{"gene":"KIR3DL2","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2004,"finding":"KIR3DL2*001 directly binds HLA-A3 and HLA-A11 in a peptide-specific manner; single amino acid substitutions in the nonamer peptide, particularly at residue 8, critically affect KIR3DL2 recognition.","method":"HLA tetramer binding to KIR3DL2*001 transfectants; peptide substitution analysis","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — direct binding assay with transfectants and systematic peptide mutagenesis, Moderate evidence","pmids":["15162437"],"is_preprint":false},{"year":2007,"finding":"HLA-B27 free heavy chain homodimers (B27₂) bind KIR3DL2 (and KIR3DL1) in a peptide-sequence-independent manner, in contrast to classical HLA-B27 heterotrimers whose KIR3DL1 binding is peptide-dependent; KIR3DL2 ligation by B27₂ inhibits NK and T cell IFN-γ production.","method":"Tetramer binding to transfectants; functional NK cell IFN-γ secretion assays; peptide analogue studies","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (binding assays + functional inhibition), Moderate evidence","pmids":["17407096"],"is_preprint":false},{"year":2010,"finding":"KIR3DL2 directly binds CpG oligodeoxynucleotides (ODNs) via its D0 domain and co-internalizes with CpG ODN upon NK cell stimulation, shuttling CpG DNA to early endosomes where TLR9 is located, thereby mediating CpG ODN-induced IFN-γ release in KIR3DL2⁺ NK cells.","method":"Soluble receptor binding assay; flow cytometric internalization; confocal microscopy of CpG ODN and KIR3DL2 co-internalization; D0 domain mutant analysis; cytokine secretion assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding demonstrated with soluble receptor, domain mapping, confocal co-localization with functional readout; Moderate evidence from single lab with multiple orthogonal methods","pmids":["20147700"],"is_preprint":false},{"year":2011,"finding":"HLA-B27 homodimer (B27₂)-expressing APCs stimulate survival, proliferation, and IL-17 production of KIR3DL2⁺ CD4 T cells; KIR3DL2⁺ CD4 T cells account for the majority of CD4 T cell IL-23R expression and produce more IL-17 in the presence of IL-23, linking HLA-B27 signaling through KIR3DL2 to Th17 expansion.","method":"Co-culture of KIR3DL2⁺ CD4 T cells with B27₂-expressing APCs; flow cytometry; cytokine (IL-17) measurement; IL-23R expression analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — functional cell-based assays with defined ligand-receptor pair and multiple readouts, replicated across patient cohorts","pmids":["21248258"],"is_preprint":false},{"year":2013,"finding":"B27 free heavy chain forms (FHC), including homodimers (B27₂), bind KIR3DL2 more strongly than other HLA class I molecules including HLA-A3; B27₂ tetramer binding, KIR3DL2Fc pulldown of multimeric/dimeric/monomeric FHC, greater KIR3DL2 phosphorylation, and enhanced KIR3DL2-CD3ε reporter cell IL-2 production all confirmed preferential B27 FHC interaction; this stronger interaction promotes greater survival of KIR3DL2⁺ CD4 T and NK cells.","method":"Tetramer binding; KIR3DL2Fc pulldown; KIR3DL2 phosphorylation assay; KIR3DL2CD3ε-reporter T cell IL-2 production; NK cell survival assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal binding, signaling, and functional assays in a single study; Moderate evidence","pmids":["23440420"],"is_preprint":false},{"year":2013,"finding":"HLA-B*27:05 forms more cell-surface B27 dimers and free heavy chain forms than HLA-B*27:09, and cells expressing HLA-B*27:05 stimulate KIR3DL2CD3ε-reporter T cells more effectively and promote KIR3DL2⁺ NK cell survival more strongly, providing a molecular basis for the differential disease association of these alleles.","method":"In vitro HLA-class I dimer/FHC formation assay; tetramer staining of KIR3DL1, KIR3DL2, LILRB2; KIR3DL2CD3ε-reporter T cell activation; KIR3DL2⁺ NK cell survival assay; FACS quantification","journal":"Rheumatology (Oxford, England)","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional assays comparing two alleles, Moderate evidence","pmids":["23804219"],"is_preprint":false},{"year":2014,"finding":"KIR3DL2 engagement by CpG ODN induces receptor internalization and caspase-dependent apoptosis of malignant Sézary T cells, correlated with dephosphorylation of constitutively active STAT3.","method":"CpG ODN treatment of Sézary cell lines; flow cytometric apoptosis assay; caspase inhibitor experiments; STAT3 phosphorylation immunoblot","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — functional assay with mechanistic follow-up (caspase dependence, STAT3), single lab","pmids":["25007046"],"is_preprint":false},{"year":2015,"finding":"The D0 Ig-like domain of KIR3DL2 plays a central role in its preferential binding to B27 FHC dimers; mutagenesis identified key residues in D0 and other Ig-like domains shared with and distinct from KIR3DL1; computational modeling predicts non-symmetrical complementary contacts of D0 and D1 with α1, α2, and α3 domains of both B27 H chains, while D2 primarily contacts one B27 H chain.","method":"Site-directed mutagenesis of KIR3DL2; functional reporter cell assays; computational structural modeling; comparison with KIR3DL1 binding residues","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis combined with functional assays and structural modeling; Moderate evidence","pmids":["25582852"],"is_preprint":false},{"year":2005,"finding":"KIR3DL2⁺ NK cells from spondyloarthritis (SpA) patients are protected from apoptosis by culture with a cell line expressing B27₂ homodimers, and show increased cytotoxicity; this demonstrates that KIR3DL2 engagement by its HLA-B27 homodimer