{"gene":"KIR2DS1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2007,"finding":"KIR2DS1-expressing NK cells from donors homozygous for HLA-C1 are activated by target cells expressing the C2 group HLA-C antigens, producing IFN-γ and mediating allocytotoxicity. This activation is blocked by antibodies to both HLA class I and KIR2DS1, confirming direct HLA-C2 recognition by KIR2DS1. NK clones expressing KIR2DS1 mRNA but lacking KIR2DL1 mRNA demonstrate that KIR2DS1 itself (not absence of inhibitory signal) mediates C2-induced IFN-γ production.","method":"NK clone functional assays (IFN-γ intracellular staining, cytotoxicity assays), antibody blocking experiments, mRNA expression analysis of KIR2DS1 vs KIR2DL1 in clones","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal antibody blocking with defined NK clones, multiple orthogonal functional readouts (IFN-γ, cytotoxicity), replicated across polyclonal NK and clonal systems","pmids":["17617576"],"is_preprint":false},{"year":2008,"finding":"In a characterized alloreactive NK clone, KIR2DS1-mediated activation by HLA-C2 targets overrides NKG2A-mediated inhibitory signaling. Homozygous HLA-C2 targets were lysed more strongly than heterozygous C1/C2 targets. Anti-CD158a (KIR2DS1) antibody blocked lysis, confirming KIR2DS1 as the responsible receptor.","method":"NK clone cytotoxicity assays with defined HLA-C2+ targets, anti-KIR2DS1 (CD158a) antibody blocking, receptor expression profiling of the clone","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, antibody blocking plus defined NK clone, two functional readouts (lysis, receptor dominance hierarchy)","pmids":["18308713"],"is_preprint":false},{"year":2011,"finding":"KIR2DS1+ NK cells efficiently kill HLA-C2+ myelomonocytic dendritic cells (DCs) and T-cell blasts. In NK clones from C2/C2 Bw4/Bw4 donors, activating signals from KIR2DS1 override inhibitory signals from NKG2A or KIR2DL2/L3 co-expressed on the same clone. In C1/C2 targets, KIR2DS1+ NK cells are inhibited by co-expressed KIR2DL2/L3 but not by NKG2A, defining a hierarchical dominance relationship.","method":"NK clone cytotoxicity assays against defined HLA-typed target cells (DCs, T-cell blasts); NK clones with defined receptor co-expression patterns","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple NK clones with defined receptor expression, multiple HLA-typed target cell types, quantitative lysis assays establishing receptor dominance hierarchy","pmids":["21355085"],"is_preprint":false},{"year":2013,"finding":"KIR2DS1+ decidual NK (dNK) cells are strongly activated upon binding HLA-C2 on trophoblasts. Activation of KIR2DS1+ dNK cells triggers production of GM-CSF (detected by intracellular FACS and ELISA). GM-CSF in turn enhances migration of primary trophoblast and JEG-3 trophoblast cells in vitro, providing a molecular mechanism for KIR2DS1-mediated improvement of placentation. Microarray analysis revealed distinct gene expression responses in dNK co-expressing KIR2DS1+KIR2DL1 vs. those expressing only KIR2DL1.","method":"Microarray transcriptomics of sorted dNK subsets, intracellular FACS for GM-CSF, ELISA for secreted GM-CSF, in vitro trophoblast migration assays (primary trophoblast and JEG-3 cells)","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (microarray, intracellular FACS, ELISA, functional migration assay) in one study with defined cellular populations","pmids":["24091323"],"is_preprint":false},{"year":2013,"finding":"KIR2DS1+ NK cells acquire CCR7 from allogeneic HLA-C2+ CCR7+ cells (lymphoblastoid cell lines, DCs, T-cell blasts) by trogocytosis, thereby gaining migratory capacity toward lymph node chemokines. This CCR7 uptake is enhanced by KIR2DS1 expression and is diminished by co-expression of inhibitory KIR2DL2/L3 (but not by NKG2A in C2/C2 targets).","method":"Flow cytometry for CCR7 surface acquisition by NK cell clones and fresh NK cells co-incubated with defined allogeneic targets; chemotaxis assays toward lymph node chemokines","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple cell types tested, flow cytometry plus functional chemotaxis assay","pmids":["23449637"],"is_preprint":false},{"year":2013,"finding":"NK cells from HLA-C2 homozygous donors expressing KIR2DS1 are frequently tolerant to HLA-C2 (reduced frequency of anti-HLA-C2 reactive clones), whereas donors heterozygous or homozygous for HLA-C1 retain high frequencies of KIR2DS1+ anti-HLA-C2 reactive clones. Anti-HLA-C2 cytotoxicity of KIR2DS1+ clones is nearly exclusively restricted to clones lacking inhibitory KIR, demonstrating that co-expression of inhibitory KIR for self-HLA mediates tolerance of KIR2DS1+ cells. KIR2DS1 single-positive anti-HLA-C2 reactive clones persist post-transplantation in HLA-C2+ recipients.","method":"NK clone cytotoxicity assays against HLA-C2+ targets from donors with defined HLA-C genotypes; receptor expression profiling of clones by PCR and flow cytometry; post-transplantation donor NK clone analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic analysis across multiple donor HLA genotype groups, clone-level receptor expression mapped to functional tolerance, confirmed in post-transplant setting","pmids":["23554313"],"is_preprint":false},{"year":2016,"finding":"KIR2DS1+ decidual NK cells acquire higher cytotoxic function than KIR2DS1− dNK when exposed to HCMV-infected decidual stromal cells, particularly when stromal cells express HLA-C2. Primary fetal extravillous trophoblasts infected with HCMV did not trigger dNK degranulation or cytokine secretion regardless of KIR2DS1 status, indicating immune privilege limits trophoblast killing even upon viral infection.","method":"Degranulation assays (CD107a), cytokine secretion assays of sorted KIR2DS1+ vs KIR2DS1− dNK co-cultured with HCMV-infected decidual stromal cells and primary fetal extravillous trophoblasts; HLA-C2 expression on target cells verified","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — sorted primary cell subsets, multiple functional readouts (degranulation and cytokine), defined HLA-typed target cells, comparison across cell types establishing context-dependence","pmids":["27956621"],"is_preprint":false},{"year":2017,"finding":"KIR2DS1 reporter cells (mouse 2B4 carrying NFAT-GFP with KIR2DS1 and modified DAP12) and primary KIR2DS1+ NK cells are activated specifically by C2-HLA-C+ fibroblasts infected with specific clones of a clinical HCMV strain, but not by uninfected fibroblasts or HLA-C-transfected 721.221 cells. Active viral gene expression is required for KIR2DS1 activation. Anti-HLA class I (W6/32) blocks KIR2DS1 reporter activation but does not block KIR2DL1, indicating differential HLA-C recognition modes by KIR2DS1 vs KIR2DL1. KIR2DS1 binding was restricted to HLA-C group 2 complexes in a systematic screen of 97 HLA-I proteins.","method":"Mouse 2B4 NFAT-GFP reporter cell system expressing KIR2DS1+DAP12; primary NK cell degranulation assays; systematic binding screen of 97 HLA-I proteins; antibody blocking with W6/32","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstituted reporter system, primary cell validation, systematic ligand screen, antibody blocking distinguishing KIR2DS1 from KIR2DL1, multiple orthogonal approaches","pmids":["28424684"],"is_preprint":false},{"year":2017,"finding":"KIR2DS1 