLA-C engagement, KIR2DL2 is phosphorylated and recruits SHP-1/SHP-2, leading to dephosphorylation of PLCγ1 and suppression of NK cell activation independently of p56(lck); this inhibition dominates over co-expressed activating KIR2DS2 on the same cell [PMID:11750651, PMID:24078689]. The peptide cargo presented by HLA-C fine-tunes KIR2DL2 binding strength, and HIV-1 and Lassa virus exploit this peptide-dependent recognition to select epitopes that enhance inhibitory KIR2DL2 engagement and evade NK cell killing [PMID:22807681, PMID:30711514, PMID:41198628]."},"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":"15086570","id":"PMC_15086570","title":"CD158k/KIR3DL2 is a new phenotypic marker of Sezary cells: relevance for the diagnosis and follow-up of Sezary syndrome.","date":"2004","source":"The Journal of investigative 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malaria","date":"2025-08-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.18.670802","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44506,"output_tokens":5147,"usd":0.105361},"stage2":{"model":"claude-opus-4-6","input_tokens":8675,"output_tokens":3465,"usd":0.195},"total_usd":0.300361,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Crystal structure of KIR2DL2 extracellular ligand-binding domains determined at 2.9–3.0 Å resolution, revealing K-type Ig topology with cis-proline residues in both domains, a hinge angle of ~80° (14° larger than KIR2DL1), and a putative ligand-binding site formed by variable loop residues with charge distribution complementary to HLA-C.\",\n      \"method\": \"X-ray crystallography (orthorhombic and trigonal crystal forms)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures in two independent crystal forms, foundational structural paper\",\n      \"pmids\": [\"10097129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KIR2DL2 binds all C1 HLA-C allotypes and also cross-reacts with several C2 allotypes (e.g., Cw*0501, Cw*0202) and two HLA-B allotypes (B*4601, B*7301); it is a stronger receptor than KIR2DL3. Site-directed mutagenesis showed that the combination of arginine at position 16 (D1) and cysteine at position 148 (D2) — residues near the flexible D1–D2 hinge — is required for the higher avidity of KIR2DL2 over KIR2DL3, suggesting these polymorphisms alter the interdomain hinge angle and ligand-binding site orientation.\",\n      \"method\": \"Binding assays to 93 HLA isoforms, site-directed mutagenesis of recombinant KIR extracellular domains, functional analysis\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding assays combined with site-directed mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"18322206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"KIR2DL2 inhibits CD28-mediated natural cytotoxicity in a p56(lck)-independent manner. Upon HLA-Cw3 engagement, KIR2DL2 undergoes phosphorylation, recruits SHP1/SHP2, and reduces CD28-induced tyrosine phosphorylation of PLC-γ1, indicating that PLC-γ1 dephosphorylation mediates KIR2DL2's inhibitory signal.\",\n      \"method\": \"Transfection of p56(lck)-negative YT-Indy cells with KIR2DL2, pervanadate-stimulated phosphorylation assays, co-immunoprecipitation of SHP1/SHP2, cytotoxicity assays with blocking antibodies, PLC-γ1 phosphorylation analysis\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in transfected cells, multiple biochemical readouts, mechanistic mutagenesis-level clarity\",\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 reveal that KIR2DL2 adopts a different docking modality over HLA-C*07:02 compared to KIR2DL3. Mutagenesis confirmed differences in the mechanism of HLA-C1 allotype recognition, and KIR2DL2's binding geometry combines with KIR2DS2 activity to distinguish functional HLA-C1 recognition.\",\n      \"method\": \"X-ray crystallography of KIR/HLA complexes, site-directed mutagenesis, primary NK cell activation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with mutagenesis validation and functional NK cell assays, multiple orthogonal methods\",\n      \"pmids\": [\"33846289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KIR2DL3*005, a KIR2DL3 allele bearing arginine at residue 11 and glutamic acid at residue 35, binds HLA-C with affinity and avidity comparable to KIR2DL2*001. Site-directed mutagenesis established that the combination of these two residues (distal to the KIR/HLA-C interface) is critical, likely by altering the interdomain hinge angle toward that of KIR2DL2*001.