{"gene":"KLRC1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1991,"finding":"KLRC1 (NKG2-A) encodes a type II integral membrane protein of 215-233 amino acids containing a C-type lectin domain, expressed on NK cells but not T or B cells. NKG2-A and NKG2-B are alternative splicing products of a single gene.","method":"cDNA cloning, sequence analysis, Northern blotting","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — full-length cDNA sequencing with structural characterization, foundational paper replicated by subsequent studies","pmids":["2007850"],"is_preprint":false},{"year":1996,"finding":"NKG2-A/B forms disulfide-bonded heterodimers with CD94 on NK cells. NKG2-A/B possesses two immunoreceptor tyrosine-based inhibition motif (ITIM) sequences in its cytoplasmic domain, providing the molecular basis for inhibitory receptor function.","method":"Biochemical characterization, immunoprecipitation, sequence analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical demonstration of disulfide-bonded heterodimer, ITIM identification confirmed by multiple subsequent labs","pmids":["8943374"],"is_preprint":false},{"year":1997,"finding":"The CD94/NKG2-A inhibitory receptor complex on NK cells recognizes HLA class I molecules via NKG2-A's ITIMs. The Z199 mAb specifically recognizes NKG2-A. NKG2-B (alternatively spliced product of the NKG2-A gene) can also assemble with CD94. Both NKG2-A and NKG2-B contain cytoplasmic ITIMs.","method":"Immunoprecipitation, mAb characterization, functional cytotoxicity assays","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal immunoprecipitation with mAb characterization, replicated across multiple labs","pmids":["9045931"],"is_preprint":false},{"year":1997,"finding":"NKG2-A delivers inhibitory signals in NK cells: chimeric NKG2-A/NKR-P1C receptor inhibited lytic activity and failed to stimulate calcium response. NKG2-A-mediated inhibition is associated with selective recruitment of SHP-1 tyrosine phosphatase to the NKG2-A cytoplasmic domain.","method":"Chimeric receptor transfection into rat NK cell line (RNK-16), cytotoxicity assays, calcium flux measurements, immunoprecipitation","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — functional reconstitution with chimeric receptors plus biochemical SHP-1 co-IP, mechanistically definitive","pmids":["9103421"],"is_preprint":false},{"year":1997,"finding":"CD94/NKG2-A inhibitory receptor complex is involved in NK cell-mediated recognition of HLA-G1; most NK clones blocked by HLA-G1 expressed CD94/NKG2-A, and CD94-specific mAbs restored cytolytic activity.","method":"NK cell clone functional assays, mAb blocking experiments, cytotoxicity assays with 721.221 transfectants","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional antibody blocking plus clone analysis, single lab but clear mechanistic readout","pmids":["9190923"],"is_preprint":false},{"year":1997,"finding":"CD94/NKG2 is the predominant inhibitory receptor for HLA-G on decidual NK cells; anti-CD94 mAb blocked recognition of HLA-G transfectants whereas KIR-specific mAbs had no effect.","method":"NK cell clone establishment from placenta, mAb blocking cytotoxicity assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blocking with receptor-specific mAbs in primary decidual NK cells, corroborated by paper 9190923","pmids":["9233599"],"is_preprint":false},{"year":1997,"finding":"CD94/NKG2 inhibitory receptor complex on Vγ9Vδ2 T cells inhibits proliferative and cytotoxic responses; signaling through CD94/NKG2 interferes with IFN-γ and TNF-α synthesis by these cells.","method":"Anti-CD94 mAb blocking of proliferation and cytokine production, cytotoxicity assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional mAb blocking demonstrating inhibitory role of CD94/NKG2-A on γδ T cells, single lab","pmids":["9550399"],"is_preprint":false},{"year":1998,"finding":"CD94/NKG2-A specifically recognizes HLA-E molecules on target cells, leading to inhibition of NK cell lysis. HLA-E surface expression requires binding of peptides from HLA class I signal sequences; only peptides with Met at position 2 confer resistance to NK lysis. CD94/NKG2-A recognition is blocked by CD94-specific (not KIR-specific) mAbs.","method":"NK cell cytotoxicity assays, peptide loading of HLA-E on 721.221 cells, mAb blocking","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal experiments (peptide loading, cytotoxicity, mAb blocking), replicated by multiple subsequent labs","pmids":["9480992"],"is_preprint":false},{"year":1998,"finding":"Engagement of CD94/NKG2-A by either specific mAb (Z199) or by HLA-E+ target cells induces tyrosine phosphorylation of the NKG2-A subunit and recruitment of SHP-1 phosphatase. This mechanism was confirmed in RBL-2H3 transfectants expressing CD94/NKG2-A, where receptor cross-linking inhibited FcεRI-triggered secretory events.","method":"mAb cross-linking, immunoprecipitation, Western blotting for phosphotyrosine and SHP-1, RBL transfectant system","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct biochemical demonstration of NKG2-A phosphorylation and SHP-1 recruitment in both NK cells and heterologous RBL transfectants","pmids":["9565368"],"is_preprint":false},{"year":1998,"finding":"HLA-E-bound peptides influence recognition by inhibitory CD94/NKG2-A; the primary structure of HLA-E-bound peptides modulates CD94/NKG2A-mediated recognition beyond their ability to stabilize surface HLA-E. CD94/NKG2A+ NK clones showed greater sensitivity to most HLA-E/peptide complexes compared to CD94/NKG2C+ cells.","method":"NK clone cytotoxicity assays with 721.221 cells loaded with synthetic nonamers, comparison of inhibitory vs activating receptor-expressing clones","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays with panels of synthetic peptides and characterized NK clones, single lab","pmids":["9754572"],"is_preprint":false},{"year":1999,"finding":"Soluble CD94/NKG2-A has higher binding affinity for HLA-E than activating CD94/NKG2-C. Both receptors show peptide-dependent recognition of HLA-E with very fast association and dissociation kinetics. Binding affinity of peptide-HLA-E complexes correlates directly with triggering of NK cell responses.","method":"Surface plasmon resonance (BIAcore) with soluble recombinant HLA-E and CD94/NKG2-A and CD94/NKG2-C proteins","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative binding kinetics with soluble recombinant proteins by SPR, mechanistically definitive","pmids":["10428963"],"is_preprint":false},{"year":1999,"finding":"Crystal structure of CD94 extracellular domain (2.6 Å) reveals a novel C-type lectin fold with a non-functional Ca2+-binding site and modified carbohydrate-binding region. The CD94 dimer interface suggests a putative HLA-E binding region and implicates how NKG2 interacts with CD94.","method":"X-ray crystallography","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 2.6 Å resolution providing atomic-level structural information","pmids":["10023772"],"is_preprint":false},{"year":1999,"finding":"CD94/NKG2-A inhibits CD16-triggered NK cell cytotoxicity by blocking tyrosine phosphorylation and activation of Syk kinase, tyrosine phosphorylation of CD16 zeta subunit, and downstream activation of ERK. Inhibition is exerted at a PTK-dependent stage upstream of p21ras, blocking Shc phosphorylation and Shc/Grb-2 complex formation.","method":"Co-engagement of CD94/NKG2-A and CD16 in primary NK cells, Western blotting for kinase phosphorylation, kinase activity assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — detailed biochemical pathway analysis with multiple signaling intermediates characterized, mechanistically comprehensive","pmids":["10358164"],"is_preprint":false},{"year":1999,"finding":"HLA-E-mediated protection of porcine endothelial cells from human NK cells is CD94/NKG2-dependent: HLA-E engagement leads to phosphorylation of the