binding is narrowly restricted to HLA-C group 2 (C2) complexes in a systematic screen of 97 HLA-I proteins, whereas KIR2DL1 shows broader binding specificity. Using KIR2DS1ζ+ Jurkat reporter cells and peptide-pulsed HLA-C*06:02+ TAP1-KO cells, the synthetic peptide SRGPVHHLL presented by HLA-C*06:02 was identified as engaging KIR2DS1. This HLA-C*06:02/SRGPVHHLL complex also activates primary KIR2DS1+ NK cell clones, demonstrating peptide-dependent engagement of KIR2DS1.","method":"Systematic HLA binding screen (97 HLA-I proteins); KIR2DS1ζ Jurkat reporter cell assay with peptide-pulsed 721.221.TAP1KO-HLA-C*06:02 cells; primary NK clone activation assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reporter system reconstitution, systematic ligand screen, peptide identification with primary cell validation, multiple orthogonal methods","pmids":["28546555"],"is_preprint":false},{"year":2011,"finding":"KIR2DS1 self-associates in a well-defined fashion as revealed by circular dichroism spectroscopy, dynamic light scattering, and atomic force microscopy, suggesting receptor oligomerization may contribute to its signaling mechanism.","method":"Circular dichroism spectroscopy, dynamic light scattering, atomic force microscopy of purified KIR2DS1 protein","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — biophysical characterization with three orthogonal methods but single lab, no functional mutagenesis validation of oligomerization relevance","pmids":["21912587"],"is_preprint":false},{"year":2025,"finding":"A clade of Plasmodium falciparum RIFIN proteins binds to the KIR2DS1 extracellular domain (the RIFIN-binding surface of KIR2DL1 is conserved in KIR2DS1), resulting in activation of KIR2DS1-expressing NK cells. This demonstrates that KIR2DS1 can recognize a pathogen-derived non-HLA ligand and mediates NK cell activation against malaria-infected erythrocytes.","method":"Binding studies of RIFIN proteins to KIR2DS1; NK cell activation assays with KIR2DS1-expressing NK cells co-cultured with RIFIN-displaying P. falciparum-infected erythrocytes; structural analysis of RIFIN-KIR binding surfaces","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — structural analysis identifying conserved binding surface, binding assays, NK cell functional activation assays, published in Nature with multiple orthogonal approaches","pmids":["40500441"],"is_preprint":false},{"year":2024,"finding":"KIR2DS1+ NK cells demonstrate dominantly repressed ADCC (CD16-triggered degranulation) toward tumor cell lines in both missing-self and KIR-ligand matched settings, even in the presence of HLA-C2 (its ligand). This repression was also observed when KIR2DS1+ NK cells were stimulated with a CD34xCD16 bispecific killer engager, indicating KIR2DS1 expression intrinsically dampens ADCC independently of educational status.","method":"Flow cytometry-based degranulation assays (CD107a) of defined NK cell subsets stimulated with rituximab or CD34xCD16 bispecific killer engager against defined tumor cell lines; NK subset characterization by KIR expression profiling","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple target cell lines, two antibody stimulation modalities, systematic NK subset comparison","pmids":["38240527"],"is_preprint":false},{"year":2019,"finding":"Co-expression of HLA-C2 ligand diminishes KIR2DL1 (but not KIR2DS1) cell surface staining without affecting the frequencies of KIR2DL1- or KIR2DS1-expressing cells within the NK repertoire, revealing differential ligand-induced receptor downregulation between the inhibitory and activating counterparts. Education (tolerization) of KIR2DS1+ NK cells by HLA-C2 can be overridden by co-expression of self-specific inhibitory receptors such as CD94/NKG2A.","method":"Flow cytometry with novel allotype-discriminating monoclonal antibodies distinguishing KIR2DL1 and KIR2DS1; analysis of 230 healthy donors; NK functional assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel discriminating antibodies enabling first clean separation of KIR2DL1 and KIR2DS1 at cell surface, large donor cohort, multiple functional readouts, single lab","pmids":["31024561"],"is_preprint":false},{"year":2010,"finding":"KIR2DS1 is expressed on approximately 10% of circulating NK cells in the absence of KIR2DL1, regardless of donor HLA-C genotype. In HLA-C2 individuals, KIR2DS1 does not induce NK cell education (acquisition of competence) and does not interfere with KIR2DL1-induced NK cell education. KIR2DS1 is also present on rare oligoclonal TCRαβ+CD8α+ and TCRαβ+CD4−CD8− T cell subsets.","method":"Flow cytometry with discriminating antibodies on primary human NK and T cells from defined HLA-C genotype donors; NK education functional assays","journal":"Clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary human cells, defined HLA-C genotype stratification, multiple lymphocyte subsets characterized, single lab","pmids":["20093094"],"is_preprint":false}],"current_model":"KIR2DS1 is an activating NK cell receptor that signals via DAP12 upon binding HLA-C group 2 (C2) molecules in a peptide-dependent manner; in decidual NK cells it drives GM-CSF secretion to enhance trophoblast invasion and placentation, while in alloreactive settings it enables killing of HLA-C2+ leukemic cells, dendritic cells, and T-cell blasts by overriding inhibitory signals from NKG2A or co-expressed inhibitory KIRs; its activity is tolerized in HLA-C2 homozygous donors through co-expression of inhibitory KIRs, and it can also be engaged by pathogen-derived RIFIN ligands on malaria-infected erythrocytes to activate NK-mediated parasite killing."},"narrative":{"mechanistic_narrative":"KIR2DS1 is an activating natural killer (NK) cell receptor that recognizes HLA-C group 2 (C2) molecules and triggers NK cell effector functions including IFN-γ production and target cell cytotoxicity [PMID:17617576]. Its ligand specificity is narrowly restricted to HLA-C2 complexes, established by systematic screening across 97 HLA-I proteins, and engagement is peptide-dependent—the HLA-C*06:02/SRGPVHHLL complex activates primary KIR2DS1+ NK clones, and KIR2DS1 recognizes HLA-C2 through a mode distinct from its inhibitory counterpart KIR2DL1 [PMID:28424684, PMID:28546555]. Upon engaging HLA-C2+ targets, KIR2DS1-derived activating signals dominate over inhibitory input from NKG2A and, in a defined hierarchy, can be overridden by co-expressed inhibitory KIR2DL2/L3, enabling killing of HLA-C2+ dendritic cells and T-cell blasts [PMID:18308713, PMID:21355085]. In decidual NK cells, HLA-C2 on trophoblasts activates KIR2DS1+ cells to secrete GM-CSF, which enhances trophoblast migration and provides a mechanism linking the receptor to placentation [PMID:24091323]. Tolerance of KIR2DS1+ cells in HLA-C2-homozygous individuals is enforced by co-expression of self-specific inhibitory KIR, restricting anti-HLA-C2 reactivity to clones lacking inhibitory receptors [PMID:23554313]. Beyond HLA, a clade of Plasmodium falciparum RIFIN proteins binds the KIR2DS1 extracellular domain to activate NK cells against malaria-infected erythrocytes, demonstrating recognition of a pathogen-derived non-HLA ligand [PMID:40500441].","teleology":[{"year":2007,"claim":"Established that KIR2DS1 is a genuine activating receptor