\",\n      \"method\": \"Surface plasmon resonance, KIR binding to HLA panel, flow cytometry, site-directed mutagenesis, molecular modeling, IFN-γ inhibition assay in KHYG-1 NK cells\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — SPR binding assay, mutagenesis, and functional NK cell assays in one study\",\n      \"pmids\": [\"23686481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HIV-1 p24 Gag peptide Gag209-218 (AAEWDRLHPV) presented by HLA-Cw*0102 allows binding of KIR2DL2 and leads to significant inhibition of KIR2DL2+ primary NK cells; sequence variations at position 7 of this epitope modulate KIR2DL2 binding, identifying a peptide-dependent mechanism by which HIV-1 could escape NK cell surveillance.\",\n      \"method\": \"KIR2DL2-IgG fusion protein binding assays, flow cytometry-based HLA stabilization assay, NK cell degranulation assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (binding assay + functional NK degranulation), replicated concept across multiple peptide variants\",\n      \"pmids\": [\"22807681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KIR2DL2+ NK cells recognize a broader spectrum of HLA-C allotypes (both C1 and C2) than KIR2DL1+ NK cells. When KIR2DL2 and KIR2DS2 are co-expressed, KIR2DL2-mediated inhibition overrides KIR2DS2-mediated activation, demonstrating a dominant inhibitory function of KIR2DL2 in the KIR2D repertoire.\",\n      \"method\": \"NK cell reactivity assays against HLA-C+ target cells, NK cell clone analysis, KIR co-expression functional assays\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean functional dissection across large cohort and NK clones with multiple orthogonal readouts\",\n      \"pmids\": [\"24078689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KIR2DL2 and KIR2DL3 can be distinguished at the serological and functional levels using novel mAb ECM41 (KIR2DL3-specific) in combination with GL183 (cross-reactive). NK cell clones expressing KIR2DL3 or KIR2DL2 (previously serologically indistinguishable) were shown to differ in HLA class I specificity. Simultaneous engagement of KIR2DL3 and KIR2DS2 in co-expressing NK clones was analyzed in redirected killing assays.\",\n      \"method\": \"Generation of KIR2DL3-specific monoclonal antibody ECM41, cell transfectants, flow cytometry, NK clone redirected killing assays\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — new KIR2DL3-specific reagent enabling functional dissection, single lab\",\n      \"pmids\": [\"15314042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HLA-C*03:04-restricted HIV-1 p24 Gag epitopes Gag144-152, Gag163-171, and Gag295-304 enable KIR2DL2 binding to HLA-C*03:04 and inhibit KIR2DL2+ primary NK cells; naturally occurring minor variants of Gag295-304 enhance KIR2DL2 binding, showing that peptide sequence variations modulate inhibitory KIR engagement.\",\n      \"method\": \"KIR2DL2-Fc construct binding assays, HLA stabilization assays, NK cell degranulation assays\",\n      \"journal\": \"AIDS (London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding assay + functional NK degranulation, single lab, moderate evidence\",\n      \"pmids\": [\"24785948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIR2DL2+ NK cells suppress HIV-1 replication in HLA-C*14:03+ or HLA-C*12:02+ cells more effectively than KIR2DL2- NK cells. The mechanism involves reduced expression of peptide-HLA complexes on the cell surface (reduced KIR2DL2 ligand availability) rather than altered KIR2DL2 binding affinity to pHLA.