CD94/NKG2 complex and recruitment of SHP-1. HLA-G protection operates via a CD94/NKG2-independent pathway.","method":"mAb blocking assays, phosphorylation analysis, SHP-1 co-immunoprecipitation","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical and functional assays confirming SHP-1 recruitment mechanism in porcine endothelial cell system, corroborates paper 9565368","pmids":["10570324"],"is_preprint":false},{"year":2000,"finding":"CD94/NKG2-A co-engagement with CD69 suppresses CD69-triggered cell degranulation by inhibiting ERK activation in NK cells. Co-engagement of CD94/NKG2-A in RBL transfectants and human NK cells inhibited CD69-induced cytotoxicity.","method":"RBL transfectants co-expressing CD69 and CD94/NKG2-A, ERK activation assays, degranulation assays, NK cell cytotoxicity","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ERK pathway mechanistically linked to NKG2-A inhibitory function using both transfectant and primary NK cell systems","pmids":["10671222"],"is_preprint":false},{"year":2000,"finding":"HLA-E is expressed on trophoblast cells and interacts with CD94/NKG2 receptors on decidual NK cells; the majority of decidual NK cells bind HLA-E tetrameric complexes in a CD94-dependent manner. The overall functional outcome of CD94/NKG2-HLA-E interaction is inhibition of decidual NK cell cytotoxicity.","method":"HLA-E tetramer staining, mAb blocking, cytotoxicity assays with polyclonal decidual NK cells","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tetramer-based receptor-ligand identification with functional cytotoxicity readout in primary decidual NK cells","pmids":["10898498"],"is_preprint":false},{"year":2000,"finding":"The activating CD94/NKG2-C receptor triggers cytotoxic effector functions via activation of the MAPK/ERK pathway; MEK inhibitor PD098059 blocked CD94/NKG2-C-dependent TNF-α production and cytotoxicity. CD94/NKG2-C signals through DAP12/KARAP.","method":"MEK inhibitor (PD098059) treatment, MAPK phosphorylation assays, cytotoxicity and TNF-α production assays, RBL transfection with CD94/NKG2-C/DAP12","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — pharmacological inhibition combined with transfection reconstitution and functional readouts, single lab","pmids":["11069065"],"is_preprint":false},{"year":2002,"finding":"IL-12 induces expression of NKG2-A and/or CD94 on CD8+ T cells in culture, leading to acquisition of a functional inhibitory receptor, as demonstrated by redirected killing assay. This induction is not mediated by IFN-γ or IL-15.","method":"Culture of T cells with IL-12, flow cytometry, RT-PCR, redirected killing assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cytokine induction with functional receptor validation using redirected killing, single lab","pmids":["11994435"],"is_preprint":false},{"year":2004,"finding":"CD94/NKG2A inhibitory receptor plays a critical role in down-regulating iNKT cell responses. IFN-γ produced during alpha-GalCer stimulation upregulates Qa-1b, which in turn inhibits iNKT cell activity via CD94/NKG2A. Blockade of the CD94/NKG2-Qa-1b interaction markedly augmented iNKT cell recall and primary responses.","method":"mAb blockade of CD94/NKG2-Qa-1b interaction, alpha-GalCer stimulation assays in vivo and in vitro, flow cytometry for receptor down-modulation","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro functional blockade experiments establishing IFN-γ-Qa-1b-CD94/NKG2A feedback circuit","pmids":["15746081"],"is_preprint":false},{"year":2004,"finding":"NKG2A preferential surface expression over NKG2C with CD94 is determined by a single amino acid difference in the transmembrane domain. The stalk domain of NKG2C enhances heterodimer formation with CD94. DAP12 enhances NKG2C's ability to compete for CD94 surface expression.","method":"Transfection of NKG2A/NKG2C chimeric and mutant constructs, flow cytometry for surface expression, DAP12 co-transfection","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis identifying transmembrane domain residues, single lab but multiple constructs tested","pmids":["15153509"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of CD94-NKG2A heterodimer at 2.5 Å reveals an asymmetric dimer interface (contrasting with homodimeric NK receptors), providing structural basis for preferred heterodimeric assembly. Structure-based mutagenesis on HLA-E and CD94-NKG2A established that CD94 plays a more dominant role than NKG2A in interacting with HLA-E.","method":"X-ray crystallography at 2.5 Å, extensive mutagenesis studies on HLA-E and CD94-NKG2A","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with extensive mutagenesis, mechanistically definitive about heterodimer assembly and ligand binding","pmids":["18083576"],"is_preprint":false},{"year":2008,"finding":"Subtle peptide conformational changes within the HLA-E binding groove, without changes in the HLA-E heavy chain, determine differential recognition by CD94-NKG2 receptors. Structures of HLA-E with HLA-Cw*07 peptide (poor CD94-NKG2 recognition) and HLA-G*01 peptide (high-affinity CD94-NKG2 ligand) both at 2.5 Å confirmed peptide-dependent recognition.","method":"X-ray crystallography at 2.5 Å of HLA-E with two different leader peptides","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — dual crystal structures providing atomic-level basis for peptide-dependent CD94-NKG2 recognition","pmids":["18339401"],"is_preprint":false},{"year":2022,"finding":"In mouse cortex, CD94/NKG2 receptor is expressed by microglial cells and interacts with Qa-1 (HLA-E homolog) expressed in layer 6 corticothalamic neurons. This neuron-microglial interaction via the Qa-1/CD94/NKG2 axis regulates activity-dependent plasticity in the visual cortex; selectively targeting this interaction phenocopies plasticity perturbation seen in Qa-1 knockouts.","method":"Mouse knockouts, in vivo pharmacological blockade of CD94/NKG2-Qa-1 interaction, ocular dominance plasticity assays, microglial morphology analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological in vivo experiments with defined functional readout, single lab","pmids":["35648829"],"is_preprint":false},{"year":2023,"finding":"KLRC1 knockout in human NK cells relieves HLA-E-mediated inhibition and significantly improves cytotoxicity against HLA-E+ solid tumor cell lines in vitro and delays tumor progression in vivo. KLRC1 KO also increases NKG2C expression on NK cells.","method":"CRISPR-mediated KLRC1 gene editing, in vitro cytotoxicity assays against multiple HLA-E+ tumor lines, xenogeneic mouse model of metastatic breast cancer","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function CRISPR KO with in vitro and in vivo functional readouts, multiple tumor lines tested","pmids":["37675109"],"is_preprint":false},{"year":2023,"finding":"Antigen-specific human NK cell memory against HIV and influenza is largely dependent on the activating CD94/NKG2C receptor and its ligand HLA-E, as demonstrated by single-cell cloning of memory NK cells and identification of individual HLA-E-restricted peptides.","method":"Single-cell NK cell cloning, complex immunophenotyping, peptide-HLA-E tetramer assays, functional memory NK cell assays","journal":"Science immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single-cell cloning with functional validation, single lab but multiple orthogonal approaches","pmids":["38064568"],"is_preprint":false},{"year":2023,"finding":"Among 16 common classical HLA class I signal peptide variants, only 6 efficiently generate epitopes enabling CD94/NKG2 engagement. HLA-B/-21M SP induces high HLA-E expression but confers the lowest receptor recognition, competing with other SPs for HLA-E epitope binding and reducing overall CD94/NKG2A recognition of target cells.","method":"Systematic quantitative analysis of signal peptide processing, HLA-E surface expression assays, CD94/NKG2A recognition assays with multiple