ligand promotes NK cell survival.","method":"Annexin V/7-AAD apoptosis assay; ⁵¹Cr-release cytotoxicity assay; flow cytometry phenotyping","journal":"Arthritis and rheumatism","confidence":"Medium","confidence_rationale":"Tier 2 — functional NK survival and cytotoxicity assays with defined ligand, single lab","pmids":["16255049"],"is_preprint":false},{"year":2009,"finding":"KIR2DS4 acquired specificity for HLA-A*11 through gene conversion with KIR3DL2 that introduced the proline-valine motif at positions 71-72, which is shared with KIR3DL2 and is largely responsible for unique HLA class I specificity; swap mutagenesis confirmed these two residues determine binding specificity.","method":"Site-directed swap mutagenesis; crystallographic structure determination of KIR2DS4; functional NK cell activation assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis plus functional assays; Strong evidence for mechanistic role of KIR3DL2 domain residues","pmids":["19858347"],"is_preprint":false},{"year":2021,"finding":"KIR3DL2 binds exogenous CpG DNA in a sequence-specific manner; abundant CpG sequences prevalent in the human genome induce inhibitory signaling in KIR3DL2⁺ NKL cells, while CpG sequences prevalent in parasitic worm genomes stimulate increased target lysis and IFN-γ production, indicating KIR3DL2 allows NK cells to discriminate self-DNA from pathogen DNA.","method":"CpG-DNA uptake assay; functional NK lysis and IFN-γ production assays in KIR3DL2⁺ NKL cells; comparative genomic analysis of CpG sequences","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 2 — functional cell-based assays with sequence-specific ligands; single lab","pmids":["34760351"],"is_preprint":false},{"year":2003,"finding":"Cross-linking of KIR3DL2/p140 on tumor-specific CTL clones does not result in inhibitory (or activatory) effects on cytotoxicity or cytokine production triggered by anti-CD3 or tumor cell contact, suggesting that KIR3DL2 engagement on CTL does not produce the canonical inhibitory signaling seen with other KIRs.","method":"Anti-KIR3DL2 antibody crosslinking; ⁵¹Cr-release cytotoxicity assay; IFN-γ cytokine secretion assay; T cell clone functional studies","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — functional assays in primary T cell clones, single lab, unexpected result warranting further study","pmids":["14562047"],"is_preprint":false},{"year":2022,"finding":"HTLV-1 infection of CD4⁺ T cells triggers KIR3DL2 expression, correlating with promoter hypomethylation; Tax alone is insufficient to induce KIR3DL2 expression; anti-KIR3DL2 antibody (lacutamab) mediates ADCC-killing of KIR3DL2⁺ primary ATL cells ex vivo.","method":"PrimeFlow RNA co-detection of TAX mRNA and KIR3DL2 protein; in vitro HTLV-1 infection of CD4⁺ T cells; methylation profiling; ex vivo ADCC assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (epigenetic, RNA, functional), single lab","pmids":["35687761"],"is_preprint":false},{"year":2014,"finding":"IPH4102 (anti-KIR3DL2 monoclonal antibody) mediates antitumor activity against CTCL cells via antibody-dependent cell cytotoxicity (ADCC) and phagocytosis, and selectively kills primary Sézary cells ex vivo including at unfavorable effector-to-target ratios.","method":"Allogeneic ADCC assays; phagocytosis assays; mouse xenograft model; autologous NK-based killing assays with primary Sézary patient cells","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays in vitro and in vivo, single lab","pmids":["25361998"],"is_preprint":false}],"current_model":"KIR3DL2 is an inhibitory NK receptor that functions as a three-domain immunoglobulin-like receptor (structured as a disulfide-bonded dimer with cytoplasmic ITIM motifs) that recognizes HLA-A3/A11 in a peptide-dependent manner via its D0, D1, and D2 domains, binds HLA-B27 free heavy chain homodimers preferentially and peptide-independently (with D0 playing a central role in stronger binding), and additionally acts as a cell-surface receptor for CpG ODNs that shuttles them to TLR9 in early endosomes; ligation by B27 homodimers inhibits NK/T cell IFN-γ production and promotes KIR3DL2⁺ lymphocyte survival and IL-17 production, while CpG ODN engagement induces receptor internalization and, in malignant T cells, caspase-dependent apoptosis associated with STAT3 dephosphorylation."},"narrative":{"teleology":[{"year":2003,"claim":"Initial functional studies asked whether KIR3DL2 delivers canonical inhibitory signals on CTL, and unexpectedly found that antibody cross-linking of KIR3DL2 on tumor-specific CTL clones produced neither inhibitory nor activating effects on cytotoxicity or cytokine output, raising the question of context-dependent signaling.","evidence":"Anti-KIR3DL2 antibody cross-linking with ⁵¹Cr-release cytotoxicity and IFN-γ assays on primary human CTL clones","pmids":["14562047"],"confidence":"Medium","gaps":["Single lab observation; absence of effect may reflect insufficient cross-linking or cell-type-specific signaling","No direct assessment of ITIM phosphorylation or SHP recruitment"]},{"year":2004,"claim":"Establishing ligand specificity, KIR3DL2*001 was shown to bind HLA-A3 and HLA-A11 in a peptide-dependent manner, with residue 8 of the nonamer peptide critically determining recognition, defining KIR3DL2 as a peptide-selective MHC class I receptor.","evidence":"HLA tetramer binding to KIR3DL2*001 transfectants with systematic peptide substitution analysis","pmids":["15162437"],"confidence":"High","gaps":["Structural basis of peptide selectivity unresolved","Allelic variation in KIR3DL2 recognition not systematically explored"]},{"year":2005,"claim":"Functional consequences