\",\n      \"method\": \"In vitro viral suppression assays, KIR2DL2+ vs KIR2DL2- NK cell functional comparison, binding affinity measurements\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional in vitro assays distinguishing two mechanistic models (ligand availability vs. binding affinity), single lab\",\n      \"pmids\": [\"27880898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIR2DL2/L3 alleles with glutamic acid at position 35 (E35) are functionally stronger (greater NK cell cytotoxicity and licensing) than those with glutamine at the same position (Q35). Molecular modeling indicates E35 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 assays, molecular modeling\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2+3 — functional cytotoxicity assay with allelic dissection, modeling without structural validation\",\n      \"pmids\": [\"27030405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIR2DL2+ NK cells are less sensitive to changes in the peptide content of HLA-C class I than KIR2DL3+ NK cells. Specifically, KIR2DL3+ NK cells are more readily activated by weak inhibitory (VAPWNSRAL) and antagonist (VAPWNSDAL) peptides, indicating that stronger KIR2DL2 avidity for HLA-C/peptide complexes reduces NK cell sensitivity to peptide repertoire variation.\",\n      \"method\": \"NK cell degranulation assays with defined inhibitory, weak inhibitory, and antagonist peptides; mathematical modeling\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean functional dissection with defined peptides, multiple donor comparisons, mathematical modeling\",\n      \"pmids\": [\"25359276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Decitabine (a DNA methyltransferase inhibitor) upregulates KIR2DL2/3 expression in KIR2DL2/3-negative γδ T cells by inhibiting KIR2DL2/3 promoter methylation, which enhances Sp-1 binding to the KIR2DL2/3 promoter and activates gene expression, resulting in reduced cytotoxicity of these cells.\",\n      \"method\": \"Flow cytometry, promoter methylation analysis, Sp-1 binding assay, cytotoxicity assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (methylation, transcription factor binding, functional cytotoxicity), single lab\",\n      \"pmids\": [\"29632540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Crystal structure of KIR2DL2 in complex with HLA-B*73:01 (a non-HLA-C ligand) reveals differences in the binding interface compared to previously solved KIR2DL2/HLA-C complex structures. Mass spectrometry-based immunopeptidome profiling of HIV-1-infected cells and KIR2DL2-HLA-C*12:02-peptide crystal structures demonstrate the molecular basis for KIR2DL2 recognition of escape mutant epitopes selected by CD8+ T cells.\",\n      \"method\": \"X-ray crystallography (KIR2DL2/HLA-C*12:02-peptide and KIR2DL2/HLA-B*73:01), mass spectrometry immunopeptidomics, NK cell functional assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with MS immunopeptidomics and functional NK assays, multiple orthogonal methods\",\n      \"pmids\": [\"41198628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Crystal structure of KIR2DL2 in complex with HLA-B*73:01 reveals that KIR2DL2 engages this non-HLA-C molecule with differences from previously solved HLA-C complexes, providing structural evidence that KIR2DL2 can recognize HLA-B allotypes in addition to HLA-C.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure of KIR2DL2/HLA-B*73:01 complex\",\n      \"pmids\": [\"40749828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In multiple sclerosis patients, CpG treatment caused NK cells to upregulate KIR2DL2 and show decreased degranulation and cytotoxicity in response to HSV-1 infection. Direct CpG treatment of purified NK cells reproduced KIR2DL2 upregulation, indicating a cell-autonomous mechanism linking TLR9 pathway activation to increased inhibitory KIR2DL2 expression and impaired NK cell function.\",\n      \"method\": \"In vitro viral infection assays, cytokine secretion, NK cell activation and degranulation assays, KIR expression measurement by flow cytometry on purified NK cells\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct NK cell CpG treatment linking TLR9 activation to KIR2DL2 upregulation and functional impairment, single lab\",\n      \"pmids\": [\"22871633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MS patients with KIR2DL2+ NK cells that fail to control HSV-1 infection produce high levels of Th17 cytokines (rather than IFN-γ), while KIR2DL2- NK cells from MS patients release Th1 cytokines (IFN-γ). This demonstrates that KIR2DL2 inhibitory signaling skews NK cell cytokine secretion toward a Th17 profile during herpesvirus infection.