peptide variants","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic quantitative approach with multiple SP variants tested, mechanistically informative about ligand hierarchy, high-profile journal","pmids":["37264229"],"is_preprint":false},{"year":2024,"finding":"LAG-3 sustains TOX expression and controls a LAG-3-dependent circuit generating a CD94/NKG2+ subset of exhausted CD8 T cells with enhanced cytotoxicity mediated by recognition of the stress ligand Qa-1b (mouse homolog of HLA-E). Loss of LAG-3 reduces this CD94/NKG2+ Tex subset.","method":"Genetic deletion of PD-1 and/or LAG-3 in mouse chronic viral infection model, transcriptomic and phenotypic analysis, functional cytotoxicity assays, validation in human samples","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with LAG-3 KO and functional readouts; CD94/NKG2A role is established but as part of a larger circuit study","pmids":["39121847"],"is_preprint":false},{"year":2025,"finding":"CRISPR-Cas9 knockin of a GD2-CAR into the KLRC1 locus in human NK cells simultaneously disrupts NKG2A inhibitory signaling (98% KO efficiency) and introduces GD2-targeting CAR, generating NK cells that overcome HLA-E-based inhibition and kill GD2+ HLA-E-expressing melanoma cells.","method":"CRISPR-Cas9 ribonucleoprotein-mediated knockin, CHANGE-seq off-target analysis, in vitro cytotoxicity assays","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function gene editing with functional cytotoxicity readout, peer-reviewed confirmation of preprint","pmids":["39815622"],"is_preprint":false}],"current_model":"KLRC1 (NKG2-A/CD159a) encodes the NKG2-A subunit of the CD94/NKG2-A heterodimeric inhibitory receptor on NK cells and T cell subsets; NKG2-A contains cytoplasmic ITIMs that recruit SHP-1 phosphatase upon engagement of its ligand HLA-E (loaded with peptides from HLA class I signal sequences), thereby blocking downstream Syk/ERK signaling cascades and suppressing cytotoxicity and cytokine production, while the structural asymmetry of the CD94-NKG2A heterodimer (crystal structure solved at 2.5 Å) places CD94 as the dominant HLA-E contact subunit and the peptide bound in HLA-E's groove dictates the affinity and outcome of CD94/NKG2A engagement."},"narrative":{"mechanistic_narrative":"KLRC1 encodes NKG2-A, the inhibitory subunit of the CD94/NKG2-A heterodimeric receptor that governs the activation threshold of NK cells and T cell subsets by sensing HLA class I status through the non-classical ligand HLA-E [PMID:2007850, PMID:9480992]. NKG2-A is a type II C-type lectin domain protein that assembles into disulfide-bonded heterodimers with CD94 and carries two cytoplasmic ITIMs that constitute the inhibitory signaling module [PMID:2007850, PMID:8943374]. Upon engagement of HLA-E — whose surface display depends on loading of peptides derived from HLA class I signal sequences — NKG2-A becomes tyrosine-phosphorylated and selectively recruits the SHP-1 phosphatase [PMID:9480992, PMID:9565368, PMID:9103421]. SHP-1 recruitment dampens activating signaling, blocking Syk activation, CD16 ζ-chain phosphorylation, Shc/Grb-2 complex formation upstream of p21ras, and downstream ERK activation, thereby suppressing degranulation, cytotoxicity, and cytokine production triggered through CD16 and CD69 [PMID:10358164, PMID:10671222]. Recognition is peptide-tuned: HLA-E-bound peptide identity dictates binding affinity and the functional outcome, with soluble CD94/NKG2-A binding HLA-E with higher affinity than the activating CD94/NKG2-C counterpart, and only a subset of common signal-peptide variants efficiently generating engaging epitopes [PMID:10428963, PMID:9754572, PMID:37264229]. Crystallography established that CD94/NKG2-A forms an asymmetric heterodimer in which CD94 is the dominant HLA-E contact subunit, and that subtle peptide conformational changes within the HLA-E groove — not the heavy chain — determine differential receptor recognition [PMID:18083576, PMID:18339401]. This axis operates across biological contexts, including inhibition of decidual NK cells via HLA-E on trophoblast, regulation of iNKT and exhausted CD8 T cell responses through the murine HLA-E homolog Qa-1, and microglia–neuron signaling controlling cortical plasticity [PMID:10898498, PMID:15746081, PMID:39121847, PMID:35648829]. Genetic disruption of KLRC1 in human NK cells relieves HLA-E-mediated inhibition and enhances anti-tumor cytotoxicity, establishing NKG2-A as an actionable immunotherapy checkpoint [PMID:37675109, PMID:39815622].","teleology":[{"year":1991,"claim":"Established the molecular identity of KLRC1 as an NK-restricted type II membrane C-type lectin protein, defining the gene and its NKG2-A/NKG2-B splice products as candidate NK receptors.","evidence":"cDNA cloning, sequence analysis, and Northern blotting of NK-derived transcripts","pmids":["2007850"],"confidence":"High","gaps":["No ligand identified","No receptor partner or signaling function defined"]},{"year":1996,"claim":"Defined the structural and signaling basis for inhibitory function by showing NKG2-A heterodimerizes with CD94 and carries two cytoplasmic ITIMs.","evidence":"Immunoprecipitation and sequence analysis on NK cells","pmids":["8943374"],"confidence":"High","gaps":["ITIM-recruited effector phosphatase not yet identified","Physiological ligand not defined"]},{"year":1997,"claim":"Showed that the CD94/NKG2-A complex transduces inhibitory signals through selective recruitment of SHP-1, linking the ITIMs to a defined phosphatase effector.","evidence":"Chimeric receptor transfection into rat NK line, cytotoxicity and calcium assays, SHP-1 co-IP","pmids":["9103421","9045931"],"confidence":"High","gaps":["Downstream activating substrates dephosphorylated not yet mapped","Native ligand still uncertain"]},{"year":1998,"claim":"Identified HLA-E as the ligand and established that signal-peptide loading and peptide identity (Met at position 2) control surface HLA-E and inhibitory recognition.","evidence":"Peptide loading of HLA-E on 721.221 cells, NK cytotoxicity, mAb blocking, plus phosphorylation/SHP-1 recruitment in RBL transfectants","pmids":["9480992","9565368","9754572"],"confidence":"High","gaps":["Quantitative binding affinities not yet measured","Atomic basis of peptide discrimination unknown"]},{"year":1999,"claim":"Quantified the receptor-ligand interaction and dissected the signaling block, showing NKG2-A binds HLA-E with higher affinity than NKG2-C and inhibits at a PTK-dependent step upstream of ERK.","evidence":"Surface plasmon resonance with soluble proteins; biochemical co-engagement of CD94/NKG2-A and CD16 in primary NK cells","pmids":["10428963","10358164"],"confidence":"High","gaps":["Structural detail of the heterodimer not yet resolved","Generality across activating receptors only partly tested"]},{"year":1999,"claim":"Provided atomic-level information on CD94, revealing a modified C-type lectin fold with non-functional Ca2+ and carbohydrate sites and a putative HLA-E binding region.","evidence":"X-ray crystallography of the CD94 extracellular domain at 2.6 Å","pmids":["10023772"],"confidence":"High","gaps":["Structure of the intact CD94-NKG2A heterodimer not solved","HLA-E contact surface inferred, not visualized"]},{"year":2002,"claim":"Showed the inhibitory receptor is inducible, with IL-12 driving NKG2-A/CD94 acquisition on CD8 T cells to confer a functional inhibitory receptor.","evidence":"IL-12 culture of T cells, flow cytometry, RT-PCR, redirected killing assay","pmids":["11994435"],"confidence":"Medium","gaps":["Transcriptional mechanism of IL-12 induction not defined","Single lab"]},{"year":2007,"claim":"Resolved the assembled receptor structure, defining an asymmetric CD94-NKG2A interface in which CD94 dominates HLA-E binding.","evidence":"X-ray crystallography of CD94-NKG2A at 2.5 Å with extensive HLA-E and receptor mutagenesis","pmids":["18083576"],"confidence":"High","gaps":["Peptide-dependent