for HLA-C2 rather than merely reflecting the absence of inhibitory signaling, resolving whether the receptor itself transmits an activating signal.","evidence":"NK clone IFN-γ and cytotoxicity assays with reciprocal anti-HLA-I and anti-KIR2DS1 blocking, plus clones expressing KIR2DS1 but not KIR2DL1 mRNA","pmids":["17617576"],"confidence":"High","gaps":["Did not define the structural or peptide basis of HLA-C2 recognition","Signaling adaptor not directly demonstrated in this study"]},{"year":2010,"claim":"Defined the baseline expression pattern of KIR2DS1 and showed it does not itself educate NK cells in HLA-C2 individuals, distinguishing activating receptor expression from functional competence.","evidence":"Flow cytometry with discriminating antibodies and NK education assays on primary cells stratified by HLA-C genotype","pmids":["20093094"],"confidence":"Medium","gaps":["Mechanism of tolerance not yet defined at the clone level","T cell subset expression role unexplored"]},{"year":2011,"claim":"Showed that KIR2DS1 activation dominates over NKG2A inhibition and that purified receptor self-associates, beginning to define both the functional signaling hierarchy and a possible oligomerization mechanism.","evidence":"NK clone cytotoxicity with anti-CD158a blocking; circular dichroism, dynamic light scattering, and atomic force microscopy of purified protein","pmids":["18308713","21912587"],"confidence":"Medium","gaps":["Oligomerization not validated by functional mutagenesis","Dominance shown in single defined clones"]},{"year":2011,"claim":"Defined a hierarchical dominance relationship in which KIR2DS1 overrides NKG2A but is suppressed by co-expressed inhibitory KIR2DL2/L3, clarifying how integration of signals dictates killing of physiological targets.","evidence":"NK clone cytotoxicity against HLA-typed DCs and T-cell blasts with defined receptor co-expression","pmids":["21355085"],"confidence":"High","gaps":["Molecular basis of the dominance hierarchy not resolved","Did not test all inhibitory receptor combinations"]},{"year":2013,"claim":"Identified GM-CSF secretion as the effector output linking KIR2DS1 engagement of trophoblast HLA-C2 to enhanced trophoblast migration, providing a mechanism for the receptor's role in placentation.","evidence":"Microarray of sorted dNK subsets, intracellular FACS and ELISA for GM-CSF, in vitro trophoblast migration assays","pmids":["24091323"],"confidence":"High","gaps":["Signaling pathway from KIR2DS1 to GM-CSF not mapped","In vivo placentation effect not directly demonstrated"]},{"year":2013,"claim":"Demonstrated that KIR2DS1 can transfer CCR7 from allogeneic targets by trogocytosis, revealing a non-classical consequence of receptor engagement that confers migratory capacity.","evidence":"Flow cytometry for CCR7 acquisition and chemotaxis assays with defined allogeneic targets","pmids":["23449637"],"confidence":"Medium","gaps":["Mechanism of trogocytic transfer not defined","In vivo relevance of acquired CCR7 untested"]},{"year":2013,"claim":"Established that tolerance of KIR2DS1+ NK cells in HLA-C2-homozygous donors is enforced by co-expression of inhibitory KIR for self-HLA, explaining how autoreactivity is restrained.","evidence":"NK clone cytotoxicity stratified by donor HLA-C genotype with clone-level receptor profiling and post-transplant analysis","pmids":["23554313"],"confidence":"High","gaps":["Molecular basis of clonal tolerance acquisition not defined","Does not address tolerance in non-transplant tissue settings"]},{"year":2016,"claim":"Showed that KIR2DS1+ dNK cytotoxicity is amplified against HCMV-infected HLA-C2+ stromal cells while infected trophoblasts remain protected, defining context-dependence and immune privilege at the maternal-fetal interface.","evidence":"CD107a degranulation and cytokine assays of sorted dNK subsets against HCMV-infected stromal cells and trophoblasts","pmids":["27956621"],"confidence":"High","gaps":["Basis of trophoblast immune privilege not molecularly resolved","Viral factors modulating HLA-C2 not identified here"]},{"year":2017,"claim":"Defined the narrow HLA-C2 ligand specificity of KIR2DS1, showed activation requires active viral gene expression in HCMV-infected cells, and distinguished its recognition mode from KIR2DL1.","evidence":"Mouse 2B4 NFAT-GFP reporter expressing KIR2DS1+DAP12, primary NK degranulation, systematic 97-protein HLA screen, and W6/32 blocking","pmids":["28424684"],"confidence":"High","gaps":["Viral gene product driving activation not identified","Structural basis of differential recognition vs KIR2DL1 not resolved"]},{"year":2017,"claim":"Demonstrated peptide-dependent engagement of KIR2DS1 by identifying a specific peptide (SRGPVHHLL) presented by HLA-C*06:02 that activates primary KIR2DS1+ clones, establishing that the receptor reads the HLA-bound peptide.","evidence":"KIR2DS1ζ Jurkat reporter with peptide-pulsed TAP1-KO HLA-C*06:02 cells and primary NK clone activation","pmids":["28546555"],"confidence":"High","gaps":["Endogenous peptide repertoire engaging KIR2DS1 not catalogued","Structural mode of peptide discrimination not resolved"]},{"year":2019,"claim":"Using allotype-discriminating antibodies, separated KIR2DS1 from KIR2DL1 at the cell surface and showed differential ligand-induced downregulation, refining how activating and inhibitory counterparts respond to HLA-C2.","evidence":"Flow cytometry with novel discriminating monoclonal antibodies across 230 donors and NK functional assays","pmids":["31024561"],"confidence":"Medium","gaps":["Mechanism of differential receptor downregulation not defined","Functional consequence of retained KIR2DS1 surface levels unclear"]},{"year":2024,"claim":"Revealed that KIR2DS1 expression intrinsically represses CD16-triggered ADCC independently of NK education, indicating an unexpected dampening role for this activating receptor in antibody-mediated killing.","evidence":"CD107a degranulation assays with rituximab and a CD34xCD16 bispecific engager across defined NK subsets and tumor lines","pmids":["38240527"],"confidence":"Medium","gaps":["Molecular mechanism of ADCC repression not identified","Single lab, requires independent confirmation"]},{"year":2025,"claim":"Extended KIR2DS1 ligand recognition beyond HLA by showing a clade of P. falciparum RIFIN proteins binds the receptor and activates NK cells against malaria-infected erythrocytes.","evidence":"RIFIN-KIR2DS1 binding studies, structural analysis of binding surfaces, and NK activation assays with RIFIN-displaying infected erythrocytes","pmids":["40500441"],"confidence":"High","gaps":["In vivo relevance to malaria control not established","Affinity and signaling kinetics versus HLA-C2 engagement not compared"]},{"year":null,"claim":"The proximal signaling pathway from KIR2DS1/DAP12 engagement to downstream effector outputs (cytotoxicity, GM-CSF, ADCC repression) and the structural basis of peptide-dependent HLA-C2 discrimination remain to be mechanistically resolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of KIR2DS1-HLA-C2-peptide complex in the corpus","Signal transduction steps downstream of receptor engagement not mapped","Mechanism reconciling activating function with ADCC repression unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[10]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,7,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,12,13]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,3,7]}],"complexes":[],"partners":["DAP12","HLA-C"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14954","full_name":"Killer cell immunoglobulin-like receptor 2DS1","aliases":["CD158 antigen-like family member H","MHC class I NK cell receptor Eb6 ActI"],"length_aa":304,"mass_kda":33.6,"function":"Receptor on natural killer (NK) cells for some HLA-C alleles such as w6. Does not inhibit the activity of NK cells","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q14954/entry"},"depmap":{"release":"DepMap","has_data":false,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KIR2DS1"},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KIR2DS1","total_profiled":1310},"omim":[{"mim_id":"610604","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, THREE DOMAINS, PSEUDOGENE 1; KIR3DP1","url":"https://www.omim.org/entry/610604"},{"mim_id":"605086","title":"TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS 2; TREM2","url":"https://www.omim.org/entry/605086"},{"mim_id":"605085","title":"TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS 1; TREM1","url":"https://www.omim.org/entry/605085"},{"mim_id":"604955","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, TWO DOMAINS, SHORT CYTOPLASMIC TAIL, 4; KIR2DS4","url":"https://www.omim.org/entry/604955"},{"mim_id":"604953","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, TWO DOMAINS, SHORT CYTOPLASMIC TAIL, 2; KIR2DS2","url":"https://www.omim.org/entry/604953"}],"hpa":{"profiled":false,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"","tissue_distribution":"","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KIR2DS1"},"hgnc":{"alias_symbol":["EB6ActI","EB6ActII","CD158H"],"prev_symbol":[]},"alphafold":{"accession":"Q14954","domains":[{"cath_id":"2.60.40.10","chopping":"26-122","consensus_level":"high","plddt":94.6834,"start":26,"end":122},{"cath_id":"2.60.40.10","chopping":"127-224","consensus_level":"high","plddt":95.3087,"start":127,"end":224}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14954","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14954-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14954-F1-predicted_aligned_error_v6.png","plddt_mean":80.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KIR2DS1","jax_strain_url":"https://www.jax.org/strain/search?query=KIR2DS1"},"sequence":{"accession":"Q14954","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14954.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14954/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14954"}},"corpus_meta":[{"pmid":"22931314","id":"PMC_22931314","title":"HLA-C-dependent prevention of leukemia relapse by donor activating KIR2DS1.","date":"2012","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22931314","citation_count":360,"is_preprint":false},{"pmid":"24091323","id":"PMC_24091323","title":"Maternal uterine NK cell-activating receptor KIR2DS1 enhances placentation.","date":"2013","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24091323","citation_count":222,"is_preprint":false},{"pmid":"17617576","id":"PMC_17617576","title":"KIR2DS1-positive NK cells mediate alloresponse against the C2 HLA-KIR ligand group in vitro.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17617576","citation_count":154,"is_preprint":false},{"pmid":"15310528","id":"PMC_15310528","title":"Gene for the activating natural killer cell receptor, KIR2DS1, is associated with susceptibility to psoriasis vulgaris.","date":"2004","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15310528","citation_count":126,"is_preprint":false},{"pmid":"21355085","id":"PMC_21355085","title":"Natural killer cells expressing the KIR2DS1-activating receptor efficiently kill T-cell blasts and dendritic cells: implications in haploidentical HSCT.","date":"2011","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/21355085","citation_count":91,"is_preprint":false},{"pmid":"16112031","id":"PMC_16112031","title":"Activating killer cell immunoglobulin-like receptor gene KIR2DS1 is associated with psoriatic arthritis.","date":"2005","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16112031","citation_count":73,"is_preprint":false},{"pmid":"27956621","id":"PMC_27956621","title":"Expression of KIR2DS1 by decidual natural killer cells increases their ability to control placental HCMV infection.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27956621","citation_count":73,"is_preprint":false},{"pmid":"20878400","id":"PMC_20878400","title":"Association of KIR2DS1 and KIR2DS3 with fatal outcome in Ebola virus infection.","date":"2010","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/20878400","citation_count":63,"is_preprint":false},{"pmid":"18308713","id":"PMC_18308713","title":"KIR2DS1-mediated activation overrides NKG2A-mediated inhibition in HLA-C C2-negative individuals.","date":"2008","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18308713","citation_count":53,"is_preprint":false},{"pmid":"23554313","id":"PMC_23554313","title":"NK cell tolerance of self-specific activating receptor KIR2DS1 in individuals with cognate HLA-C2 ligand.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23554313","citation_count":50,"is_preprint":false},{"pmid":"28424684","id":"PMC_28424684","title":"Modulation of Human Leukocyte Antigen-C by Human Cytomegalovirus Stimulates KIR2DS1 Recognition by Natural Killer Cells.","date":"2017","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28424684","citation_count":49,"is_preprint":false},{"pmid":"31932846","id":"PMC_31932846","title":"External validation of models for KIR2DS1/KIR3DL1-informed selection of hematopoietic cell donors fails.","date":"2020","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/31932846","citation_count":43,"is_preprint":false},{"pmid":"21844874","id":"PMC_21844874","title":"KIR2DS1 genotype predicts for complete cytogenetic response and survival in newly diagnosed chronic myeloid leukemia patients treated with imatinib.","date":"2011","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/21844874","citation_count":40,"is_preprint":false},{"pmid":"23449637","id":"PMC_23449637","title":"KIR2DS1-dependent acquisition of CCR7 and migratory properties by human NK cells interacting with allogeneic HLA-C2+ DCs or T-cell blasts.","date":"2013","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/23449637","citation_count":37,"is_preprint":false},{"pmid":"28546555","id":"PMC_28546555","title":"Peptide-specific engagement of the activating NK cell receptor KIR2DS1.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28546555","citation_count":35,"is_preprint":false},{"pmid":"31024561","id":"PMC_31024561","title":"Novel Approach to Cell Surface Discrimination Between KIR2DL1 Subtypes and KIR2DS1 Identifies Hierarchies in NK Repertoire, Education, and Tolerance.