{"gene":"KIR2DS4","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2009,"finding":"KIR2DS4 binds specifically to subsets of C1+ and C2+ HLA-C alleles and to HLA-A*11 (specifically HLA-A*1102 but not HLA-A*1101). The proline-valine motif at positions 71-72, shared with KIR3DL2 and introduced by gene conversion, is largely responsible for this unique HLA class I specificity, as demonstrated by site-directed swap mutagenesis. Crystal structure determination revealed two major differences from inhibitory KIR2DL: displacement of contact loop L2 and altered bonding potential due to substitutions at positions 71 and 72.","method":"Site-directed swap mutagenesis, crystallographic structure determination, functional NK cell activation assays (NKL cells with A*1102 as ligand)","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus site-directed mutagenesis plus functional activation assays in a single rigorous study","pmids":["19858347"],"is_preprint":false},{"year":2002,"finding":"A common 22 bp deletion in exon 5 of KIR2DS4 causes a frameshift predicting a truncated protein with an altered D2 domain that lacks transmembrane/cytoplasmic domains and would be secreted rather than membrane-anchored.","method":"cDNA cloning and sequencing of KIR2DS4 deletion variant allele, population screening with deletion-specific probe","journal":"Tissue antigens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sequence-based characterization with predicted functional consequence; protein secretion confirmed in a follow-up study (PMID:17321903)","pmids":["12445308"],"is_preprint":false},{"year":2007,"finding":"The KIR2DS4 deletion variant (22 bp deletion, frameshift) encodes a soluble form of KIR2DS4 that is not anchored to the cell membrane but is potentially secreted, as determined using an in vitro cell line model system and in vivo protein expression studies.","method":"In vitro cell line model system, in vivo protein expression studies (functional investigation of the deletion variant)","journal":"Human immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein expression studies in cell line and in vivo, single lab, replicating prediction from earlier sequencing work","pmids":["17321903"],"is_preprint":false},{"year":2004,"finding":"KIR2DS4 can interact with a non-MHC class I ligand expressed on melanoma cell lines and primary melanoma, in addition to HLA-Cw4. Site-directed mutagenesis analysis revealed that the amino acid residues involved in recognition of this novel non-class I ligand are different from those interacting with HLA-Cw4, indicating distinct binding interfaces for MHC-dependent and MHC-independent recognition.","method":"Functional binding assays, site-directed mutagenesis, cytotoxicity assays against melanoma cell lines","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-directed mutagenesis plus functional assays, single lab; non-class I ligand identity not fully defined","pmids":["15265913"],"is_preprint":false},{"year":2019,"finding":"KIR2DS4 has a strong preference for peptides carrying a tryptophan at position 8 (p8) of 9-mer peptides bound to HLA-C*05:01. This pHLA complex is sufficient to activate primary KIR2DS4+ NK cells independently of other activating receptors and prior NK cell licensing. A conserved RecA epitope shared across >1,000 bacterial species (including Helicobacter, Chlamydia, Brucella, Campylobacter) activates KIR2DS4+ NK cells when presented by HLA-C*05:01.","method":"Primary NK cell degranulation assays, HLA-C*05:01-peptide binding and presentation assays, peptide library screening, functional activation assays with primary KIR2DS4+ NK cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (peptide library, primary NK cell functional assays, bacterial RecA epitope validation) establishing mechanistic specificity","pmids":["31138701"],"is_preprint":false},{"year":2016,"finding":"KIR2DS4 is expressed by ~45% of uterine NK (uNK) cells. Triggering of KIR2DS4 on uNK cells leads to secretion of GM-CSF, XCL1, CCL1, and other chemokines that promote placental trophoblast invasion. This functional role parallels that of KIR2DS1, suggesting activation of uNK cells by KIR binding to HLA-C is a generic mechanism promoting trophoblast invasion.","method":"Flow cytometry (expression on uNK cells), functional stimulation assays of primary uNK cells with KIR2DS4 triggering, cytokine screen of 120 different cytokines","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct functional assays on primary uNK cells with multiple cytokine readouts and flow cytometry, multiple orthogonal methods in one study","pmids":["27815424"],"is_preprint":false},{"year":2015,"finding":"KIR2DS4 can induce trogocytosis (uptake of CCR7) by KIR2DS4+NKG2A+ NK cell clones after interacting with CCR7+ target cells expressing HLA-Cw4 or HLA-Cw6 alleles. This interaction is not always sufficient to override the