of KIR3DL2 engagement were demonstrated when B27₂ homodimer-expressing cells protected KIR3DL2⁺ NK cells from apoptosis and enhanced their cytotoxicity, establishing a survival-promoting role for this receptor-ligand interaction in spondyloarthritis patients.","evidence":"Annexin V/7-AAD apoptosis and ⁵¹Cr-release cytotoxicity assays with SpA patient NK cells co-cultured with B27₂-expressing cells","pmids":["16255049"],"confidence":"Medium","gaps":["Signaling pathway downstream of survival effect not identified","Single disease cohort studied"]},{"year":2007,"claim":"A major advance was the discovery that HLA-B27 free heavy chain homodimers bind KIR3DL2 in a peptide-independent manner — fundamentally different from conventional HLA recognition — and that this ligation inhibits NK and T cell IFN-γ production, providing a mechanistic link between HLA-B27 and immune dysregulation.","evidence":"Tetramer binding to transfectants, peptide analogue studies, and functional IFN-γ secretion assays","pmids":["17407096"],"confidence":"High","gaps":["Structural basis of peptide-independent recognition unresolved","Relative contribution of monomeric vs. dimeric FHC unclear"]},{"year":2009,"claim":"Structural and mutagenesis work on KIR2DS4 identified that a proline-valine motif at positions 71–72, acquired by gene conversion from KIR3DL2, confers HLA-A*11 specificity, thereby mapping key specificity-determining residues in the KIR3DL2 binding surface.","evidence":"Crystal structure of KIR2DS4, swap mutagenesis of positions 71–72, and functional NK cell activation assays","pmids":["19858347"],"confidence":"High","gaps":["No crystal structure of KIR3DL2 itself in complex with HLA ligand","Role of these residues in B27₂ recognition not tested"]},{"year":2010,"claim":"KIR3DL2 was discovered to function beyond MHC recognition as a direct receptor for CpG oligodeoxynucleotides, binding CpG DNA via its D0 domain, co-internalizing with it, and shuttling it to TLR9 in early endosomes to trigger IFN-γ release — establishing a novel innate sensing role.","evidence":"Soluble receptor binding assay, D0 domain mutant analysis, confocal co-localization of CpG ODN and KIR3DL2, and cytokine secretion assays in NK cells","pmids":["20147700"],"confidence":"High","gaps":["Structural basis of CpG–D0 interaction not determined","Whether CpG binding and HLA binding are mutually exclusive unknown"]},{"year":2011,"claim":"The disease-relevant downstream consequence of KIR3DL2–B27₂ interaction was established: B27₂-expressing APCs drive survival, proliferation, and IL-17 production by KIR3DL2⁺ CD4 T cells, which express IL-23R, linking this pathway directly to Th17 expansion in spondyloarthritis.","evidence":"Co-culture of KIR3DL2⁺ CD4 T cells with B27₂-expressing APCs, flow cytometry for IL-23R, and IL-17 cytokine measurement across patient cohorts","pmids":["21248258"],"confidence":"High","gaps":["Intracellular signaling cascade connecting KIR3DL2 ligation to IL-17 transcription not defined","Whether ITIM motifs are required for Th17 expansion not tested"]},{"year":2013,"claim":"Quantitative comparison established that B27 free heavy chains bind KIR3DL2 more strongly than HLA-A3, with greater receptor phosphorylation and functional output, and that the disease-associated B*27:05 allele forms more surface dimers and stimulates KIR3DL2 more effectively than the non-disease-associated B*27:09, providing a molecular explanation for differential disease risk.","evidence":"Tetramer binding, KIR3DL2Fc pulldown, phosphorylation assays, reporter cell IL-2 production, and allele-specific dimer quantification","pmids":["23440420","23804219"],"confidence":"High","gaps":["Affinity measurements in solution (SPR/ITC) not reported","Contribution of cis vs. trans B27₂ engagement in vivo unknown"]},{"year":2014,"claim":"Two studies expanded the functional repertoire: CpG ODN engagement of KIR3DL2 on malignant Sézary T cells induces receptor internalization, STAT3 dephosphorylation, and caspase-dependent apoptosis, while an anti-KIR3DL2 antibody (IPH4102) mediates ADCC and phagocytosis against CTCL cells, validating KIR3DL2 as a therapeutic target in T-cell lymphoma.","evidence":"CpG ODN treatment with caspase inhibitor and STAT3 immunoblot in Sézary cells; ADCC/phagocytosis assays and mouse xenograft with IPH4102","pmids":["25007046","25361998"],"confidence":"Medium","gaps":["Mechanism linking STAT3 dephosphorylation to apoptosis induction not delineated","Whether CpG-induced apoptosis occurs in non-malignant KIR3DL2⁺ cells not addressed"]},{"year":2015,"claim":"Domain-level mapping through mutagenesis demonstrated that the D0 domain of KIR3DL2 is central to preferential B27₂ binding, with computational modeling predicting asymmetric contacts of D0 and D1 with both B27 heavy chains in the homodimer — the most detailed structural model of this interaction to date.","evidence":"Site-directed mutagenesis of KIR3DL2 Ig domains, functional reporter assays, and computational docking model","pmids":["25582852"],"confidence":"High","gaps":["No experimental crystal or cryo-EM structure of the KIR3DL2–B27₂ complex","Contribution of individual D0 residues to CpG binding vs. B27₂ binding not dissected"]},{"year":2021,"claim":"CpG DNA sensing by KIR3DL2 was shown to be sequence-specific, with human-genome-prevalent CpG sequences delivering inhibitory signals and parasite-genome-prevalent sequences activating NK cytotoxicity and IFN-γ production, suggesting KIR3DL2 discriminates self-DNA from pathogen DNA.","evidence":"Comparative genomic CpG analysis with functional lysis and IFN-γ assays in KIR3DL2⁺ NKL