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31024561","citation_count":32,"is_preprint":false},{"pmid":"23831511","id":"PMC_23831511","title":"Protective effect of the KIR2DS1 gene in atopic dermatitis.","date":"2013","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/23831511","citation_count":32,"is_preprint":false},{"pmid":"21797986","id":"PMC_21797986","title":"KIR3DL1+HLA-B Bw4Ile80 and KIR2DS1+HLA-C2 combinations are both associated with ankylosing spondylitis in the Iranian population.","date":"2011","source":"International journal of immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/21797986","citation_count":26,"is_preprint":false},{"pmid":"26589762","id":"PMC_26589762","title":"Recurrent Pregnancy Loss in Women with Killer Cell Immunoglobulin-Like Receptor KIR2DS1 is Associated with an Increased HLA-C2 Allelic Frequency.","date":"2015","source":"American journal of reproductive immunology (New York, N.Y. : 1989)","url":"https://pubmed.ncbi.nlm.nih.gov/26589762","citation_count":24,"is_preprint":false},{"pmid":"20093094","id":"PMC_20093094","title":"Expression of the HLA-C2-specific activating killer-cell Ig-like receptor KIR2DS1 on NK and T cells.","date":"2010","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/20093094","citation_count":23,"is_preprint":false},{"pmid":"18643961","id":"PMC_18643961","title":"A study of the killer cell immunoglobulin-like receptor gene KIR2DS1 in a Caucasoid Brazilian population with psoriasis vulgaris.","date":"2008","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/18643961","citation_count":23,"is_preprint":false},{"pmid":"21791599","id":"PMC_21791599","title":"Role of alloreactive KIR2DS1(+) NK cells in haploidentical hematopoietic stem cell transplantation.","date":"2011","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/21791599","citation_count":22,"is_preprint":false},{"pmid":"16829306","id":"PMC_16829306","title":"A role for KIR gene variants other than KIR2DS1 in conferring susceptibility to psoriasis.","date":"2006","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16829306","citation_count":21,"is_preprint":false},{"pmid":"29408295","id":"PMC_29408295","title":"KIR2DS1, 2DS5, 3DS1 and KIR2DL5 are associated with the risk of head and neck squamous cell carcinoma in Iranians.","date":"2018","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29408295","citation_count":20,"is_preprint":false},{"pmid":"24529855","id":"PMC_24529855","title":"The role of KIR2DS1 in multiple sclerosis--KIR in Portuguese MS patients.","date":"2014","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/24529855","citation_count":18,"is_preprint":false},{"pmid":"18643963","id":"PMC_18643963","title":"Investigation of killer cell immunoglobulin-like receptor gene diversity, KIR2DL1 and KIR2DS1.","date":"2008","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/18643963","citation_count":14,"is_preprint":false},{"pmid":"27747156","id":"PMC_27747156","title":"Multiple sclerosis is accompanied by lack of KIR2DS1 gene: A meta-analysis.","date":"2016","source":"Genomics data","url":"https://pubmed.ncbi.nlm.nih.gov/27747156","citation_count":13,"is_preprint":false},{"pmid":"21912587","id":"PMC_21912587","title":"Self-association of an activating natural killer cell receptor, KIR2DS1.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21912587","citation_count":10,"is_preprint":false},{"pmid":"31899360","id":"PMC_31899360","title":"Donor KIR2DS1-Mediated Decreased Relapse and Improved Survival Depending on Remission Status at HLA-Haploidentical Transplantation with Post-Transplantation Cyclophosphamide.","date":"2019","source":"Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/31899360","citation_count":9,"is_preprint":false},{"pmid":"35114151","id":"PMC_35114151","title":"KIR2DS1-HLA-C status as a predictive marker for benefit from rituximab: a post-hoc analysis of the RICOVER-60 and CLL8 trials.","date":"2022","source":"The Lancet. Haematology","url":"https://pubmed.ncbi.nlm.nih.gov/35114151","citation_count":7,"is_preprint":false},{"pmid":"36720995","id":"PMC_36720995","title":"Association of KIR2DL5, KIR2DS5, and KIR2DS1 allelic variation and atopic dermatitis.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36720995","citation_count":5,"is_preprint":false},{"pmid":"31237928","id":"PMC_31237928","title":"Donor KIR2DS1 reduces the risk of transplant related mortality in HLA-C2 positive young recipients with hematological malignancies treated by myeloablative conditioning.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31237928","citation_count":5,"is_preprint":false},{"pmid":"40500441","id":"PMC_40500441","title":"RIFINs displayed on malaria-infected erythrocytes bind KIR2DL1 and KIR2DS1.","date":"2025","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/40500441","citation_count":4,"is_preprint":false},{"pmid":"38240527","id":"PMC_38240527","title":"KIR2DS1 and KIR2DL1-C245 Dominantly Repress NK Cell Degranulation Triggered by Monoclonal or Bispecific Antibodies, whereas Education by Uptuning Inhibitory Killer Ig-related Receptors Exerts No Advantage in Ab-dependent Cellular Cytotoxicity.","date":"2024","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/38240527","citation_count":4,"is_preprint":false},{"pmid":"29099970","id":"PMC_29099970","title":"Expression of KIR2DS1 does not significantly contribute to NK cell cytotoxicity in HLA-C1/C2 heterozygous haplotype B donors.","date":"2017","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29099970","citation_count":4,"is_preprint":false},{"pmid":"42125902","id":"PMC_42125902","title":"Antibody S22019F Selectively Recognises KIR2DS1 and Enables Analysis of KIR2DS1+ NK Cells and T Cells.","date":"2026","source":"HLA","url":"https://pubmed.ncbi.nlm.nih.gov/42125902","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.09.25325484","title":"Examining the association between fetal<i>HLA-C</i>, maternal<i>KIR</i>haplotypes and birth weight","date":"2025-04-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.09.25325484","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22230,"output_tokens":4515,"usd":0.067208,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12545,"output_tokens":4218,"usd":0.084087,"stage2_stop_reason":"end_turn"},"total_usd":0.151295,"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\": 2007,\n      \"finding\": \"KIR2DS1-expressing NK cells from donors homozygous for HLA-C1 are activated by target cells expressing the C2 group HLA-C antigens, producing IFN-γ and mediating allocytotoxicity. This activation is blocked by antibodies to both HLA class I and KIR2DS1, confirming direct HLA-C2 recognition by KIR2DS1. NK clones expressing KIR2DS1 mRNA but lacking KIR2DL1 mRNA demonstrate that KIR2DS1 itself (not absence of inhibitory signal) mediates C2-induced IFN-γ production.\",\n      \"method\": \"NK clone functional assays (IFN-γ intracellular staining, cytotoxicity assays), antibody blocking experiments, mRNA expression analysis of KIR2DS1 vs KIR2DL1 in clones\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal antibody blocking with defined NK clones, multiple orthogonal functional readouts (IFN-γ, cytotoxicity), replicated across polyclonal NK and clonal systems\",\n      \"pmids\": [\"17617576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In a characterized alloreactive NK clone, KIR2DS1-mediated activation by HLA-C2 targets overrides NKG2A-mediated inhibitory signaling. Homozygous HLA-C2 targets were lysed more strongly than heterozygous C1/C2 targets. Anti-CD158a (KIR2DS1) antibody blocked lysis, confirming KIR2DS1 as the responsible receptor.