\",\n      \"method\": \"In vitro HSV-1 infection assays, cytokine secretion analysis by flow cytometry/ELISA in KIR2DL2+ vs. KIR2DL2- NK cell subsets\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional comparison of KIR2DL2+ vs KIR2DL2- NK cells with defined viral challenge, single lab\",\n      \"pmids\": [\"27138091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Lassa virus (LASV) NP and GP-derived peptides presented by HLA-C molecules (but not HLA-B or HLA-A) strongly inhibit degranulation of KIR2DL2+ NK cells. A specific variant of glycoprotein epitope vGP420 significantly increases this inhibitory effect, suggesting LASV exploits the HLA-C/KIR2DL2 axis to escape NK cell killing.\",\n      \"method\": \"In silico peptide screening, peptide-HLA stabilization assays, KIR2DL2 binding assays, NK cell degranulation polyfunction assays\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding assays and functional NK degranulation assays, moderate evidence from single study\",\n      \"pmids\": [\"30711514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HIV-1 clade C avoids acquiring a p24 Gag mutation that would abolish KIR2DL2 binding to HLA-C*03:04, demonstrating in vivo selection pressure to maintain KIR2DL2-mediated NK inhibition in individuals with the KIR2DL2+/HLA-C*03:04+ genotype.\",\n      \"method\": \"HIV-1 sequence analysis in KIR2DL2+/HLA-C*03:04+ individuals, KIR2DL2-Fc binding assays, NK cell disinhibition assays\",\n      \"journal\": \"AIDS (London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding assays and NK cell functional assays combined with in vivo sequence data, single lab\",\n      \"pmids\": [\"33273184\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIR2DL2 is an inhibitory Ig-superfamily receptor on NK cells whose extracellular D1–D2 domains bind HLA-C (both C1 and C2 group allotypes, with broader specificity than KIR2DL1), as well as select HLA-B allotypes; upon ligand engagement it undergoes phosphorylation and recruits SHP1/SHP2, leading to dephosphorylation of PLC-γ1 and inhibition of NK cytotoxicity independently of p56(lck); the interdomain hinge angle determined by residues at positions 16 and 148 (and allele-specific contacts at positions 11, 35) modulates ligand-binding avidity; peptide cargo presented by HLA-C fine-tunes KIR2DL2 binding strength, enabling viral pathogens to evade NK killing by selecting epitopes that increase inhibitory KIR engagement; and KIR2DL2 inhibition dominates over co-expressed activating KIR2DS2 on the same NK cell.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KIR2DL2 is an inhibitory killer-cell immunoglobulin-like receptor on NK cells that suppresses cytotoxicity upon engagement of HLA class I ligands, functioning as a key checkpoint in innate immune surveillance of virally infected and transformed cells. Its extracellular D1–D2 domains adopt a K-type Ig fold with a characteristic ~80° interdomain hinge angle; polymorphic residues at positions 16, 148, 11, and 35 tune this hinge geometry and confer higher binding avidity than the related KIR2DL3, enabling recognition of all C1-group HLA-C allotypes plus cross-reactivity with several C2-group HLA-C and HLA-B allotypes [PMID:10097129, PMID:18322206, PMID:23686481, PMID:40749828]. Upon HLA-C engagement, KIR2DL2 is phosphorylated and recruits SHP-1/SHP-2, leading to dephosphorylation of PLCγ1 and suppression of NK cell activation independently of p56(lck); this inhibition dominates over co-expressed activating KIR2DS2 on the same cell [PMID:11750651, PMID:24078689]. The peptide cargo presented by HLA-C fine-tunes KIR2DL2 binding strength, and HIV-1 and Lassa virus exploit this peptide-dependent recognition to select epitopes that enhance inhibitory KIR2DL2 engagement and evade NK cell killing [PMID:22807681, PMID:30711514, PMID:41198628].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Determining the three-dimensional structure of the KIR2DL2 extracellular domains established the K-type Ig fold topology, a distinctive ~80° interdomain hinge angle, and a putative ligand-binding site with charge complementarity to HLA-C, providing the first atomic framework for understanding inhibitory KIR recognition.\",\n      \"evidence\": \"X-ray crystallography of KIR2DL2 D1–D2 in two independent crystal forms at 2.9–3.0 Å\",\n      \"pmids\": [\"10097129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No complex structure with HLA-C ligand at this stage\", \"Role of individual residues in ligand contact not yet tested by mutagenesis\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Reconstitution of KIR2DL2 signaling in lck-negative cells demonstrated that ligand engagement triggers receptor phosphorylation, SHP-1/SHP-2 recruitment, and PLCγ1 dephosphorylation, establishing the proximal inhibitory signaling cascade independently of Src-family kinase p56(lck).