inhibition generated by NKG2A co-expressed on the same NK cells. Recognition of HLA-Cw4 was confirmed by cytotoxicity assays against HLA-C-transfected cells.","method":"Trogocytosis assay with NK cell clones, cytotoxicity assays against HLA-C-transfected target cells, flow cytometry","journal":"Journal of immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays with NK clones using two orthogonal readouts (trogocytosis and cytotoxicity), single lab","pmids":["25961063"],"is_preprint":false},{"year":2018,"finding":"Acute aerobic exercise decreases KIR2DS4 promoter DNA methylation and increases KIR2DS4 gene expression in NK cells. A high gene expression correlated with low methylation of specific CpG sites altered by acute exercise, indicating epigenetic regulation of KIR2DS4 expression via promoter demethylation.","method":"Targeted deep-amplicon sequencing of promoter methylation, qRT-PCR of gene expression, flow cytometry of NK cell subsets in human donors before/after graded exercise test","journal":"International journal of sports medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (methylation sequencing + qRT-PCR) in a controlled human intervention, single lab","pmids":["30508863"],"is_preprint":false},{"year":2012,"finding":"KIR2DS4 promoter contains a CpG island with three cytosine sites. Increased unmethylated sites in the KIR2DS4 promoter CpG island are associated with increased KIR2DS4 mRNA expression, and promoter hypomethylation frequency increases after hematopoietic cell transplantation, suggesting epigenetic control of KIR2DS4 expression linked to NK clonal expansion.","method":"Sodium bisulfite treatment of genomic DNA followed by sequencing (methylation analysis), mRNA-cDNA quantitative PCR","journal":"Human immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bisulfite sequencing and qPCR in donor/recipient cells, single lab, two orthogonal methods","pmids":["22939905"],"is_preprint":false},{"year":2014,"finding":"Full-length (membrane-bound) KIR2DS4 expression on NK cells from HIV-1 infected individuals is associated with enrichment of polyfunctional NK cells (co-degranulation and secretion of IFN-γ and MIP-1β), suggesting that KIR2DS4 surface expression promotes a pro-inflammatory NK cell state during chronic HIV infection.","method":"NK cell functional assays (degranulation, IFN-γ and MIP-1β secretion) stratified by KIR2DS4 surface expression, longitudinal mixed model analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional comparisons based on KIR2DS4 surface expression in HIV-infected individuals, multiple functional readouts, single lab","pmids":["24901871"],"is_preprint":false}],"current_model":"KIR2DS4 is a membrane-bound activating NK cell receptor whose full-length form (the 22 bp deletion variant produces a non-functional, secreted truncated protein) binds subsets of HLA-C alleles (with preference for peptides bearing Trp at position 8 in the context of HLA-C*05:01) and HLA-A*11, with binding specificity determined by a gene-conversion-derived Pro-Val motif at positions 71–72 that also displaces contact loop L2 relative to inhibitory KIR2DL; upon ligand engagement KIR2DS4 activates NK cells to degranulate and secrete cytokines/chemokines (GM-CSF, XCL1, CCL1, IFN-γ, MIP-1β), promotes trogocytosis of CCR7, and in uterine NK cells drives trophoblast invasion—while its expression is epigenetically regulated via promoter CpG methylation and can be increased by acute exercise-induced demethylation."},"narrative":{"mechanistic_narrative":"KIR2DS4 is an activating natural killer (NK) cell receptor that recognizes HLA class I ligands and triggers NK cell effector responses [PMID:19858347, PMID:31138701]. Its full-length membrane-bound form binds subsets of C1+ and C2+ HLA-C alleles and HLA-A*11 (HLA-A*1102), with specificity dictated by a gene-conversion-derived proline-valine motif at positions 71-72; crystallographic and swap-mutagenesis analysis showed this motif, together with displacement of contact loop L2, distinguishes KIR2DS4 from inhibitory KIR2DL receptors [PMID:19858347]. Ligand recognition is peptide-selective: KIR2DS4 strongly prefers HLA-C*05:01 presenting 9-mer peptides bearing tryptophan at position 8, and a conserved bacterial RecA epitope presented in this context is sufficient to activate primary KIR2DS4+ NK cells independently of licensing or other activating receptors [PMID:31138701]. KIR2DS4 also engages a non-MHC class I ligand on melanoma cells through a binding interface distinct from its HLA-Cw4 contacts [PMID:15265913]. Engagement drives functional outputs including degranulation and pro-inflammatory cytokine/chemokine secretion (IFN-γ, MIP-1β, GM-CSF, XCL1, CCL1) [PMID:27815424, PMID:24901871], trogocytic uptake of CCR7 from target cells [PMID:25961063], and, in uterine NK cells, secretion of factors that promote placental trophoblast invasion [PMID:27815424]. A common 22-bp exon 5 deletion produces a frameshifted, truncated protein lacking transmembrane and cytoplasmic domains that is secreted rather than membrane-anchored [PMID:12445308, PMID:17321903]. KIR2DS4 surface expression is controlled epigenetically through promoter CpG-island methylation, with hypomethylation correlating with increased expression following hematopoietic transplantation and after acute exercise [PMID:30508863, PMID:22939905].","teleology":[{"year":2002,"claim":"Establishing that a common KIR2DS4 allele cannot function as a membrane receptor reframed the gene as existing in functional and non-functional forms across populations.","evidence":"cDNA cloning and sequencing of the 22-bp exon 5 deletion variant with population screening","pmids":["12445308"],"confidence":"Medium","gaps":["Protein-level secretion was predicted, not demonstrated, at this stage","Functional consequence of the secreted form for NK activity not addressed"]},{"year":2004,"claim":"Demonstrating a non-MHC melanoma ligand engaged through residues distinct from the HLA-Cw4 contacts showed KIR2DS4 recognition is not restricted to classical MHC class I.","evidence":"Functional binding assays, site-directed mutagenesis, and cytotoxicity assays against melanoma lines","pmids":["15265913"],"confidence":"Medium","gaps":["Identity of the non-class I ligand not defined","In vivo relevance of MHC-independent recognition unknown"]},{"year":2007,"claim":"Direct protein-expression studies confirmed the deletion variant yields a soluble, non-membrane-anchored protein, validating the predicted secretion.","evidence":"In vitro cell line model and in vivo protein expression analysis of the deletion variant","pmids":["17321903"],"confidence":"Medium","gaps":["Biological function of the secreted form not established","Whether secreted protein retains any ligand binding not tested"]},{"year":2009,"claim":"Crystal structure and mutagenesis defined the molecular basis of KIR2DS4's HLA specificity, explaining how a gene-conversion-derived motif diverges it from inhibitory KIR2DL receptors.","evidence":"Site-directed swap mutagenesis, crystallography, and NK activation assays using A*1102 as ligand","pmids":["19858347"],"confidence":"High","gaps":["Peptide selectivity of HLA recognition not yet resolved at this stage","Downstream signaling adaptor not characterized in the corpus"]},{"year":2012,"claim":"Linking promoter CpG-island demethylation to KIR2DS4 mRNA levels established epigenetic control of receptor expression and connected it to NK clonal expansion after transplantation.","evidence":"Bisulfite sequencing and mRNA-cDNA quantitative PCR in transplant donor/recipient cells","pmids":["22939905"],"confidence":"Medium","gaps":["Transcription factors acting at the demethylated promoter not identified","Causality between methylation change and expression not directly tested"]},{"year":2014,"claim":"Associating full-length surface KIR2DS4 with polyfunctional NK responses in HIV infection indicated the receptor promotes a pro-inflammatory effector state in chronic disease.","evidence":"Degranulation and IFN-γ/MIP-1β secretion assays stratified by surface KIR2DS4 with longitudinal modeling","pmids":["24901871"],"confidence":"Medium","gaps":["Correlative, not causal, link to polyfunctionality","Ligand driving activation in vivo not identified"]},{"year":2015,"claim":"Showing KIR2DS4 can drive CCR7 trogocytosis upon HLA-Cw4/Cw6 recognition, yet not always override NKG2A inhibition, defined how its activating signal integrates with co-expressed inhibitory receptors.","evidence":"Trogocytosis and cytotoxicity assays with NK clones against HLA-C-transfected targets","pmids":["25961063"],"confidence":"Medium","gaps":["Mechanism balancing activation against NKG2A inhibition not resolved","Functional consequence of acquired CCR7 for NK trafficking untested"]},{"year":2016,"claim":"Identifying KIR2DS4 on uterine NK cells and its triggering of trophoblast-invasion-promoting chemokines extended its role from immune defense to reproductive tissue remodeling.","evidence":"Flow cytometry and functional stimulation of primary uNK cells with a 120-cytokine screen","pmids":["27815424"],"confidence":"High","gaps":["In vivo contribution to placentation not demonstrated","Peptide/ligand presented by trophoblast HLA-C not defined"]},{"year":2019,"claim":"Defining a tryptophan-at-p8 peptide preference on HLA-C*05:01 and a cross-reactive bacterial RecA epitope established KIR2DS4 as a peptide-specific activating receptor with potential pathogen-sensing function.","evidence":"Peptide library screening, HLA-C*05:01 presentation assays, and primary KIR2DS4+ NK degranulation assays with bacterial RecA validation","pmids":["31138701"],"confidence":"High","gaps":["Physiological relevance of bacterial epitope recognition in vivo not shown","Range of self versus microbial peptides recognized not fully mapped"]},{"year":null,"claim":"The intracellular signaling machinery and adaptor coupling that translate KIR2DS4 ligand engagement into NK activation remain uncharacterized in the available corpus.