\",\n      \"method\": \"NK clone cytotoxicity assays with defined HLA-C2+ targets, anti-KIR2DS1 (CD158a) antibody blocking, receptor expression profiling of the clone\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, antibody blocking plus defined NK clone, two functional readouts (lysis, receptor dominance hierarchy)\",\n      \"pmids\": [\"18308713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KIR2DS1+ NK cells efficiently kill HLA-C2+ myelomonocytic dendritic cells (DCs) and T-cell blasts. In NK clones from C2/C2 Bw4/Bw4 donors, activating signals from KIR2DS1 override inhibitory signals from NKG2A or KIR2DL2/L3 co-expressed on the same clone. In C1/C2 targets, KIR2DS1+ NK cells are inhibited by co-expressed KIR2DL2/L3 but not by NKG2A, defining a hierarchical dominance relationship.\",\n      \"method\": \"NK clone cytotoxicity assays against defined HLA-typed target cells (DCs, T-cell blasts); NK clones with defined receptor co-expression patterns\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple NK clones with defined receptor expression, multiple HLA-typed target cell types, quantitative lysis assays establishing receptor dominance hierarchy\",\n      \"pmids\": [\"21355085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KIR2DS1+ decidual NK (dNK) cells are strongly activated upon binding HLA-C2 on trophoblasts. Activation of KIR2DS1+ dNK cells triggers production of GM-CSF (detected by intracellular FACS and ELISA). GM-CSF in turn enhances migration of primary trophoblast and JEG-3 trophoblast cells in vitro, providing a molecular mechanism for KIR2DS1-mediated improvement of placentation. Microarray analysis revealed distinct gene expression responses in dNK co-expressing KIR2DS1+KIR2DL1 vs. those expressing only KIR2DL1.\",\n      \"method\": \"Microarray transcriptomics of sorted dNK subsets, intracellular FACS for GM-CSF, ELISA for secreted GM-CSF, in vitro trophoblast migration assays (primary trophoblast and JEG-3 cells)\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (microarray, intracellular FACS, ELISA, functional migration assay) in one study with defined cellular populations\",\n      \"pmids\": [\"24091323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KIR2DS1+ NK cells acquire CCR7 from allogeneic HLA-C2+ CCR7+ cells (lymphoblastoid cell lines, DCs, T-cell blasts) by trogocytosis, thereby gaining migratory capacity toward lymph node chemokines. This CCR7 uptake is enhanced by KIR2DS1 expression and is diminished by co-expression of inhibitory KIR2DL2/L3 (but not by NKG2A in C2/C2 targets).\",\n      \"method\": \"Flow cytometry for CCR7 surface acquisition by NK cell clones and fresh NK cells co-incubated with defined allogeneic targets; chemotaxis assays toward lymph node chemokines\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple cell types tested, flow cytometry plus functional chemotaxis assay\",\n      \"pmids\": [\"23449637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NK cells from HLA-C2 homozygous donors expressing KIR2DS1 are frequently tolerant to HLA-C2 (reduced frequency of anti-HLA-C2 reactive clones), whereas donors heterozygous or homozygous for HLA-C1 retain high frequencies of KIR2DS1+ anti-HLA-C2 reactive clones. Anti-HLA-C2 cytotoxicity of KIR2DS1+ clones is nearly exclusively restricted to clones lacking inhibitory KIR, demonstrating that co-expression of inhibitory KIR for self-HLA mediates tolerance of KIR2DS1+ cells. KIR2DS1 single-positive anti-HLA-C2 reactive clones persist post-transplantation in HLA-C2+ recipients.\",\n      \"method\": \"NK clone cytotoxicity assays against HLA-C2+ targets from donors with defined HLA-C genotypes; receptor expression profiling of clones by PCR and flow cytometry; post-transplantation donor NK clone analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic analysis across multiple donor HLA genotype groups, clone-level receptor expression mapped to functional tolerance, confirmed in post-transplant setting\",\n      \"pmids\": [\"23554313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIR2DS1+ decidual NK cells acquire higher cytotoxic function than KIR2DS1− dNK when exposed to HCMV-infected decidual stromal cells, particularly when stromal cells express HLA-C2. Primary fetal extravillous trophoblasts infected with HCMV did not trigger dNK degranulation or cytokine secretion regardless of KIR2DS1 status, indicating immune privilege limits trophoblast killing even upon viral infection.\",\n      \"method\": \"Degranulation assays (CD107a), cytokine secretion assays of sorted KIR2DS1+ vs KIR2DS1− dNK co-cultured with HCMV-infected decidual stromal cells and primary fetal extravillous trophoblasts; HLA-C2 expression on target cells verified\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — sorted primary cell subsets, multiple functional readouts (degranulation and cytokine), defined HLA-typed target cells, comparison across cell types establishing context-dependence\",\n      \"pmids\": [\"27956621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KIR2DS1 reporter cells (mouse 2B4 carrying NFAT-GFP with KIR2DS1 and modified DAP12) and primary KIR2DS1+ NK cells are activated specifically by C2-HLA-C+ fibroblasts infected with specific clones of a clinical HCMV strain, but not by uninfected fibroblasts or HLA-C-transfected 721.221 cells. Active viral gene expression is required for KIR2DS1 activation. Anti-HLA class I (W6/32) blocks KIR2DS1 reporter activation but does not block KIR2DL1, indicating differential HLA-C recognition modes by KIR2DS1 vs KIR2DL1. KIR2DS1 binding was restricted to HLA-C group 2 complexes in a systematic screen of 97 HLA-I proteins.\",\n      \"method\": \"Mouse 2B4 NFAT-GFP reporter cell system expressing KIR2DS1+DAP12; primary NK cell degranulation assays; systematic binding screen of 97 HLA-I proteins; antibody blocking with W6/32\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstituted reporter system, primary cell validation, systematic ligand screen, antibody blocking distinguishing KIR2DS1 from KIR2DL1, multiple orthogonal approaches\",\n      \"pmids\": [\"28424684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KIR2DS1 binding is narrowly restricted to HLA-C group 2 (C2) complexes in a systematic screen of 97 HLA-I proteins, whereas KIR2DL1 shows broader binding specificity. Using KIR2DS1ζ+ Jurkat reporter cells and peptide-pulsed HLA-C*06:02+ TAP1-KO cells, the synthetic peptide SRGPVHHLL presented by HLA-C*06:02 was identified as engaging KIR2DS1. This HLA-C*06:02/SRGPVHHLL complex also activates primary KIR2DS1+ NK cell clones, demonstrating peptide-dependent engagement of KIR2DS1.\",\n      \"method\": \"Systematic HLA binding screen (97 HLA-I proteins); KIR2DS1ζ Jurkat reporter cell assay with peptide-pulsed 721.221.TAP1KO-HLA-C*06:02 cells; primary NK clone activation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reporter system reconstitution, systematic ligand screen, peptide identification with primary cell validation, multiple orthogonal methods\",\n      \"pmids\": [\"28546555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KIR2DS1 self-associates in a well-defined fashion as revealed by circular dichroism spectroscopy, dynamic light scattering, and atomic force microscopy, suggesting receptor oligomerization may contribute to its signaling mechanism.