cells","pmids":["34760351"],"confidence":"Medium","gaps":["Single cell line (NKL); not confirmed in primary NK cells","Structural basis of sequence-specific CpG discrimination unknown","In vivo relevance of DNA sensing in infection not tested"]},{"year":2022,"claim":"HTLV-1 infection was found to drive KIR3DL2 surface expression on CD4⁺ T cells through promoter hypomethylation rather than Tax-mediated transactivation, and anti-KIR3DL2 antibody (lacutamab) killed primary ATL cells via ADCC, establishing KIR3DL2 as a target in HTLV-1-driven malignancy.","evidence":"PrimeFlow RNA co-detection, in vitro HTLV-1 infection, methylation profiling, and ex vivo ADCC assay on primary ATL cells","pmids":["35687761"],"confidence":"Medium","gaps":["Epigenetic mechanism of promoter demethylation not fully characterized","Whether KIR3DL2 has a functional role in HTLV-1 pathogenesis beyond serving as a surface marker is unclear"]},{"year":null,"claim":"A high-resolution experimental structure of KIR3DL2 in complex with B27₂ homodimers or CpG DNA is still lacking, and the intracellular signaling pathways downstream of KIR3DL2 ligation — particularly how the same receptor can mediate inhibitory signaling, survival, IL-17 induction, or apoptosis depending on ligand and cell context — remain poorly defined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of KIR3DL2 with any ligand","Signaling intermediates linking ITIM phosphorylation to Th17 expansion or CpG-induced apoptosis not identified","Whether CpG and HLA binding sites on D0 overlap is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2,4,7,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,3,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2,4,6,12]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2,3,4,7,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,6,10]}],"complexes":[],"partners":["HLA-A3","HLA-A11","HLA-B27","TLR9"],"other_free_text":[]},"mechanistic_narrative":"KIR3DL2 is a three-domain immunoglobulin-like killer cell receptor expressed on NK cells and subsets of CD4 T cells that integrates recognition of classical MHC class I molecules, non-classical HLA free heavy chain forms, and microbial CpG DNA to regulate innate and adaptive immune responses. KIR3DL2 binds HLA-A3 and HLA-A11 in a peptide-dependent manner, with single amino acid substitutions at position 8 of the nonamer peptide critically affecting recognition, while it preferentially binds HLA-B27 free heavy chain homodimers (B27₂) in a peptide-independent manner via its D0 domain, triggering inhibition of IFN-γ production, promotion of KIR3DL2⁺ lymphocyte survival, and expansion of IL-17-producing CD4 T cells linked to spondyloarthritis pathogenesis [PMID:15162437, PMID:17407096, PMID:25582852, PMID:21248258]. KIR3DL2 also functions as a cell-surface receptor for CpG oligodeoxynucleotides, binding them through its D0 domain and co-internalizing to deliver CpG DNA to TLR9 in early endosomes; this CpG engagement discriminates self-derived from pathogen-derived DNA sequences and, in malignant Sézary T cells, induces caspase-dependent apoptosis with STAT3 dephosphorylation [PMID:20147700, PMID:34760351, PMID:25007046]. KIR3DL2 is aberrantly expressed on malignant T cells in cutaneous T-cell lymphoma and adult T-cell leukemia/lymphoma following HTLV-1-driven promoter hypomethylation, making it a therapeutic target for antibody-dependent cellular cytotoxicity [PMID:35687761, PMID:25361998]."},"prefetch_data":{"uniprot":{"accession":"P43630","full_name":"Killer cell immunoglobulin-like receptor 3DL2","aliases":["CD158 antigen-like family member K","Natural killer-associated transcript 4","NKAT-4","p70 natural killer cell receptor clone CL-5","p70 NK receptor CL-5"],"length_aa":455,"mass_kda":50.2,"function":"Receptor on natural killer (NK) cells and T cells for MHC class I molecules (PubMed:24018270, PubMed:28636952). Upon binding of peptide-free HLA-F open conformer, negatively regulates NK and T cell effector functions (PubMed:24018270). Acts as a receptor on astrocytes for HLA-F. Through interaction with HLA-F, may protect motor neurons from astrocyte-induced toxicity (PubMed:26928464)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P43630/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KIR3DL2","classification":"Not Classified","n_dependent_lines":21,"n_total_lines":1208,"dependency_fraction":0.0173841059602649},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KIR3DL2","total_profiled":1310},"omim":[{"mim_id":"604947","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, THREE DOMAINS, LONG CYTOPLASMIC TAIL, 2; KIR3DL2","url":"https://www.omim.org/entry/604947"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":1.8}],"url":"https://www.proteinatlas.org/search/KIR3DL2"},"hgnc":{"alias_symbol":["cl-5","nkat4","nkat4a","nkat4b","CD158K"],"prev_symbol":[]},"alphafold":{"accession":"P43630","domains":[{"cath_id":"2.60.40.10","chopping":"29-117","consensus_level":"high","plddt":80.6217,"start":29,"end":117},{"cath_id":"2.60.40.10","chopping":"122-217","consensus_level":"high","plddt":93.6421,"start":122,"end":217},{"cath_id":"2.60.40.10","chopping":"224-315","consensus_level":"high","plddt":92.0772,"start":224,"end":315}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P43630","model_url":"https://alphafold.ebi.ac.uk/files/AF-P43630-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P43630-F1-predicted_aligned_error_v6.png","plddt_mean":74.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KIR3DL2","jax_strain_url":"https://www.jax.org/strain/search?query=KIR3DL2"},"sequence":{"accession":"P43630","fasta_url":"https://rest.uniprot.org/uniprotkb/P43630.