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No signaling adaptor (e.g. coupling partner) identified in the timeline","Function of the secreted deletion-variant protein unresolved","Identity of the non-MHC melanoma ligand unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,9]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,5,9]}],"complexes":[],"partners":["HLA-C","HLA-A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P43632","full_name":"Killer cell immunoglobulin-like receptor 2DS4","aliases":["CD158 antigen-like family member I","Natural killer-associated transcript 8","NKAT-8","P58 natural killer cell receptor clones CL-39/CL-17","p58 NK receptor CL-39/CL-17"],"length_aa":304,"mass_kda":33.6,"function":"Receptor on natural killer (NK) cells for HLA-C alleles. Does not inhibit the activity of NK cells","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P43632/entry"},"depmap":{"release":"DepMap","has_data":false,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KIR2DS4"},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KIR2DS4","total_profiled":1310},"omim":[{"mim_id":"620778","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, THREE DOMAINS, SHORT CYTOPLASMIC TAIL, 1; KIR3DS1","url":"https://www.omim.org/entry/620778"},{"mim_id":"604955","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, TWO DOMAINS, SHORT CYTOPLASMIC TAIL, 4; KIR2DS4","url":"https://www.omim.org/entry/604955"},{"mim_id":"604946","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, THREE DOMAINS, LONG CYTOPLASMIC TAIL, 1; KIR3DL1","url":"https://www.omim.org/entry/604946"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Not detected","tissue_distribution":"Not detected","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KIR2DS4"},"hgnc":{"alias_symbol":["cl-39","KKA3","nkat8","CD158I"],"prev_symbol":[]},"alphafold":{"accession":"P43632","domains":[{"cath_id":"2.60.40.10","chopping":"24-122","consensus_level":"high","plddt":94.1703,"start":24,"end":122},{"cath_id":"2.60.40.10","chopping":"127-223","consensus_level":"high","plddt":95.8896,"start":127,"end":223}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P43632","model_url":"https://alphafold.ebi.ac.uk/files/AF-P43632-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P43632-F1-predicted_aligned_error_v6.png","plddt_mean":81.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KIR2DS4","jax_strain_url":"https://www.jax.org/strain/search?query=KIR2DS4"},"sequence":{"accession":"P43632","fasta_url":"https://rest.uniprot.org/uniprotkb/P43632.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P43632/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P43632"}},"corpus_meta":[{"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":201,"is_preprint":false},{"pmid":"12445308","id":"PMC_12445308","title":"A common KIR2DS4 deletion variant in the human that predicts a soluble KIR molecule analogous to the KIR1D molecule observed in the rhesus monkey.","date":"2002","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/12445308","citation_count":112,"is_preprint":false},{"pmid":"15265913","id":"PMC_15265913","title":"MHC class I-independent recognition of NK-activating receptor KIR2DS4.","date":"2004","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/15265913","citation_count":84,"is_preprint":false},{"pmid":"17321903","id":"PMC_17321903","title":"Studies on the expression of the deleted KIR2DS4*003 gene product and distribution of KIR2DS4 deleted and nondeleted versions in different populations.","date":"2007","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17321903","citation_count":83,"is_preprint":false},{"pmid":"27815424","id":"PMC_27815424","title":"Activating KIR2DS4 Is Expressed by Uterine NK Cells and Contributes to Successful Pregnancy.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/27815424","citation_count":78,"is_preprint":false},{"pmid":"31138701","id":"PMC_31138701","title":"Human NK cell receptor KIR2DS4 detects a conserved bacterial epitope presented by HLA-C.