recognition basis not yet structurally explained"]},{"year":2008,"claim":"Explained peptide-dependent recognition structurally, showing peptide conformation within the HLA-E groove, not the heavy chain, dictates CD94-NKG2 affinity.","evidence":"Crystal structures of HLA-E with two distinct leader peptides at 2.5 Å","pmids":["18339401"],"confidence":"High","gaps":["Functional hierarchy across the full repertoire of signal-peptide variants not yet quantified"]},{"year":2022,"claim":"Extended the axis beyond immunity, showing microglial CD94/NKG2 engages neuronal Qa-1 to regulate activity-dependent cortical plasticity.","evidence":"Mouse knockouts and in vivo blockade of CD94/NKG2-Qa-1, ocular dominance plasticity and microglial morphology assays","pmids":["35648829"],"confidence":"Medium","gaps":["Intracellular signaling in microglia not dissected","Single lab; human relevance untested"]},{"year":2023,"claim":"Established KLRC1 as a therapeutic checkpoint by showing its knockout relieves HLA-E inhibition and improves NK cytotoxicity against HLA-E+ tumors, and quantified which signal-peptide variants drive recognition.","evidence":"CRISPR KLRC1 knockout in human NK cells with in vitro/in vivo tumor assays; systematic signal-peptide variant recognition analysis","pmids":["37675109","37264229"],"confidence":"High","gaps":["Durability and safety of NKG2-A disruption in vivo not fully characterized","Compensation by NKG2C upregulation not fully resolved"]},{"year":2024,"claim":"Linked CD94/NKG2 to T cell exhaustion programs, showing a LAG-3-dependent circuit generates a CD94/NKG2+ exhausted CD8 T cell subset recognizing Qa-1b.","evidence":"PD-1/LAG-3 genetic deletion in mouse chronic infection, transcriptomic/phenotypic and cytotoxicity analysis with human validation","pmids":["39121847"],"confidence":"Medium","gaps":["NKG2-A-specific signaling in these Tex cells not isolated from the broader circuit","Mechanism of receptor induction by LAG-3/TOX undefined"]},{"year":2025,"claim":"Demonstrated locus-directed engineering by knocking a GD2-CAR into KLRC1, simultaneously ablating NKG2-A inhibition and arming NK cells to kill HLA-E+ tumor cells.","evidence":"CRISPR-Cas9 RNP knockin, CHANGE-seq off-target analysis, in vitro cytotoxicity","pmids":["39815622"],"confidence":"Medium","gaps":["In vivo efficacy and persistence not assessed","Single lab"]},{"year":null,"claim":"How NKG2-A surface expression, ligand-affinity tuning, and competition with the activating NKG2-C receptor are integrated to set the activation threshold across diverse cell types remains incompletely defined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Transcriptional and post-translational control of NKG2-A levels across cell types not mapped","Quantitative rules balancing inhibitory NKG2-A vs activating NKG2-C signaling in vivo unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,7,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,12,8]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[7,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,7]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,7,12,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,8,12]}],"complexes":["CD94/NKG2-A heterodimer"],"partners":["CD94","PTPN6 (SHP-1)","HLA-E"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P26715","full_name":"NKG2-A/NKG2-B type II integral membrane protein","aliases":["CD159 antigen-like family member A","NK cell receptor A","NKG2-A/B-activating NK receptor"],"length_aa":233,"mass_kda":26.3,"function":"Immune inhibitory receptor involved in self-nonself discrimination. In complex with KLRD1 on cytotoxic and regulatory lymphocyte subsets, recognizes non-classical major histocompatibility (MHC) class Ib molecule HLA-E loaded with self-peptides derived from the signal sequence of classical MHC class Ia molecules. Enables cytotoxic cells to monitor the expression of MHC class I molecules in healthy cells and to tolerate self (PubMed:18083576, PubMed:37264229, PubMed:9430220, PubMed:9486650). Upon HLA-E-peptide binding, transmits intracellular signals through two immunoreceptor tyrosine-based inhibition motifs (ITIMs) by recruiting INPP5D/SHP-1 and INPPL1/SHP-2 tyrosine phosphatases to ITIMs, and ultimately opposing signals transmitted by activating receptors through dephosphorylation of proximal signaling molecules (PubMed:12165520, PubMed:9485206). Key inhibitory receptor on natural killer (NK) cells that regulates their activation and effector functions (PubMed:30860984, PubMed:9430220, PubMed:9485206, PubMed:9486650). Dominantly counteracts T cell receptor signaling on a subset of memory/effector CD8-positive T cells as part of an antigen-driven response to avoid autoimmunity (PubMed:12387742). On intraepithelial CD8-positive gamma-delta regulatory T cells triggers TGFB1 secretion, which in turn limits the cytotoxic programming of intraepithelial CD8-positive alpha-beta T cells, distinguishing harmless from pathogenic antigens (PubMed:18064301). In HLA-E-rich tumor microenvironment, acts as an immune inhibitory checkpoint and may contribute to progressive loss of effector functions of NK cells and tumor-specific T cells, a state known as cell exhaustion (PubMed:30503213, PubMed:30860984) (Microbial infection) Viruses like human cytomegalovirus have evolved an escape mechanism whereby virus-induced down-regulation of host MHC class I molecules is coupled to the binding of viral peptides to HLA-E, restoring HLA-E expression and inducing HLA-E-dependent NK cell immune tolerance to infected cells. Recognizes HLA-E in complex with human cytomegalovirus UL40-derived peptide (VMAPRTLIL) and inhibits NK cell cytotoxicity (Microbial infection) May recognize HLA-E in complex with HIV-1 gag/Capsid protein p24-derived peptide (AISPRTLNA) on infected cells and may inhibit NK cell cytotoxicity, a mechanism that allows HIV-1 to escape immune recognition (Microbial infection) Upon SARS-CoV-2 infection, may contribute to functional exhaustion of cytotoxic NK cells and CD8-positive T cells (PubMed:32203188, PubMed:32859121). On NK cells, may recognize HLA-E in complex with SARS-CoV-2 S/Spike protein S1-derived peptide (LQPRTFLL) expressed on the surface of lung epithelial cells, inducing NK cell exhaustion and dampening antiviral immune surveillance (PubMed:32859121)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P26715/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KLRC1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KLRC1","total_profiled":1310},"omim":[{"mim_id":"606782","title":"C-TYPE LECTIN DOMAIN FAMILY 1, MEMBER A; CLEC1A","url":"https://www.omim.org/entry/606782"},{"mim_id":"605029","title":"KILLER CELL LECTIN-LIKE RECEPTOR F1; 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infection","url":"https://pubmed.ncbi.nlm.nih.gov/10817639","citation_count":8,"is_preprint":false},{"pmid":"10320637","id":"PMC_10320637","title":"Direct binding of purified HLA class I antigens by soluble NKG2/CD94 C-type lectins from natural killer cells.","date":"1999","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10320637","citation_count":7,"is_preprint":false},{"pmid":"35888169","id":"PMC_35888169","title":"Characterization of NKG2-A/-C, Kir and CD57 on NK Cells Stimulated with pp65 and IE-1 Antigens in Patients Awaiting Lung Transplant.","date":"2022","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35888169","citation_count":6,"is_preprint":false},{"pmid":"37901227","id":"PMC_37901227","title":"Significance of HLA-E and its two NKG2 receptors in development of complications after allogeneic transplantation of hematopoietic stem cells.