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P43630/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P43630"}},"corpus_meta":[{"pmid":"15162437","id":"PMC_15162437","title":"Recognition of HLA-A3 and HLA-A11 by KIR3DL2 is peptide-specific.","date":"2004","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15162437","citation_count":262,"is_preprint":false},{"pmid":"21248258","id":"PMC_21248258","title":"Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis.","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21248258","citation_count":229,"is_preprint":false},{"pmid":"19858347","id":"PMC_19858347","title":"KIR2DS4 is a product of gene conversion with KIR3DL2 that introduced specificity for HLA-A*11 while diminishing avidity for HLA-C.","date":"2009","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19858347","citation_count":200,"is_preprint":false},{"pmid":"16255049","id":"PMC_16255049","title":"Expansion and enhanced survival of natural killer cells expressing the killer immunoglobulin-like receptor KIR3DL2 in spondylarthritis.","date":"2005","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/16255049","citation_count":157,"is_preprint":false},{"pmid":"31253572","id":"PMC_31253572","title":"IPH4102, a first-in-class anti-KIR3DL2 monoclonal antibody, in patients with relapsed or refractory cutaneous T-cell lymphoma: an international, first-in-human, open-label, phase 1 trial.","date":"2019","source":"The Lancet. 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\"confidence_rationale\": \"Tier 2 — direct binding assay with transfectants and systematic peptide mutagenesis, Moderate evidence\",\n      \"pmids\": [\"15162437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HLA-B27 free heavy chain homodimers (B27₂) bind KIR3DL2 (and KIR3DL1) in a peptide-sequence-independent manner, in contrast to classical HLA-B27 heterotrimers whose KIR3DL1 binding is peptide-dependent; KIR3DL2 ligation by B27₂ inhibits NK and T cell IFN-γ production.\",\n      \"method\": \"Tetramer binding to transfectants; functional NK cell IFN-γ secretion assays; peptide analogue studies\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (binding assays + functional inhibition), Moderate evidence\",\n      \"pmids\": [\"17407096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KIR3DL2 directly binds CpG oligodeoxynucleotides (ODNs) via its D0 domain and co-internalizes with CpG ODN upon NK cell stimulation, shuttling CpG DNA to early endosomes where TLR9 is located, thereby mediating CpG ODN-induced IFN-γ release in KIR3DL2⁺ NK cells.\",\n      \"method\": \"Soluble receptor binding assay; flow cytometric internalization; confocal microscopy of CpG ODN and KIR3DL2 co-internalization; D0 domain mutant analysis; cytokine secretion assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding demonstrated with soluble receptor, domain mapping, confocal co-localization with functional readout; Moderate evidence from single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20147700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HLA-B27 homodimer (B27₂)-expressing APCs stimulate survival, proliferation, and IL-17 production of KIR3DL2⁺ CD4 T cells; KIR3DL2⁺ CD4 T cells account for the majority of CD4 T cell IL-23R expression and produce more IL-17 in the presence of IL-23, linking HLA-B27 signaling through KIR3DL2 to Th17 expansion.\",\n      \"method\": \"Co-culture of KIR3DL2⁺ CD4 T cells with B27₂-expressing APCs; flow cytometry; cytokine (IL-17) measurement; IL-23R expression analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional cell-based assays with defined ligand-receptor pair and multiple readouts, replicated across patient cohorts\",\n      \"pmids\": [\"21248258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"B27 free heavy chain forms (FHC), including homodimers (B27₂), bind KIR3DL2 more strongly than other HLA class I molecules including HLA-A3; B27₂ tetramer binding, KIR3DL2Fc pulldown of multimeric/dimeric/monomeric FHC, greater KIR3DL2 phosphorylation, and enhanced KIR3DL2-CD3ε reporter cell IL-2 production all confirmed preferential B27 FHC interaction; this stronger interaction promotes greater survival of KIR3DL2⁺ CD4 T and NK cells.\",\n      \"method\": \"Tetramer binding; KIR3DL2Fc pulldown; KIR3DL2 phosphorylation assay; KIR3DL2CD3ε-reporter T cell IL-2 production; NK cell survival assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal binding, signaling, and functional assays in a single study; Moderate evidence\",\n      \"pmids\": [\"23440420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HLA-B*27:05 forms more cell-surface B27 dimers and free heavy chain forms than HLA-B*27:09, and cells expressing HLA-B*27:05 stimulate KIR3DL2CD3ε-reporter T cells more effectively and promote KIR3DL2⁺ NK cell survival more strongly, providing a molecular basis for the differential disease association of these alleles.\",\n      \"method\": \"In vitro HLA-class I dimer/FHC formation assay; tetramer staining of KIR3DL1, KIR3DL2, LILRB2; KIR3DL2CD3ε-reporter T cell activation; KIR3DL2⁺ NK cell survival assay; FACS quantification\",\n      \"journal\": \"Rheumatology (Oxford, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays comparing two alleles, Moderate evidence\",\n      \"pmids\": [\"23804219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIR3DL2 engagement by CpG ODN induces receptor internalization and caspase-dependent apoptosis of malignant Sézary T cells, correlated with dephosphorylation of constitutively active STAT3.