\",\n      \"method\": \"Circular dichroism spectroscopy, dynamic light scattering, atomic force microscopy of purified KIR2DS1 protein\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — biophysical characterization with three orthogonal methods but single lab, no functional mutagenesis validation of oligomerization relevance\",\n      \"pmids\": [\"21912587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A clade of Plasmodium falciparum RIFIN proteins binds to the KIR2DS1 extracellular domain (the RIFIN-binding surface of KIR2DL1 is conserved in KIR2DS1), resulting in activation of KIR2DS1-expressing NK cells. This demonstrates that KIR2DS1 can recognize a pathogen-derived non-HLA ligand and mediates NK cell activation against malaria-infected erythrocytes.\",\n      \"method\": \"Binding studies of RIFIN proteins to KIR2DS1; NK cell activation assays with KIR2DS1-expressing NK cells co-cultured with RIFIN-displaying P. falciparum-infected erythrocytes; structural analysis of RIFIN-KIR binding surfaces\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — structural analysis identifying conserved binding surface, binding assays, NK cell functional activation assays, published in Nature with multiple orthogonal approaches\",\n      \"pmids\": [\"40500441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIR2DS1+ NK cells demonstrate dominantly repressed ADCC (CD16-triggered degranulation) toward tumor cell lines in both missing-self and KIR-ligand matched settings, even in the presence of HLA-C2 (its ligand). This repression was also observed when KIR2DS1+ NK cells were stimulated with a CD34xCD16 bispecific killer engager, indicating KIR2DS1 expression intrinsically dampens ADCC independently of educational status.\",\n      \"method\": \"Flow cytometry-based degranulation assays (CD107a) of defined NK cell subsets stimulated with rituximab or CD34xCD16 bispecific killer engager against defined tumor cell lines; NK subset characterization by KIR expression profiling\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple target cell lines, two antibody stimulation modalities, systematic NK subset comparison\",\n      \"pmids\": [\"38240527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Co-expression of HLA-C2 ligand diminishes KIR2DL1 (but not KIR2DS1) cell surface staining without affecting the frequencies of KIR2DL1- or KIR2DS1-expressing cells within the NK repertoire, revealing differential ligand-induced receptor downregulation between the inhibitory and activating counterparts. Education (tolerization) of KIR2DS1+ NK cells by HLA-C2 can be overridden by co-expression of self-specific inhibitory receptors such as CD94/NKG2A.\",\n      \"method\": \"Flow cytometry with novel allotype-discriminating monoclonal antibodies distinguishing KIR2DL1 and KIR2DS1; analysis of 230 healthy donors; NK functional assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel discriminating antibodies enabling first clean separation of KIR2DL1 and KIR2DS1 at cell surface, large donor cohort, multiple functional readouts, single lab\",\n      \"pmids\": [\"31024561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KIR2DS1 is expressed on approximately 10% of circulating NK cells in the absence of KIR2DL1, regardless of donor HLA-C genotype. In HLA-C2 individuals, KIR2DS1 does not induce NK cell education (acquisition of competence) and does not interfere with KIR2DL1-induced NK cell education. KIR2DS1 is also present on rare oligoclonal TCRαβ+CD8α+ and TCRαβ+CD4−CD8− T cell subsets.\",\n      \"method\": \"Flow cytometry with discriminating antibodies on primary human NK and T cells from defined HLA-C genotype donors; NK education functional assays\",\n      \"journal\": \"Clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary human cells, defined HLA-C genotype stratification, multiple lymphocyte subsets characterized, single lab\",\n      \"pmids\": [\"20093094\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIR2DS1 is an activating NK cell receptor that signals via DAP12 upon binding HLA-C group 2 (C2) molecules in a peptide-dependent manner; in decidual NK cells it drives GM-CSF secretion to enhance trophoblast invasion and placentation, while in alloreactive settings it enables killing of HLA-C2+ leukemic cells, dendritic cells, and T-cell blasts by overriding inhibitory signals from NKG2A or co-expressed inhibitory KIRs; its activity is tolerized in HLA-C2 homozygous donors through co-expression of inhibitory KIRs, and it can also be engaged by pathogen-derived RIFIN ligands on malaria-infected erythrocytes to activate NK-mediated parasite killing.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIR2DS1 is an activating natural killer (NK) cell receptor that recognizes HLA-C group 2 (C2) molecules and triggers NK cell effector functions including IFN-γ production and target cell cytotoxicity [#0]. Its ligand specificity is narrowly restricted to HLA-C2 complexes, established by systematic screening across 97 HLA-I proteins, and engagement is peptide-dependent—the HLA-C*06:02/SRGPVHHLL complex activates primary KIR2DS1+ NK clones, and KIR2DS1 recognizes HLA-C2 through a mode distinct from its inhibitory counterpart KIR2DL1 [#7, #8]. Upon engaging HLA-C2+ targets, KIR2DS1-derived activating signals dominate over inhibitory input from NKG2A and, in a defined hierarchy, can be overridden by co-expressed inhibitory KIR2DL2/L3, enabling killing of HLA-C2+ dendritic cells and T-cell blasts [#1, #2]. In decidual NK cells, HLA-C2 on trophoblasts activates KIR2DS1+ cells to secrete GM-CSF, which enhances trophoblast migration and provides a mechanism linking the receptor to placentation [#3]. Tolerance of KIR2DS1+ cells in HLA-C2-homozygous individuals is enforced by co-expression of self-specific inhibitory KIR, restricting anti-HLA-C2 reactivity to clones lacking inhibitory receptors [#5]. Beyond HLA, a clade of Plasmodium falciparum RIFIN proteins binds the KIR2DS1 extracellular domain to activate NK cells against malaria-infected erythrocytes, demonstrating recognition of a pathogen-derived non-HLA ligand [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that KIR2DS1 is a genuine activating receptor for HLA-C2 rather than merely reflecting the absence of inhibitory signaling, resolving whether the receptor itself transmits an activating signal.\",\n      \"evidence\": \"NK clone IFN-γ and cytotoxicity assays with reciprocal anti-HLA-I and anti-KIR2DS1 blocking, plus clones expressing KIR2DS1 but not KIR2DL1 mRNA\",\n      \"pmids\": [\"17617576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural or peptide basis of HLA-C2 recognition\", \"Signaling adaptor not directly demonstrated in this study\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the baseline expression pattern of KIR2DS1 and showed it does not itself educate NK cells in HLA-C2 individuals, distinguishing activating receptor expression from functional competence.