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37901227","citation_count":6,"is_preprint":false},{"pmid":"31320124","id":"PMC_31320124","title":"Haplotype block 1 variant (HB-1v) of the NKG2 family of receptors.","date":"2019","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31320124","citation_count":6,"is_preprint":false},{"pmid":"10488737","id":"PMC_10488737","title":"N-linked oligosaccharides can protect target cells from the lysis mediated by NK cells but not by cytotoxic T lymphocytes: role of NKG2-A.","date":"1999","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/10488737","citation_count":6,"is_preprint":false},{"pmid":"37352688","id":"PMC_37352688","title":"Association between NKG2/KLR gene variants and epilepsy in Autism Spectrum Disorder.","date":"2023","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/37352688","citation_count":4,"is_preprint":false},{"pmid":"39798802","id":"PMC_39798802","title":"The Association of HLA-E Ligand and NKG2 Receptor Variation With Relapse and Mortality After Haploidentical Related Donor Transplantation.","date":"2025","source":"Transplantation and cellular therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39798802","citation_count":4,"is_preprint":false},{"pmid":"40683494","id":"PMC_40683494","title":"Molecular characterization and functional prioritization of CD46, IL6R, KLRC1, LEAP2 and SMOX as candidate targets in acute kidney injury.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40683494","citation_count":3,"is_preprint":false},{"pmid":"39401997","id":"PMC_39401997","title":"DNA Methylation of KLRC1 and KLRC3 in Autoimmune Thyroiditis: Perspective of Different Water Iodine Exposure.","date":"2024","source":"Biomedical and environmental sciences : BES","url":"https://pubmed.ncbi.nlm.nih.gov/39401997","citation_count":3,"is_preprint":false},{"pmid":"17545086","id":"PMC_17545086","title":"[Identification of a novel candidate gene KLRC1 within the putative susceptibility locus for systemic lupus erythematosus at 12p12.3-13.2 in a Chinese cohort].","date":"2007","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/17545086","citation_count":1,"is_preprint":false},{"pmid":"17896104","id":"PMC_17896104","title":"Variation in the ligand binding domains of the CD94/NKG2 family of receptors in the squirrel monkey.","date":"2007","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/17896104","citation_count":1,"is_preprint":false},{"pmid":"38405747","id":"PMC_38405747","title":"Virus-free CRISPR knock-in of a chimeric antigen receptor into KLRC1 generates potent GD2-specific natural killer cells.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38405747","citation_count":0,"is_preprint":false},{"pmid":"41153412","id":"PMC_41153412","title":"Genetic Variability in NKG2 Receptors and Their Ligands: Associations with SARS-CoV-2 Infection and COVID-19 Severity.","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/41153412","citation_count":0,"is_preprint":false},{"pmid":"41811633","id":"PMC_41811633","title":"Tumor-intrinsic KLRC1 exerts tumor-suppressive functions in colorectal cancer.","date":"2026","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41811633","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43035,"output_tokens":6609,"usd":0.11412,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15593,"output_tokens":4139,"usd":0.09072,"stage2_stop_reason":"end_turn"},"total_usd":0.20484,"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\": 1991,\n      \"finding\": \"KLRC1 (NKG2-A) encodes a type II integral membrane protein of 215-233 amino acids containing a C-type lectin domain, expressed on NK cells but not T or B cells. NKG2-A and NKG2-B are alternative splicing products of a single gene.\",\n      \"method\": \"cDNA cloning, sequence analysis, Northern blotting\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — full-length cDNA sequencing with structural characterization, foundational paper replicated by subsequent studies\",\n      \"pmids\": [\"2007850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"NKG2-A/B forms disulfide-bonded heterodimers with CD94 on NK cells. NKG2-A/B possesses two immunoreceptor tyrosine-based inhibition motif (ITIM) sequences in its cytoplasmic domain, providing the molecular basis for inhibitory receptor function.\",\n      \"method\": \"Biochemical characterization, immunoprecipitation, sequence analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical demonstration of disulfide-bonded heterodimer, ITIM identification confirmed by multiple subsequent labs\",\n      \"pmids\": [\"8943374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The CD94/NKG2-A inhibitory receptor complex on NK cells recognizes HLA class I molecules via NKG2-A's ITIMs. The Z199 mAb specifically recognizes NKG2-A. NKG2-B (alternatively spliced product of the NKG2-A gene) can also assemble with CD94. Both NKG2-A and NKG2-B contain cytoplasmic ITIMs.\",\n      \"method\": \"Immunoprecipitation, mAb characterization, functional cytotoxicity assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal immunoprecipitation with mAb characterization, replicated across multiple labs\",\n      \"pmids\": [\"9045931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"NKG2-A delivers inhibitory signals in NK cells: chimeric NKG2-A/NKR-P1C receptor inhibited lytic activity and failed to stimulate calcium response. NKG2-A-mediated inhibition is associated with selective recruitment of SHP-1 tyrosine phosphatase to the NKG2-A cytoplasmic domain.\",\n      \"method\": \"Chimeric receptor transfection into rat NK cell line (RNK-16), cytotoxicity assays, calcium flux measurements, immunoprecipitation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — functional reconstitution with chimeric receptors plus biochemical SHP-1 co-IP, mechanistically definitive\",\n      \"pmids\": [\"9103421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CD94/NKG2-A inhibitory receptor complex is involved in NK cell-mediated recognition of HLA-G1; most NK clones blocked by HLA-G1 expressed CD94/NKG2-A, and CD94-specific mAbs restored cytolytic activity.\",\n      \"method\": \"NK cell clone functional assays, mAb blocking experiments, cytotoxicity assays with 721.221 transfectants\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional antibody blocking plus clone analysis, single lab but clear mechanistic readout\",\n      \"pmids\": [\"9190923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CD94/NKG2 is the predominant inhibitory receptor for HLA-G on decidual NK cells; anti-CD94 mAb blocked recognition of HLA-G transfectants whereas KIR-specific mAbs had no effect.\",\n      \"method\": \"NK cell clone establishment from placenta, mAb blocking cytotoxicity assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blocking with receptor-specific mAbs in primary decidual NK cells, corroborated by paper 9190923\",\n      \"pmids\": [\"9233599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CD94/NKG2 inhibitory receptor complex on Vγ9Vδ2 T cells inhibits proliferative and cytotoxic responses; signaling through CD94/NKG2 interferes with IFN-γ and TNF-α synthesis by these cells.\",\n      \"method\": \"Anti-CD94 mAb blocking of proliferation and cytokine production, cytotoxicity assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional mAb blocking demonstrating inhibitory role of CD94/NKG2-A on γδ T cells, single lab\",\n      \"pmids\": [\"9550399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CD94/NKG2-A specifically recognizes HLA-E molecules on target cells, leading to inhibition of NK cell lysis. HLA-E surface expression requires binding of peptides from HLA class I signal sequences; only peptides with Met at position 2 confer resistance to NK lysis. CD94/NKG2-A recognition is blocked by CD94-specific (not KIR-specific) mAbs.