\",\n      \"method\": \"CpG ODN treatment of Sézary cell lines; flow cytometric apoptosis assay; caspase inhibitor experiments; STAT3 phosphorylation immunoblot\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assay with mechanistic follow-up (caspase dependence, STAT3), single lab\",\n      \"pmids\": [\"25007046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The D0 Ig-like domain of KIR3DL2 plays a central role in its preferential binding to B27 FHC dimers; mutagenesis identified key residues in D0 and other Ig-like domains shared with and distinct from KIR3DL1; computational modeling predicts non-symmetrical complementary contacts of D0 and D1 with α1, α2, and α3 domains of both B27 H chains, while D2 primarily contacts one B27 H chain.\",\n      \"method\": \"Site-directed mutagenesis of KIR3DL2; functional reporter cell assays; computational structural modeling; comparison with KIR3DL1 binding residues\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis combined with functional assays and structural modeling; Moderate evidence\",\n      \"pmids\": [\"25582852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KIR3DL2⁺ NK cells from spondyloarthritis (SpA) patients are protected from apoptosis by culture with a cell line expressing B27₂ homodimers, and show increased cytotoxicity; this demonstrates that KIR3DL2 engagement by its HLA-B27 homodimer ligand promotes NK cell survival.\",\n      \"method\": \"Annexin V/7-AAD apoptosis assay; ⁵¹Cr-release cytotoxicity assay; flow cytometry phenotyping\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional NK survival and cytotoxicity assays with defined ligand, single lab\",\n      \"pmids\": [\"16255049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KIR2DS4 acquired specificity for HLA-A*11 through gene conversion with KIR3DL2 that introduced the proline-valine motif at positions 71-72, which is shared with KIR3DL2 and is largely responsible for unique HLA class I specificity; swap mutagenesis confirmed these two residues determine binding specificity.\",\n      \"method\": \"Site-directed swap mutagenesis; crystallographic structure determination of KIR2DS4; functional NK cell activation assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis plus functional assays; Strong evidence for mechanistic role of KIR3DL2 domain residues\",\n      \"pmids\": [\"19858347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KIR3DL2 binds exogenous CpG DNA in a sequence-specific manner; abundant CpG sequences prevalent in the human genome induce inhibitory signaling in KIR3DL2⁺ NKL cells, while CpG sequences prevalent in parasitic worm genomes stimulate increased target lysis and IFN-γ production, indicating KIR3DL2 allows NK cells to discriminate self-DNA from pathogen DNA.\",\n      \"method\": \"CpG-DNA uptake assay; functional NK lysis and IFN-γ production assays in KIR3DL2⁺ NKL cells; comparative genomic analysis of CpG sequences\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional cell-based assays with sequence-specific ligands; single lab\",\n      \"pmids\": [\"34760351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Cross-linking of KIR3DL2/p140 on tumor-specific CTL clones does not result in inhibitory (or activatory) effects on cytotoxicity or cytokine production triggered by anti-CD3 or tumor cell contact, suggesting that KIR3DL2 engagement on CTL does not produce the canonical inhibitory signaling seen with other KIRs.\",\n      \"method\": \"Anti-KIR3DL2 antibody crosslinking; ⁵¹Cr-release cytotoxicity assay; IFN-γ cytokine secretion assay; T cell clone functional studies\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assays in primary T cell clones, single lab, unexpected result warranting further study\",\n      \"pmids\": [\"14562047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HTLV-1 infection of CD4⁺ T cells triggers KIR3DL2 expression, correlating with promoter hypomethylation; Tax alone is insufficient to induce KIR3DL2 expression; anti-KIR3DL2 antibody (lacutamab) mediates ADCC-killing of KIR3DL2⁺ primary ATL cells ex vivo.\",\n      \"method\": \"PrimeFlow RNA co-detection of TAX mRNA and KIR3DL2 protein; in vitro HTLV-1 infection of CD4⁺ T cells; methylation profiling; ex vivo ADCC assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (epigenetic, RNA, functional), single lab\",\n      \"pmids\": [\"35687761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IPH4102 (anti-KIR3DL2 monoclonal antibody) mediates antitumor activity against CTCL cells via antibody-dependent cell cytotoxicity (ADCC) and phagocytosis, and selectively kills primary Sézary cells ex vivo including at unfavorable effector-to-target ratios.\",\n      \"method\": \"Allogeneic ADCC assays; phagocytosis assays; mouse xenograft model; autologous NK-based killing assays with primary Sézary patient cells\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"25361998\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIR3DL2 is an inhibitory NK receptor that functions as a three-domain immunoglobulin-like receptor (structured as a disulfide-bonded dimer with cytoplasmic ITIM motifs) that recognizes HLA-A3/A11 in a peptide-dependent manner via its D0, D1, and D2 domains, binds HLA-B27 free heavy chain homodimers preferentially and peptide-independently (with D0 playing a central role in stronger binding), and additionally acts as a cell-surface receptor for CpG ODNs that shuttles them to TLR9 in early endosomes; ligation by B27 homodimers inhibits NK/T cell IFN-γ production and promotes KIR3DL2⁺ lymphocyte survival and IL-17 production, while CpG ODN engagement induces receptor internalization and, in malignant T cells, caspase-dependent