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/31138701","citation_count":69,"is_preprint":false},{"pmid":"21216870","id":"PMC_21216870","title":"Impact of a functional KIR2DS4 allele on heterosexual HIV-1 transmission among discordant Zambian couples.","date":"2011","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21216870","citation_count":47,"is_preprint":false},{"pmid":"15219381","id":"PMC_15219381","title":"Investigation of killer cell immunoglobulin-like receptor gene diversity: II. KIR2DS4.","date":"2004","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15219381","citation_count":40,"is_preprint":false},{"pmid":"25715101","id":"PMC_25715101","title":"The HLA-C*04: 01/KIR2DS4 gene combination and human leukocyte antigen alleles with high population frequency drive rate of HIV disease progression.","date":"2015","source":"AIDS (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25715101","citation_count":33,"is_preprint":false},{"pmid":"21596150","id":"PMC_21596150","title":"Expression of activating KIR2DS2 and KIR2DS4 genes after hematopoietic cell transplantation: relevance to cytomegalovirus infection.","date":"2011","source":"Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/21596150","citation_count":30,"is_preprint":false},{"pmid":"24901871","id":"PMC_24901871","title":"KIR2DS4 promotes HIV-1 pathogenesis: new evidence from analyses 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28186587","citation_count":2,"is_preprint":false},{"pmid":"24659081","id":"PMC_24659081","title":"Investigation of deletion of 22pb in KIR2DS4 gene in a population of southern Brazil.","date":"2014","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/24659081","citation_count":2,"is_preprint":false},{"pmid":"37150297","id":"PMC_37150297","title":"KIR2DS4 and Its Variant KIR1D in KIR-AA Genotype Donors Showed Differential Survival Impact in Patients with Lymphoid Disease after HLA-Matched Unrelated Hematopoietic Stem Cell Transplantation.","date":"2023","source":"Transplantation and cellular therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37150297","citation_count":1,"is_preprint":false},{"pmid":"22939905","id":"PMC_22939905","title":"KIR2DS2 and KIR2DS4 promoter hypomethylation patterns in patients undergoing hematopoietic cell transplantation (HCT).","date":"2012","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22939905","citation_count":1,"is_preprint":false},{"pmid":"21223724","id":"PMC_21223724","title":"[The impact of KIR2DS4 gene on clinical outcomes of HLA matched unrelated allo-HSCT].","date":"2010","source":"Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi","url":"https://pubmed.ncbi.nlm.nih.gov/21223724","citation_count":1,"is_preprint":false},{"pmid":"35773759","id":"PMC_35773759","title":"[Establishment of sequence-based typing assay for KIR2DS4 gene and identification of a new allele KIR2DS4*016].","date":"2022","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35773759","citation_count":0,"is_preprint":false},{"pmid":"18549650","id":"PMC_18549650","title":"[Construction and identification of Kir2ds4 RNAi lentiviral vector].","date":"2008","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/18549650","citation_count":0,"is_preprint":false},{"pmid":"41230735","id":"PMC_41230735","title":"Genetically predicted KIR2DS4 mediate the association between gut microbe K10 and osteoporosis fractures: A mediation Mendelian randomization study.","date":"2025","source":"PM & R : the journal of injury, function, and rehabilitation","url":"https://pubmed.ncbi.nlm.nih.gov/41230735","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.03.626612","title":"High KIR diversity in Uganda and Botswana children living with HIV","date":"2024-12-07","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.03.626612","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22753,"output_tokens":2809,"usd":0.055197,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10093,"output_tokens":3115,"usd":0.06417,"stage2_stop_reason":"end_turn"},"total_usd":0.119367,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"KIR2DS4 binds specifically to subsets of C1+ and C2+ HLA-C alleles and to HLA-A*11 (specifically HLA-A*1102 but not HLA-A*1101). The proline-valine motif at positions 71-72, shared with KIR3DL2 and introduced by gene conversion, is largely responsible for this unique HLA class I specificity, as demonstrated by site-directed swap mutagenesis. Crystal structure determination revealed two major differences from inhibitory KIR2DL: displacement of contact loop L2 and altered bonding potential due to substitutions at positions 71 and 72.\",\n      \"method\": \"Site-directed swap mutagenesis, crystallographic structure determination, functional NK cell activation assays (NKL cells with A*1102 as ligand)\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus site-directed mutagenesis plus functional activation assays in a single rigorous study\",\n      \"pmids\": [\"19858347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A common 22 bp deletion in exon 5 of KIR2DS4 causes a frameshift predicting a truncated protein with an altered D2 domain that lacks transmembrane/cytoplasmic domains and would be secreted rather than membrane-anchored.