\",\n      \"method\": \"NK cell cytotoxicity assays, peptide loading of HLA-E on 721.221 cells, mAb blocking\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal experiments (peptide loading, cytotoxicity, mAb blocking), replicated by multiple subsequent labs\",\n      \"pmids\": [\"9480992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Engagement of CD94/NKG2-A by either specific mAb (Z199) or by HLA-E+ target cells induces tyrosine phosphorylation of the NKG2-A subunit and recruitment of SHP-1 phosphatase. This mechanism was confirmed in RBL-2H3 transfectants expressing CD94/NKG2-A, where receptor cross-linking inhibited FcεRI-triggered secretory events.\",\n      \"method\": \"mAb cross-linking, immunoprecipitation, Western blotting for phosphotyrosine and SHP-1, RBL transfectant system\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct biochemical demonstration of NKG2-A phosphorylation and SHP-1 recruitment in both NK cells and heterologous RBL transfectants\",\n      \"pmids\": [\"9565368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"HLA-E-bound peptides influence recognition by inhibitory CD94/NKG2-A; the primary structure of HLA-E-bound peptides modulates CD94/NKG2A-mediated recognition beyond their ability to stabilize surface HLA-E. CD94/NKG2A+ NK clones showed greater sensitivity to most HLA-E/peptide complexes compared to CD94/NKG2C+ cells.\",\n      \"method\": \"NK clone cytotoxicity assays with 721.221 cells loaded with synthetic nonamers, comparison of inhibitory vs activating receptor-expressing clones\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays with panels of synthetic peptides and characterized NK clones, single lab\",\n      \"pmids\": [\"9754572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Soluble CD94/NKG2-A has higher binding affinity for HLA-E than activating CD94/NKG2-C. Both receptors show peptide-dependent recognition of HLA-E with very fast association and dissociation kinetics. Binding affinity of peptide-HLA-E complexes correlates directly with triggering of NK cell responses.\",\n      \"method\": \"Surface plasmon resonance (BIAcore) with soluble recombinant HLA-E and CD94/NKG2-A and CD94/NKG2-C proteins\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative binding kinetics with soluble recombinant proteins by SPR, mechanistically definitive\",\n      \"pmids\": [\"10428963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Crystal structure of CD94 extracellular domain (2.6 Å) reveals a novel C-type lectin fold with a non-functional Ca2+-binding site and modified carbohydrate-binding region. The CD94 dimer interface suggests a putative HLA-E binding region and implicates how NKG2 interacts with CD94.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 2.6 Å resolution providing atomic-level structural information\",\n      \"pmids\": [\"10023772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD94/NKG2-A inhibits CD16-triggered NK cell cytotoxicity by blocking tyrosine phosphorylation and activation of Syk kinase, tyrosine phosphorylation of CD16 zeta subunit, and downstream activation of ERK. Inhibition is exerted at a PTK-dependent stage upstream of p21ras, blocking Shc phosphorylation and Shc/Grb-2 complex formation.\",\n      \"method\": \"Co-engagement of CD94/NKG2-A and CD16 in primary NK cells, Western blotting for kinase phosphorylation, kinase activity assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — detailed biochemical pathway analysis with multiple signaling intermediates characterized, mechanistically comprehensive\",\n      \"pmids\": [\"10358164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"HLA-E-mediated protection of porcine endothelial cells from human NK cells is CD94/NKG2-dependent: HLA-E engagement leads to phosphorylation of the CD94/NKG2 complex and recruitment of SHP-1. HLA-G protection operates via a CD94/NKG2-independent pathway.\",\n      \"method\": \"mAb blocking assays, phosphorylation analysis, SHP-1 co-immunoprecipitation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical and functional assays confirming SHP-1 recruitment mechanism in porcine endothelial cell system, corroborates paper 9565368\",\n      \"pmids\": [\"10570324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD94/NKG2-A co-engagement with CD69 suppresses CD69-triggered cell degranulation by inhibiting ERK activation in NK cells. Co-engagement of CD94/NKG2-A in RBL transfectants and human NK cells inhibited CD69-induced cytotoxicity.\",\n      \"method\": \"RBL transfectants co-expressing CD69 and CD94/NKG2-A, ERK activation assays, degranulation assays, NK cell cytotoxicity\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ERK pathway mechanistically linked to NKG2-A inhibitory function using both transfectant and primary NK cell systems\",\n      \"pmids\": [\"10671222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"HLA-E is expressed on trophoblast cells and interacts with CD94/NKG2 receptors on decidual NK cells; the majority of decidual NK cells bind HLA-E tetrameric complexes in a CD94-dependent manner. The overall functional outcome of CD94/NKG2-HLA-E interaction is inhibition of decidual NK cell cytotoxicity.\",\n      \"method\": \"HLA-E tetramer staining, mAb blocking, cytotoxicity assays with polyclonal decidual NK cells\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tetramer-based receptor-ligand identification with functional cytotoxicity readout in primary decidual NK cells\",\n      \"pmids\": [\"10898498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The activating CD94/NKG2-C receptor triggers cytotoxic effector functions via activation of the MAPK/ERK pathway; MEK inhibitor PD098059 blocked CD94/NKG2-C-dependent TNF-α production and cytotoxicity. CD94/NKG2-C signals through DAP12/KARAP.\",\n      \"method\": \"MEK inhibitor (PD098059) treatment, MAPK phosphorylation assays, cytotoxicity and TNF-α production assays, RBL transfection with CD94/NKG2-C/DAP12\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — pharmacological inhibition combined with transfection reconstitution and functional readouts, single lab\",\n      \"pmids\": [\"11069065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IL-12 induces expression of NKG2-A and/or CD94 on CD8+ T cells in culture, leading to acquisition of a functional inhibitory receptor, as demonstrated by redirected killing assay. This induction is not mediated by IFN-γ or IL-15.\",\n      \"method\": \"Culture of T cells with IL-12, flow cytometry, RT-PCR, redirected killing assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cytokine induction with functional receptor validation using redirected killing, single lab\",\n      \"pmids\": [\"11994435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD94/NKG2A inhibitory receptor plays a critical role in down-regulating iNKT cell responses. IFN-γ produced during alpha-GalCer stimulation upregulates Qa-1b, which in turn inhibits iNKT cell activity via CD94/NKG2A. Blockade of the CD94/NKG2-Qa-1b interaction markedly augmented iNKT cell recall and primary responses.\",\n      \"method\": \"mAb blockade of CD94/NKG2-Qa-1b interaction, alpha-GalCer stimulation assays in vivo and in vitro, flow cytometry for receptor down-modulation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro functional blockade experiments establishing IFN-γ-Qa-1b-CD94/NKG2A feedback circuit\",\n      \"pmids\": [\"15746081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NKG2A preferential surface expression over NKG2C with CD94 is determined by a single amino acid difference in the transmembrane domain. The stalk domain of NKG2C enhances heterodimer formation with CD94. DAP12 enhances NKG2C's ability to compete for CD94 surface expression.\",\n      \"method\": \"Transfection of NKG2A/NKG2C chimeric and mutant constructs, flow cytometry for surface expression, DAP12 co-transfection\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis identifying transmembrane domain residues, single lab but multiple constructs tested\",\n      \"pmids\": [\"15153509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of CD94-NKG2A heterodimer at 2.5 Å reveals an asymmetric dimer interface (contrasting with homodimeric NK receptors), providing structural basis for preferred heterodimeric assembly. Structure-based mutagenesis on HLA-E and CD94-NKG2A established that CD94 plays a more dominant role than NKG2A in interacting with HLA-E.