apoptosis associated with STAT3 dephosphorylation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KIR3DL2 is a three-domain immunoglobulin-like killer cell receptor expressed on NK cells and subsets of CD4 T cells that integrates recognition of classical MHC class I molecules, non-classical HLA free heavy chain forms, and microbial CpG DNA to regulate innate and adaptive immune responses. KIR3DL2 binds HLA-A3 and HLA-A11 in a peptide-dependent manner, with single amino acid substitutions at position 8 of the nonamer peptide critically affecting recognition, while it preferentially binds HLA-B27 free heavy chain homodimers (B27₂) in a peptide-independent manner via its D0 domain, triggering inhibition of IFN-γ production, promotion of KIR3DL2⁺ lymphocyte survival, and expansion of IL-17-producing CD4 T cells linked to spondyloarthritis pathogenesis [PMID:15162437, PMID:17407096, PMID:25582852, PMID:21248258]. KIR3DL2 also functions as a cell-surface receptor for CpG oligodeoxynucleotides, binding them through its D0 domain and co-internalizing to deliver CpG DNA to TLR9 in early endosomes; this CpG engagement discriminates self-derived from pathogen-derived DNA sequences and, in malignant Sézary T cells, induces caspase-dependent apoptosis with STAT3 dephosphorylation [PMID:20147700, PMID:34760351, PMID:25007046]. KIR3DL2 is aberrantly expressed on malignant T cells in cutaneous T-cell lymphoma and adult T-cell leukemia/lymphoma following HTLV-1-driven promoter hypomethylation, making it a therapeutic target for antibody-dependent cellular cytotoxicity [PMID:35687761, PMID:25361998].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Initial functional studies asked whether KIR3DL2 delivers canonical inhibitory signals on CTL, and unexpectedly found that antibody cross-linking of KIR3DL2 on tumor-specific CTL clones produced neither inhibitory nor activating effects on cytotoxicity or cytokine output, raising the question of context-dependent signaling.\",\n      \"evidence\": \"Anti-KIR3DL2 antibody cross-linking with ⁵¹Cr-release cytotoxicity and IFN-γ assays on primary human CTL clones\",\n      \"pmids\": [\"14562047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab observation; absence of effect may reflect insufficient cross-linking or cell-type-specific signaling\", \"No direct assessment of ITIM phosphorylation or SHP recruitment\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing ligand specificity, KIR3DL2*001 was shown to bind HLA-A3 and HLA-A11 in a peptide-dependent manner, with residue 8 of the nonamer peptide critically determining recognition, defining KIR3DL2 as a peptide-selective MHC class I receptor.\",\n      \"evidence\": \"HLA tetramer binding to KIR3DL2*001 transfectants with systematic peptide substitution analysis\",\n      \"pmids\": [\"15162437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of peptide selectivity unresolved\", \"Allelic variation in KIR3DL2 recognition not systematically explored\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Functional consequences of KIR3DL2 engagement were demonstrated when B27₂ homodimer-expressing cells protected KIR3DL2⁺ NK cells from apoptosis and enhanced their cytotoxicity, establishing a survival-promoting role for this receptor-ligand interaction in spondyloarthritis patients.\",\n      \"evidence\": \"Annexin V/7-AAD apoptosis and ⁵¹Cr-release cytotoxicity assays with SpA patient NK cells co-cultured with B27₂-expressing cells\",\n      \"pmids\": [\"16255049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway downstream of survival effect not identified\", \"Single disease cohort studied\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A major advance was the discovery that HLA-B27 free heavy chain homodimers bind KIR3DL2 in a peptide-independent manner — fundamentally different from conventional HLA recognition — and that this ligation inhibits NK and T cell IFN-γ production, providing a mechanistic link between HLA-B27 and immune dysregulation.\",\n      \"evidence\": \"Tetramer binding to transfectants, peptide analogue studies, and functional IFN-γ secretion assays\",\n      \"pmids\": [\"17407096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of peptide-independent recognition unresolved\", \"Relative contribution of monomeric vs. dimeric FHC unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Structural and mutagenesis work on KIR2DS4 identified that a proline-valine motif at positions 71–72, acquired by gene conversion from KIR3DL2, confers HLA-A*11 specificity, thereby mapping key specificity-determining residues in the KIR3DL2 binding surface.\",\n      \"evidence\": \"Crystal structure of KIR2DS4, swap mutagenesis of positions 71–72, and functional NK cell activation assays\",\n      \"pmids\": [\"19858347\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of KIR3DL2 itself in complex with HLA ligand\", \"Role of these residues in B27₂ recognition not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"KIR3DL2 was discovered to function beyond MHC recognition as a direct receptor for CpG oligodeoxynucleotides, binding CpG DNA via its D0 domain, co-internalizing with it, and shuttling it to TLR9 in early endosomes to trigger IFN-γ release — establishing a novel innate sensing role.