\",\n      \"evidence\": \"Transfection of KIR2DL2 into p56(lck)-negative YT-Indy cells; pervanadate-stimulated phosphorylation, co-immunoprecipitation of SHP-1/SHP-2, cytotoxicity and PLCγ1 phosphorylation assays\",\n      \"pmids\": [\"11750651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the kinase that phosphorylates KIR2DL2 ITIMs in the absence of lck remains undefined\", \"Downstream substrates beyond PLCγ1 not characterized\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Systematic binding analysis across 93 HLA isoforms revealed that KIR2DL2 recognizes all C1-group and several C2-group HLA-C allotypes plus HLA-B*4601 and HLA-B*7301, and site-directed mutagenesis pinpointed residues Arg16 and Cys148 near the interdomain hinge as determinants of higher avidity relative to KIR2DL3.\",\n      \"evidence\": \"Recombinant KIR extracellular domain binding assays to 93 HLA isoforms; site-directed mutagenesis of positions 16 and 148\",\n      \"pmids\": [\"18322206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for cross-reactivity with HLA-B allotypes not resolved\", \"How hinge angle change translates to altered binding kinetics not quantified by SPR in this study\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that HLA-C-presented HIV-1 Gag peptides modulate KIR2DL2 binding and NK cell inhibition established a peptide-dependent mechanism of viral immune evasion, showing that the peptide cargo is not merely a passenger but an active determinant of inhibitory KIR engagement.\",\n      \"evidence\": \"KIR2DL2-Fc binding assays, HLA stabilization assays, and primary NK cell degranulation assays with variant Gag peptides\",\n      \"pmids\": [\"22807681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for peptide discrimination not yet determined at atomic resolution\", \"In vivo selection pressure on viral peptides not demonstrated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Functional and mutagenesis studies showed that allele-specific residues at positions 11 and 35 (distal to the HLA-C contact surface) modulate KIR2DL2/L3 binding avidity by altering the interdomain hinge angle, and that KIR2DL2-mediated inhibition dominates over co-expressed KIR2DS2 activation, establishing KIR2DL2 as the functionally dominant receptor in NK cells bearing both.\",\n      \"evidence\": \"SPR binding, flow cytometry, mutagenesis, IFN-γ inhibition in KHYG-1 cells; NK clone reactivity assays across HLA-C panels\",\n      \"pmids\": [\"23686481\", \"24078689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure confirming hinge angle change from positions 11/35 not available at this time\", \"Mechanism by which inhibitory signal overrides activating KIR2DS2 at the signalosome level is undefined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extending the peptide-dependent evasion paradigm, additional HIV-1 Gag epitopes presented by HLA-C*03:04 were shown to promote KIR2DL2 binding and NK inhibition, and KIR2DL2+ NK cells were found to be less sensitive than KIR2DL3+ cells to peptide repertoire changes owing to their higher avidity, linking receptor strength to functional tuning of peptide discrimination.\",\n      \"evidence\": \"KIR2DL2-Fc binding and NK degranulation assays with defined peptides; mathematical modeling of inhibitory thresholds\",\n      \"pmids\": [\"24785948\", \"25359276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether higher avidity uniformly reduces sensitivity to all peptide variants or is context-dependent remains untested\", \"No in vivo data confirming differential peptide sensitivity between KIR2DL2 and KIR2DL3\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Position-35 polymorphism (E35 vs Q35) was shown to modulate NK cytotoxicity and licensing strength, and KIR2DL2 expression was linked to skewing of NK cytokine secretion toward a Th17 profile during herpesvirus infection, expanding the functional consequences of KIR2DL2 signaling beyond degranulation.