\",\n      \"method\": \"X-ray crystallography at 2.5 Å, extensive mutagenesis studies on HLA-E and CD94-NKG2A\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with extensive mutagenesis, mechanistically definitive about heterodimer assembly and ligand binding\",\n      \"pmids\": [\"18083576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Subtle peptide conformational changes within the HLA-E binding groove, without changes in the HLA-E heavy chain, determine differential recognition by CD94-NKG2 receptors. Structures of HLA-E with HLA-Cw*07 peptide (poor CD94-NKG2 recognition) and HLA-G*01 peptide (high-affinity CD94-NKG2 ligand) both at 2.5 Å confirmed peptide-dependent recognition.\",\n      \"method\": \"X-ray crystallography at 2.5 Å of HLA-E with two different leader peptides\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — dual crystal structures providing atomic-level basis for peptide-dependent CD94-NKG2 recognition\",\n      \"pmids\": [\"18339401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In mouse cortex, CD94/NKG2 receptor is expressed by microglial cells and interacts with Qa-1 (HLA-E homolog) expressed in layer 6 corticothalamic neurons. This neuron-microglial interaction via the Qa-1/CD94/NKG2 axis regulates activity-dependent plasticity in the visual cortex; selectively targeting this interaction phenocopies plasticity perturbation seen in Qa-1 knockouts.\",\n      \"method\": \"Mouse knockouts, in vivo pharmacological blockade of CD94/NKG2-Qa-1 interaction, ocular dominance plasticity assays, microglial morphology analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological in vivo experiments with defined functional readout, single lab\",\n      \"pmids\": [\"35648829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KLRC1 knockout in human NK cells relieves HLA-E-mediated inhibition and significantly improves cytotoxicity against HLA-E+ solid tumor cell lines in vitro and delays tumor progression in vivo. KLRC1 KO also increases NKG2C expression on NK cells.\",\n      \"method\": \"CRISPR-mediated KLRC1 gene editing, in vitro cytotoxicity assays against multiple HLA-E+ tumor lines, xenogeneic mouse model of metastatic breast cancer\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function CRISPR KO with in vitro and in vivo functional readouts, multiple tumor lines tested\",\n      \"pmids\": [\"37675109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Antigen-specific human NK cell memory against HIV and influenza is largely dependent on the activating CD94/NKG2C receptor and its ligand HLA-E, as demonstrated by single-cell cloning of memory NK cells and identification of individual HLA-E-restricted peptides.\",\n      \"method\": \"Single-cell NK cell cloning, complex immunophenotyping, peptide-HLA-E tetramer assays, functional memory NK cell assays\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single-cell cloning with functional validation, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"38064568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Among 16 common classical HLA class I signal peptide variants, only 6 efficiently generate epitopes enabling CD94/NKG2 engagement. HLA-B/-21M SP induces high HLA-E expression but confers the lowest receptor recognition, competing with other SPs for HLA-E epitope binding and reducing overall CD94/NKG2A recognition of target cells.\",\n      \"method\": \"Systematic quantitative analysis of signal peptide processing, HLA-E surface expression assays, CD94/NKG2A recognition assays with multiple peptide variants\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic quantitative approach with multiple SP variants tested, mechanistically informative about ligand hierarchy, high-profile journal\",\n      \"pmids\": [\"37264229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LAG-3 sustains TOX expression and controls a LAG-3-dependent circuit generating a CD94/NKG2+ subset of exhausted CD8 T cells with enhanced cytotoxicity mediated by recognition of the stress ligand Qa-1b (mouse homolog of HLA-E). Loss of LAG-3 reduces this CD94/NKG2+ Tex subset.\",\n      \"method\": \"Genetic deletion of PD-1 and/or LAG-3 in mouse chronic viral infection model, transcriptomic and phenotypic analysis, functional cytotoxicity assays, validation in human samples\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with LAG-3 KO and functional readouts; CD94/NKG2A role is established but as part of a larger circuit study\",\n      \"pmids\": [\"39121847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CRISPR-Cas9 knockin of a GD2-CAR into the KLRC1 locus in human NK cells simultaneously disrupts NKG2A inhibitory signaling (98% KO efficiency) and introduces GD2-targeting CAR, generating NK cells that overcome HLA-E-based inhibition and kill GD2+ HLA-E-expressing melanoma cells.\",\n      \"method\": \"CRISPR-Cas9 ribonucleoprotein-mediated knockin, CHANGE-seq off-target analysis, in vitro cytotoxicity assays\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function gene editing with functional cytotoxicity readout, peer-reviewed confirmation of preprint\",\n      \"pmids\": [\"39815622\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KLRC1 (NKG2-A/CD159a) encodes the NKG2-A subunit of the CD94/NKG2-A heterodimeric inhibitory receptor on NK cells and T cell subsets; NKG2-A contains cytoplasmic ITIMs that recruit SHP-1 phosphatase upon engagement of its ligand HLA-E (loaded with peptides from HLA class I signal sequences), thereby blocking downstream Syk/ERK signaling cascades and suppressing cytotoxicity and cytokine production, while the structural asymmetry of the CD94-NKG2A heterodimer (crystal structure solved at 2.5 Å) places CD94 as the dominant HLA-E contact subunit and the peptide bound in HLA-E's groove dictates the affinity and outcome of CD94/NKG2A engagement.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KLRC1 encodes NKG2-A, the inhibitory subunit of the CD94/NKG2-A heterodimeric receptor that governs the activation threshold of NK cells and T cell subsets by sensing HLA class I status through the non-classical ligand HLA-E [#0, #7]. NKG2-A is a type II C-type lectin domain protein that assembles into disulfide-bonded heterodimers with CD94 and carries two cytoplasmic ITIMs that constitute the inhibitory signaling module [#0, #1]. Upon engagement of HLA-E — whose surface display depends on loading of peptides derived from HLA class I signal sequences — NKG2-A becomes tyrosine-phosphorylated and selectively recruits the SHP-1 phosphatase [#7, #8, #3]. SHP-1 recruitment dampens activating signaling, blocking Syk activation, CD16 ζ-chain phosphorylation, Shc/Grb-2 complex formation upstream of p21ras, and downstream ERK activation, thereby suppressing degranulation, cytotoxicity, and cytokine production triggered through CD16 and CD69 [#12, #14]. Recognition is peptide-tuned: HLA-E-bound peptide identity dictates binding affinity and the functional outcome, with soluble CD94/NKG2-A binding HLA-E with higher affinity than the activating CD94/NKG2-C counterpart, and only a subset of common signal-peptide variants efficiently generating engaging epitopes [#10, #9, #25]. Crystallography established that CD94/NKG2-A forms an asymmetric heterodimer in which CD94 is the dominant HLA-E contact subunit, and that subtle peptide conformational changes within the HLA-E groove — not the heavy chain — determine differential receptor recognition [#20, #21]. This axis operates across biological contexts, including inhibition of decidual NK cells via HLA-E on trophoblast, regulation of iNKT and exhausted CD8 T cell responses through the murine HLA-E homolog Qa-1, and microglia–neuron signaling controlling cortical plasticity [#15, #18, #26, #22]. Genetic disruption of KLRC1 in human NK cells relieves HLA-E-mediated inhibition and enhances anti-tumor cytotoxicity, establishing NKG2-A as an actionable immunotherapy checkpoint [#23, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established the molecular identity of KLRC1 as an NK-restricted type II membrane C-type lectin protein, defining the gene and its NKG2-A/NKG2-B splice products as candidate NK receptors.