\",\n      \"method\": \"cDNA cloning and sequencing of KIR2DS4 deletion variant allele, population screening with deletion-specific probe\",\n      \"journal\": \"Tissue antigens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sequence-based characterization with predicted functional consequence; protein secretion confirmed in a follow-up study (PMID:17321903)\",\n      \"pmids\": [\"12445308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The KIR2DS4 deletion variant (22 bp deletion, frameshift) encodes a soluble form of KIR2DS4 that is not anchored to the cell membrane but is potentially secreted, as determined using an in vitro cell line model system and in vivo protein expression studies.\",\n      \"method\": \"In vitro cell line model system, in vivo protein expression studies (functional investigation of the deletion variant)\",\n      \"journal\": \"Human immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein expression studies in cell line and in vivo, single lab, replicating prediction from earlier sequencing work\",\n      \"pmids\": [\"17321903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KIR2DS4 can interact with a non-MHC class I ligand expressed on melanoma cell lines and primary melanoma, in addition to HLA-Cw4. Site-directed mutagenesis analysis revealed that the amino acid residues involved in recognition of this novel non-class I ligand are different from those interacting with HLA-Cw4, indicating distinct binding interfaces for MHC-dependent and MHC-independent recognition.\",\n      \"method\": \"Functional binding assays, site-directed mutagenesis, cytotoxicity assays against melanoma cell lines\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-directed mutagenesis plus functional assays, single lab; non-class I ligand identity not fully defined\",\n      \"pmids\": [\"15265913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KIR2DS4 has a strong preference for peptides carrying a tryptophan at position 8 (p8) of 9-mer peptides bound to HLA-C*05:01. This pHLA complex is sufficient to activate primary KIR2DS4+ NK cells independently of other activating receptors and prior NK cell licensing. A conserved RecA epitope shared across >1,000 bacterial species (including Helicobacter, Chlamydia, Brucella, Campylobacter) activates KIR2DS4+ NK cells when presented by HLA-C*05:01.\",\n      \"method\": \"Primary NK cell degranulation assays, HLA-C*05:01-peptide binding and presentation assays, peptide library screening, functional activation assays with primary KIR2DS4+ NK cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (peptide library, primary NK cell functional assays, bacterial RecA epitope validation) establishing mechanistic specificity\",\n      \"pmids\": [\"31138701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIR2DS4 is expressed by ~45% of uterine NK (uNK) cells. Triggering of KIR2DS4 on uNK cells leads to secretion of GM-CSF, XCL1, CCL1, and other chemokines that promote placental trophoblast invasion. This functional role parallels that of KIR2DS1, suggesting activation of uNK cells by KIR binding to HLA-C is a generic mechanism promoting trophoblast invasion.\",\n      \"method\": \"Flow cytometry (expression on uNK cells), functional stimulation assays of primary uNK cells with KIR2DS4 triggering, cytokine screen of 120 different cytokines\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct functional assays on primary uNK cells with multiple cytokine readouts and flow cytometry, multiple orthogonal methods in one study\",\n      \"pmids\": [\"27815424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KIR2DS4 can induce trogocytosis (uptake of CCR7) by KIR2DS4+NKG2A+ NK cell clones after interacting with CCR7+ target cells expressing HLA-Cw4 or HLA-Cw6 alleles. This interaction is not always sufficient to override the inhibition generated by NKG2A co-expressed on the same NK cells. Recognition of HLA-Cw4 was confirmed by cytotoxicity assays against HLA-C-transfected cells.\",\n      \"method\": \"Trogocytosis assay with NK cell clones, cytotoxicity assays against HLA-C-transfected target cells, flow cytometry\",\n      \"journal\": \"Journal of immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays with NK clones using two orthogonal readouts (trogocytosis and cytotoxicity), single lab\",\n      \"pmids\": [\"25961063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Acute aerobic exercise decreases KIR2DS4 promoter DNA methylation and increases KIR2DS4 gene expression in NK cells. A high gene expression correlated with low methylation of specific CpG sites altered by acute exercise, indicating epigenetic regulation of KIR2DS4 expression via promoter demethylation.\",\n      \"method\": \"Targeted deep-amplicon sequencing of promoter methylation, qRT-PCR of gene expression, flow cytometry of NK cell subsets in human donors before/after graded exercise test\",\n      \"journal\": \"International journal of sports medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (methylation sequencing + qRT-PCR) in a controlled human intervention, single lab\",\n      \"pmids\": [\"30508863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KIR2DS4 promoter contains a CpG island with three cytosine sites. Increased unmethylated sites in the KIR2DS4 promoter CpG island are associated with increased KIR2DS4 mRNA expression, and promoter hypomethylation frequency increases after hematopoietic cell transplantation, suggesting epigenetic control of KIR2DS4 expression linked to NK clonal expansion.