\",\n      \"evidence\": \"Soluble receptor binding assay, D0 domain mutant analysis, confocal co-localization of CpG ODN and KIR3DL2, and cytokine secretion assays in NK cells\",\n      \"pmids\": [\"20147700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CpG–D0 interaction not determined\", \"Whether CpG binding and HLA binding are mutually exclusive unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The disease-relevant downstream consequence of KIR3DL2–B27₂ interaction was established: B27₂-expressing APCs drive survival, proliferation, and IL-17 production by KIR3DL2⁺ CD4 T cells, which express IL-23R, linking this pathway directly to Th17 expansion in spondyloarthritis.\",\n      \"evidence\": \"Co-culture of KIR3DL2⁺ CD4 T cells with B27₂-expressing APCs, flow cytometry for IL-23R, and IL-17 cytokine measurement across patient cohorts\",\n      \"pmids\": [\"21248258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling cascade connecting KIR3DL2 ligation to IL-17 transcription not defined\", \"Whether ITIM motifs are required for Th17 expansion not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Quantitative comparison established that B27 free heavy chains bind KIR3DL2 more strongly than HLA-A3, with greater receptor phosphorylation and functional output, and that the disease-associated B*27:05 allele forms more surface dimers and stimulates KIR3DL2 more effectively than the non-disease-associated B*27:09, providing a molecular explanation for differential disease risk.\",\n      \"evidence\": \"Tetramer binding, KIR3DL2Fc pulldown, phosphorylation assays, reporter cell IL-2 production, and allele-specific dimer quantification\",\n      \"pmids\": [\"23440420\", \"23804219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity measurements in solution (SPR/ITC) not reported\", \"Contribution of cis vs. trans B27₂ engagement in vivo unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Two studies expanded the functional repertoire: CpG ODN engagement of KIR3DL2 on malignant Sézary T cells induces receptor internalization, STAT3 dephosphorylation, and caspase-dependent apoptosis, while an anti-KIR3DL2 antibody (IPH4102) mediates ADCC and phagocytosis against CTCL cells, validating KIR3DL2 as a therapeutic target in T-cell lymphoma.\",\n      \"evidence\": \"CpG ODN treatment with caspase inhibitor and STAT3 immunoblot in Sézary cells; ADCC/phagocytosis assays and mouse xenograft with IPH4102\",\n      \"pmids\": [\"25007046\", \"25361998\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking STAT3 dephosphorylation to apoptosis induction not delineated\", \"Whether CpG-induced apoptosis occurs in non-malignant KIR3DL2⁺ cells not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Domain-level mapping through mutagenesis demonstrated that the D0 domain of KIR3DL2 is central to preferential B27₂ binding, with computational modeling predicting asymmetric contacts of D0 and D1 with both B27 heavy chains in the homodimer — the most detailed structural model of this interaction to date.\",\n      \"evidence\": \"Site-directed mutagenesis of KIR3DL2 Ig domains, functional reporter assays, and computational docking model\",\n      \"pmids\": [\"25582852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental crystal or cryo-EM structure of the KIR3DL2–B27₂ complex\", \"Contribution of individual D0 residues to CpG binding vs. B27₂ binding not dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CpG DNA sensing by KIR3DL2 was shown to be sequence-specific, with human-genome-prevalent CpG sequences delivering inhibitory signals and parasite-genome-prevalent sequences activating NK cytotoxicity and IFN-γ production, suggesting KIR3DL2 discriminates self-DNA from pathogen DNA.\",\n      \"evidence\": \"Comparative genomic CpG analysis with functional lysis and IFN-γ assays in KIR3DL2⁺ NKL cells\",\n      \"pmids\": [\"34760351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line (NKL); not confirmed in primary NK cells\", \"Structural basis of sequence-specific CpG discrimination unknown\", \"In vivo relevance of DNA sensing in infection not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"HTLV-1 infection was found to drive KIR3DL2 surface expression on CD4⁺ T cells through promoter hypomethylation rather than Tax-mediated transactivation, and anti-KIR3DL2 antibody (lacutamab) killed primary ATL cells via ADCC, establishing KIR3DL2 as a target in HTLV-1-driven malignancy.\",\n      \"evidence\": \"PrimeFlow RNA co-detection, in vitro HTLV-1 infection, methylation profiling, and ex vivo ADCC assay on primary ATL cells\",\n      \"pmids\": [\"35687761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Epigenetic mechanism of promoter demethylation not fully characterized\", \"Whether KIR3DL2 has a functional role in HTLV-1 pathogenesis beyond serving as a surface marker is unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution experimental structure of KIR3DL2 in complex with B27₂ homodimers or CpG DNA is still lacking, and the intracellular signaling pathways downstream of KIR3DL2 ligation — particularly how the same receptor can mediate inhibitory signaling, survival, IL-17 induction, or apoptosis depending on ligand and cell context — remain poorly defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of KIR3DL2 with any ligand\", \"Signaling intermediates linking ITIM phosphorylation to Th17 expansion or CpG-induced apoptosis not identified\", \"Whether CpG and HLA binding sites on D0 overlap is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2, 4, 7, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 3, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2, 4, 6, 12]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 7, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 6, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"HLA-A3\",\n      \"HLA-A11\",\n      \"HLA-B27\",\n      \"TLR9\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}