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and Northern blotting of NK-derived transcripts\",\n      \"pmids\": [\"2007850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ligand identified\", \"No receptor partner or signaling function defined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defined the structural and signaling basis for inhibitory function by showing NKG2-A heterodimerizes with CD94 and carries two cytoplasmic ITIMs.\",\n      \"evidence\": \"Immunoprecipitation and sequence analysis on NK cells\",\n      \"pmids\": [\"8943374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ITIM-recruited effector phosphatase not yet identified\", \"Physiological ligand not defined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed that the CD94/NKG2-A complex transduces inhibitory signals through selective recruitment of SHP-1, linking the ITIMs to a defined phosphatase effector.\",\n      \"evidence\": \"Chimeric receptor transfection into rat NK line, cytotoxicity and calcium assays, SHP-1 co-IP\",\n      \"pmids\": [\"9103421\", \"9045931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream activating substrates dephosphorylated not yet mapped\", \"Native ligand still uncertain\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identified HLA-E as the ligand and established that signal-peptide loading and peptide identity (Met at position 2) control surface HLA-E and inhibitory recognition.\",\n      \"evidence\": \"Peptide loading of HLA-E on 721.221 cells, NK cytotoxicity, mAb blocking, plus phosphorylation/SHP-1 recruitment in RBL transfectants\",\n      \"pmids\": [\"9480992\", \"9565368\", \"9754572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative binding affinities not yet measured\", \"Atomic basis of peptide discrimination unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Quantified the receptor-ligand interaction and dissected the signaling block, showing NKG2-A binds HLA-E with higher affinity than NKG2-C and inhibits at a PTK-dependent step upstream of ERK.\",\n      \"evidence\": \"Surface plasmon resonance with soluble proteins; biochemical co-engagement of CD94/NKG2-A and CD16 in primary NK cells\",\n      \"pmids\": [\"10428963\", \"10358164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the heterodimer not yet resolved\", \"Generality across activating receptors only partly tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Provided atomic-level information on CD94, revealing a modified C-type lectin fold with non-functional Ca2+ and carbohydrate sites and a putative HLA-E binding region.\",\n      \"evidence\": \"X-ray crystallography of the CD94 extracellular domain at 2.6 Å\",\n      \"pmids\": [\"10023772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the intact CD94-NKG2A heterodimer not solved\", \"HLA-E contact surface inferred, not visualized\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed the inhibitory receptor is inducible, with IL-12 driving NKG2-A/CD94 acquisition on CD8 T cells to confer a functional inhibitory receptor.\",\n      \"evidence\": \"IL-12 culture of T cells, flow cytometry, RT-PCR, redirected killing assay\",\n      \"pmids\": [\"11994435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional mechanism of IL-12 induction not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved the assembled receptor structure, defining an asymmetric CD94-NKG2A interface in which CD94 dominates HLA-E binding.\",\n      \"evidence\": \"X-ray crystallography of CD94-NKG2A at 2.5 Å with extensive HLA-E and receptor mutagenesis\",\n      \"pmids\": [\"18083576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Peptide-dependent recognition basis not yet structurally explained\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Explained peptide-dependent recognition structurally, showing peptide conformation within the HLA-E groove, not the heavy chain, dictates CD94-NKG2 affinity.\",\n      \"evidence\": \"Crystal structures of HLA-E with two distinct leader peptides at 2.5 Å\",\n      \"pmids\": [\"18339401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional hierarchy across the full repertoire of signal-peptide variants not yet quantified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the axis beyond immunity, showing microglial CD94/NKG2 engages neuronal Qa-1 to regulate activity-dependent cortical plasticity.\",\n      \"evidence\": \"Mouse knockouts and in vivo blockade of CD94/NKG2-Qa-1, ocular dominance plasticity and microglial morphology assays\",\n      \"pmids\": [\"35648829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular signaling in microglia not dissected\", \"Single lab; human relevance untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established KLRC1 as a therapeutic checkpoint by showing its knockout relieves HLA-E inhibition and improves NK cytotoxicity against HLA-E+ tumors, and quantified which signal-peptide variants drive recognition.\",\n      \"evidence\": \"CRISPR KLRC1 knockout in human NK cells with in vitro/in vivo tumor assays; systematic signal-peptide variant recognition analysis\",\n      \"pmids\": [\"37675109\", \"37264229\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Durability and safety of NKG2-A disruption in vivo not fully characterized\", \"Compensation by NKG2C upregulation not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked CD94/NKG2 to T cell exhaustion programs, showing a LAG-3-dependent circuit generates a CD94/NKG2+ exhausted CD8 T cell subset recognizing Qa-1b.\",\n      \"evidence\": \"PD-1/LAG-3 genetic deletion in mouse chronic infection, transcriptomic/phenotypic and cytotoxicity analysis with human validation\",\n      \"pmids\": [\"39121847\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NKG2-A-specific signaling in these Tex cells not isolated from the broader circuit\", \"Mechanism of receptor induction by LAG-3/TOX undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated locus-directed engineering by knocking a GD2-CAR into KLRC1, simultaneously ablating NKG2-A inhibition and arming NK cells to kill HLA-E+ tumor cells.\",\n      \"evidence\": \"CRISPR-Cas9 RNP knockin, CHANGE-seq off-target analysis, in vitro cytotoxicity\",\n      \"pmids\": [\"39815622\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo efficacy and persistence not assessed\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NKG2-A surface expression, ligand-affinity tuning, and competition with the activating NKG2-C receptor are integrated to set the activation threshold across diverse cell types remains incompletely defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional and post-translational control of NKG2-A levels across cell types not mapped\", \"Quantitative rules balancing inhibitory NKG2-A vs activating NKG2-C signaling in vivo unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 7, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 12, 8]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [7, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 7, 12, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 8, 12]}\n    ],\n    \"complexes\": [\"CD94/NKG2-A heterodimer\"],\n    \"partners\": [\"CD94\", \"PTPN6 (SHP-1)\", \"HLA-E\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}