\",\n      \"method\": \"Sodium bisulfite treatment of genomic DNA followed by sequencing (methylation analysis), mRNA-cDNA quantitative PCR\",\n      \"journal\": \"Human immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bisulfite sequencing and qPCR in donor/recipient cells, single lab, two orthogonal methods\",\n      \"pmids\": [\"22939905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Full-length (membrane-bound) KIR2DS4 expression on NK cells from HIV-1 infected individuals is associated with enrichment of polyfunctional NK cells (co-degranulation and secretion of IFN-γ and MIP-1β), suggesting that KIR2DS4 surface expression promotes a pro-inflammatory NK cell state during chronic HIV infection.\",\n      \"method\": \"NK cell functional assays (degranulation, IFN-γ and MIP-1β secretion) stratified by KIR2DS4 surface expression, longitudinal mixed model analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional comparisons based on KIR2DS4 surface expression in HIV-infected individuals, multiple functional readouts, single lab\",\n      \"pmids\": [\"24901871\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIR2DS4 is a membrane-bound activating NK cell receptor whose full-length form (the 22 bp deletion variant produces a non-functional, secreted truncated protein) binds subsets of HLA-C alleles (with preference for peptides bearing Trp at position 8 in the context of HLA-C*05:01) and HLA-A*11, with binding specificity determined by a gene-conversion-derived Pro-Val motif at positions 71–72 that also displaces contact loop L2 relative to inhibitory KIR2DL; upon ligand engagement KIR2DS4 activates NK cells to degranulate and secrete cytokines/chemokines (GM-CSF, XCL1, CCL1, IFN-γ, MIP-1β), promotes trogocytosis of CCR7, and in uterine NK cells drives trophoblast invasion—while its expression is epigenetically regulated via promoter CpG methylation and can be increased by acute exercise-induced demethylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIR2DS4 is an activating natural killer (NK) cell receptor that recognizes HLA class I ligands and triggers NK cell effector responses [#0, #4]. Its full-length membrane-bound form binds subsets of C1+ and C2+ HLA-C alleles and HLA-A*11 (HLA-A*1102), with specificity dictated by a gene-conversion-derived proline-valine motif at positions 71-72; crystallographic and swap-mutagenesis analysis showed this motif, together with displacement of contact loop L2, distinguishes KIR2DS4 from inhibitory KIR2DL receptors [#0]. Ligand recognition is peptide-selective: KIR2DS4 strongly prefers HLA-C*05:01 presenting 9-mer peptides bearing tryptophan at position 8, and a conserved bacterial RecA epitope presented in this context is sufficient to activate primary KIR2DS4+ NK cells independently of licensing or other activating receptors [#4]. KIR2DS4 also engages a non-MHC class I ligand on melanoma cells through a binding interface distinct from its HLA-Cw4 contacts [#3]. Engagement drives functional outputs including degranulation and pro-inflammatory cytokine/chemokine secretion (IFN-\\u03b3, MIP-1\\u03b2, GM-CSF, XCL1, CCL1) [#5, #9], trogocytic uptake of CCR7 from target cells [#6], and, in uterine NK cells, secretion of factors that promote placental trophoblast invasion [#5]. A common 22-bp exon 5 deletion produces a frameshifted, truncated protein lacking transmembrane and cytoplasmic domains that is secreted rather than membrane-anchored [#1, #2]. KIR2DS4 surface expression is controlled epigenetically through promoter CpG-island methylation, with hypomethylation correlating with increased expression following hematopoietic transplantation and after acute exercise [#7, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that a common KIR2DS4 allele cannot function as a membrane receptor reframed the gene as existing in functional and non-functional forms across populations.\",\n      \"evidence\": \"cDNA cloning and sequencing of the 22-bp exon 5 deletion variant with population screening\",\n      \"pmids\": [\"12445308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protein-level secretion was predicted, not demonstrated, at this stage\", \"Functional consequence of the secreted form for NK activity not addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating a non-MHC melanoma ligand engaged through residues distinct from the HLA-Cw4 contacts showed KIR2DS4 recognition is not restricted to classical MHC class I.