\",\n      \"evidence\": \"NK cytotoxicity assays with allelic dissection and molecular modeling; in vitro HSV-1 infection with cytokine profiling of KIR2DL2+ vs KIR2DL2− NK subsets\",\n      \"pmids\": [\"27030405\", \"27138091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E35-H55 interaction predicted by modeling lacks crystallographic validation\", \"Th17 skewing mechanism downstream of ITIM signaling is uncharacterized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstration that decitabine upregulates KIR2DL2/3 transcription by demethylating the promoter and enabling Sp-1 binding revealed an epigenetic mechanism controlling KIR2DL2 expression and consequent inhibition of γδ T cell cytotoxicity.\",\n      \"evidence\": \"Flow cytometry, promoter methylation analysis, Sp-1 binding assay, and cytotoxicity assays in γδ T cells treated with decitabine\",\n      \"pmids\": [\"29632540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this epigenetic regulation operates identically in conventional NK cells is untested\", \"Chromatin accessibility or histone modification data not provided\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Lassa virus-derived peptides presented by HLA-C were shown to strongly inhibit KIR2DL2+ NK degranulation, extending the peptide-dependent evasion mechanism beyond HIV-1 and indicating it is a general viral strategy exploiting the HLA-C/KIR2DL2 axis.\",\n      \"evidence\": \"Peptide-HLA stabilization, KIR2DL2 binding, and NK polyfunction degranulation assays with LASV NP and GP peptides\",\n      \"pmids\": [\"30711514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No crystal structure of KIR2DL2 with LASV peptide-HLA complex\", \"In vivo relevance in Lassa fever patients not examined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Crystal structures of KIR2DL2 and KIR2DL3 bound to HLA-C*07:02 revealed distinct docking modalities, explaining their differential recognition of C1 allotypes at atomic resolution, and in vivo HIV-1 sequence data showed that clade C virus avoids mutations that would abolish KIR2DL2 binding, confirming peptide-dependent NK evasion under physiological selection pressure.\",\n      \"evidence\": \"X-ray crystallography of KIR2DL2/HLA-C*07:02 complex with mutagenesis and primary NK assays; HIV-1 clade C sequence analysis combined with KIR2DL2-Fc binding and disinhibition assays\",\n      \"pmids\": [\"33846289\", \"33273184\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full energetic decomposition of docking modality differences not performed\", \"Whether KIR2DL2 docking differences extend to all C1 allotypes or are HLA-C*07:02-specific is not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Crystal structures of KIR2DL2 with HLA-B*73:01 and with HLA-C*12:02 presenting HIV-derived escape-mutant peptides provided the structural basis for KIR2DL2 cross-reactivity with non-HLA-C ligands and for peptide-dependent modulation of inhibitory engagement, unifying the molecular mechanism of viral immune evasion at atomic resolution.\",\n      \"evidence\": \"X-ray crystallography of KIR2DL2/HLA-B*73:01 and KIR2DL2/HLA-C*12:02-peptide complexes; mass spectrometry immunopeptidomics of HIV-1-infected cells; NK functional assays\",\n      \"pmids\": [\"41198628\", \"40749828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KIR2DL2 engages other HLA-B allotypes (e.g., B*46:01) with the same docking mode is untested\", \"Immunopeptidome data are from cell lines and may not fully recapitulate in vivo peptide presentation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the kinase(s) that phosphorylate KIR2DL2 ITIMs, the structural basis for dominance of KIR2DL2 inhibition over KIR2DS2 activation at the signalosome level, and whether peptide-dependent evasion by non-HIV/non-LASV viruses and tumors is a general phenomenon.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"ITIM kinase identity unknown\", \"Signalosome-level mechanism of inhibitory dominance over KIR2DS2 not resolved\", \"Breadth of peptide-dependent evasion across diverse pathogens and cancer untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 5, 6, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PTPN6\",\n      \"PTPN11\",\n      \"PLCG1\",\n      \"HLA-C\",\n      \"KIR2DS2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}