\",\n      \"evidence\": \"Flow cytometry with discriminating antibodies and NK education assays on primary cells stratified by HLA-C genotype\",\n      \"pmids\": [\"20093094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of tolerance not yet defined at the clone level\", \"T cell subset expression role unexplored\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed that KIR2DS1 activation dominates over NKG2A inhibition and that purified receptor self-associates, beginning to define both the functional signaling hierarchy and a possible oligomerization mechanism.\",\n      \"evidence\": \"NK clone cytotoxicity with anti-CD158a blocking; circular dichroism, dynamic light scattering, and atomic force microscopy of purified protein\",\n      \"pmids\": [\"18308713\", \"21912587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Oligomerization not validated by functional mutagenesis\", \"Dominance shown in single defined clones\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined a hierarchical dominance relationship in which KIR2DS1 overrides NKG2A but is suppressed by co-expressed inhibitory KIR2DL2/L3, clarifying how integration of signals dictates killing of physiological targets.\",\n      \"evidence\": \"NK clone cytotoxicity against HLA-typed DCs and T-cell blasts with defined receptor co-expression\",\n      \"pmids\": [\"21355085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the dominance hierarchy not resolved\", \"Did not test all inhibitory receptor combinations\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified GM-CSF secretion as the effector output linking KIR2DS1 engagement of trophoblast HLA-C2 to enhanced trophoblast migration, providing a mechanism for the receptor's role in placentation.\",\n      \"evidence\": \"Microarray of sorted dNK subsets, intracellular FACS and ELISA for GM-CSF, in vitro trophoblast migration assays\",\n      \"pmids\": [\"24091323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway from KIR2DS1 to GM-CSF not mapped\", \"In vivo placentation effect not directly demonstrated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that KIR2DS1 can transfer CCR7 from allogeneic targets by trogocytosis, revealing a non-classical consequence of receptor engagement that confers migratory capacity.\",\n      \"evidence\": \"Flow cytometry for CCR7 acquisition and chemotaxis assays with defined allogeneic targets\",\n      \"pmids\": [\"23449637\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of trogocytic transfer not defined\", \"In vivo relevance of acquired CCR7 untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that tolerance of KIR2DS1+ NK cells in HLA-C2-homozygous donors is enforced by co-expression of inhibitory KIR for self-HLA, explaining how autoreactivity is restrained.\",\n      \"evidence\": \"NK clone cytotoxicity stratified by donor HLA-C genotype with clone-level receptor profiling and post-transplant analysis\",\n      \"pmids\": [\"23554313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of clonal tolerance acquisition not defined\", \"Does not address tolerance in non-transplant tissue settings\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed that KIR2DS1+ dNK cytotoxicity is amplified against HCMV-infected HLA-C2+ stromal cells while infected trophoblasts remain protected, defining context-dependence and immune privilege at the maternal-fetal interface.\",\n      \"evidence\": \"CD107a degranulation and cytokine assays of sorted dNK subsets against HCMV-infected stromal cells and trophoblasts\",\n      \"pmids\": [\"27956621\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis of trophoblast immune privilege not molecularly resolved\", \"Viral factors modulating HLA-C2 not identified here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the narrow HLA-C2 ligand specificity of KIR2DS1, showed activation requires active viral gene expression in HCMV-infected cells, and distinguished its recognition mode from KIR2DL1.\",\n      \"evidence\": \"Mouse 2B4 NFAT-GFP reporter expressing KIR2DS1+DAP12, primary NK degranulation, systematic 97-protein HLA screen, and W6/32 blocking\",\n      \"pmids\": [\"28424684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Viral gene product driving activation not identified\", \"Structural basis of differential recognition vs KIR2DL1 not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated peptide-dependent engagement of KIR2DS1 by identifying a specific peptide (SRGPVHHLL) presented by HLA-C*06:02 that activates primary KIR2DS1+ clones, establishing that the receptor reads the HLA-bound peptide.\",\n      \"evidence\": \"KIR2DS1ζ Jurkat reporter with peptide-pulsed TAP1-KO HLA-C*06:02 cells and primary NK clone activation\",\n      \"pmids\": [\"28546555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous peptide repertoire engaging KIR2DS1 not catalogued\", \"Structural mode of peptide discrimination not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Using allotype-discriminating antibodies, separated KIR2DS1 from KIR2DL1 at the cell surface and showed differential ligand-induced downregulation, refining how activating and inhibitory counterparts respond to HLA-C2.\",\n      \"evidence\": \"Flow cytometry with novel discriminating monoclonal antibodies across 230 donors and NK functional assays\",\n      \"pmids\": [\"31024561\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of differential receptor downregulation not defined\", \"Functional consequence of retained KIR2DS1 surface levels unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed that KIR2DS1 expression intrinsically represses CD16-triggered ADCC independently of NK education, indicating an unexpected dampening role for this activating receptor in antibody-mediated killing.\",\n      \"evidence\": \"CD107a degranulation assays with rituximab and a CD34xCD16 bispecific engager across defined NK subsets and tumor lines\",\n      \"pmids\": [\"38240527\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of ADCC repression not identified\", \"Single lab, requires independent confirmation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended KIR2DS1 ligand recognition beyond HLA by showing a clade of P. falciparum RIFIN proteins binds the receptor and activates NK cells against malaria-infected erythrocytes.\",\n      \"evidence\": \"RIFIN-KIR2DS1 binding studies, structural analysis of binding surfaces, and NK activation assays with RIFIN-displaying infected erythrocytes\",\n      \"pmids\": [\"40500441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance to malaria control not established\", \"Affinity and signaling kinetics versus HLA-C2 engagement not compared\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The proximal signaling pathway from KIR2DS1/DAP12 engagement to downstream effector outputs (cytotoxicity, GM-CSF, ADCC repression) and the structural basis of peptide-dependent HLA-C2 discrimination remain to be mechanistically resolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of KIR2DS1-HLA-C2-peptide complex in the corpus\", \"Signal transduction steps downstream of receptor engagement not mapped\", \"Mechanism reconciling activating function with ADCC repression unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 7, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 12, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 3, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DAP12\", \"HLA-C\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}