\",\n      \"evidence\": \"Functional binding assays, site-directed mutagenesis, and cytotoxicity assays against melanoma lines\",\n      \"pmids\": [\"15265913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the non-class I ligand not defined\", \"In vivo relevance of MHC-independent recognition unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Direct protein-expression studies confirmed the deletion variant yields a soluble, non-membrane-anchored protein, validating the predicted secretion.\",\n      \"evidence\": \"In vitro cell line model and in vivo protein expression analysis of the deletion variant\",\n      \"pmids\": [\"17321903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biological function of the secreted form not established\", \"Whether secreted protein retains any ligand binding not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Crystal structure and mutagenesis defined the molecular basis of KIR2DS4's HLA specificity, explaining how a gene-conversion-derived motif diverges it from inhibitory KIR2DL receptors.\",\n      \"evidence\": \"Site-directed swap mutagenesis, crystallography, and NK activation assays using A*1102 as ligand\",\n      \"pmids\": [\"19858347\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Peptide selectivity of HLA recognition not yet resolved at this stage\", \"Downstream signaling adaptor not characterized in the corpus\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linking promoter CpG-island demethylation to KIR2DS4 mRNA levels established epigenetic control of receptor expression and connected it to NK clonal expansion after transplantation.\",\n      \"evidence\": \"Bisulfite sequencing and mRNA-cDNA quantitative PCR in transplant donor/recipient cells\",\n      \"pmids\": [\"22939905\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factors acting at the demethylated promoter not identified\", \"Causality between methylation change and expression not directly tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Associating full-length surface KIR2DS4 with polyfunctional NK responses in HIV infection indicated the receptor promotes a pro-inflammatory effector state in chronic disease.\",\n      \"evidence\": \"Degranulation and IFN-\\u03b3/MIP-1\\u03b2 secretion assays stratified by surface KIR2DS4 with longitudinal modeling\",\n      \"pmids\": [\"24901871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative, not causal, link to polyfunctionality\", \"Ligand driving activation in vivo not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showing KIR2DS4 can drive CCR7 trogocytosis upon HLA-Cw4/Cw6 recognition, yet not always override NKG2A inhibition, defined how its activating signal integrates with co-expressed inhibitory receptors.\",\n      \"evidence\": \"Trogocytosis and cytotoxicity assays with NK clones against HLA-C-transfected targets\",\n      \"pmids\": [\"25961063\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism balancing activation against NKG2A inhibition not resolved\", \"Functional consequence of acquired CCR7 for NK trafficking untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying KIR2DS4 on uterine NK cells and its triggering of trophoblast-invasion-promoting chemokines extended its role from immune defense to reproductive tissue remodeling.\",\n      \"evidence\": \"Flow cytometry and functional stimulation of primary uNK cells with a 120-cytokine screen\",\n      \"pmids\": [\"27815424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution to placentation not demonstrated\", \"Peptide/ligand presented by trophoblast HLA-C not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defining a tryptophan-at-p8 peptide preference on HLA-C*05:01 and a cross-reactive bacterial RecA epitope established KIR2DS4 as a peptide-specific activating receptor with potential pathogen-sensing function.\",\n      \"evidence\": \"Peptide library screening, HLA-C*05:01 presentation assays, and primary KIR2DS4+ NK degranulation assays with bacterial RecA validation\",\n      \"pmids\": [\"31138701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of bacterial epitope recognition in vivo not shown\", \"Range of self versus microbial peptides recognized not fully mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intracellular signaling machinery and adaptor coupling that translate KIR2DS4 ligand engagement into NK activation remain uncharacterized in the available corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No signaling adaptor (e.g. coupling partner) identified in the timeline\", \"Function of the secreted deletion-variant protein unresolved\", \"Identity of the non-MHC melanoma ligand unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 9]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 5, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HLA-C\", \"HLA-A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}