{"gene":"CD7","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1984,"finding":"CD7 (gp40) is a monomeric transmembrane glycoprotein of Mr=40,000 that is asymmetrically inserted into the rough endoplasmic reticulum as a transmembrane structure, undergoes N-linked glycosylation (two high-mannose type glycans processed to complex oligosaccharides during transport), also contains O-linked glycans, covalently associated fatty acid, and is phosphorylated on phosphoserine.","method":"Biosynthetic labeling, tunicamycin inhibition, endo-F/endo-H cleavage, gal-NAc oligosaccharidase digestion, 32P phosphate labeling, phosphoamino acid analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal biochemical methods in a single rigorous study","pmids":["6609985"],"is_preprint":false},{"year":1988,"finding":"Immobilized anti-CD7 monoclonal antibody delivers a co-mitogenic signal to T cells in conjunction with suboptimal anti-CD3 stimulation, promoting IL-2 production and IL-2 receptor expression; this co-mitogenic effect can be replicated by PMA but not by calcium ionophore.","method":"Co-mitogenic proliferation assay with solid-phase antibodies, IL-2 and IL-2R measurement, PKC/PTK pharmacological dissection","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — clean functional assay with multiple stimulation conditions; single lab","pmids":["2459196"],"is_preprint":false},{"year":1991,"finding":"CD7 cross-linking on TCRγ/δ+ T cell lines causes rapid cytoplasmic free calcium elevation, IL-2 production, and induction of TNF-α, TNF-β, and GM-CSF mRNAs, directly activating these cells; the same anti-CD7 antibody fails to activate TCRα/β+ T cells.","method":"Calcium flux measurement, cytokine ELISA, mRNA induction assay, proliferation assay with anti-CD7 mAb stimulation","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional evidence with multiple readouts; single lab","pmids":["1709867"],"is_preprint":false},{"year":1991,"finding":"CD7 gene transcription is selectively induced by calcium flux (ionomycin) in a cyclosporin A-sensitive, extracellular calcium-dependent, tyrosine-kinase-independent manner; transcriptional induction peaks at 1 hour and precedes surface upregulation.","method":"Ionomycin stimulation, CD7 mRNA half-life measurement, transcriptional run-on analysis, pharmacological inhibitors, flow cytometry","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — transcriptional mechanism defined by run-on assay and multiple inhibitor controls","pmids":["1717576"],"is_preprint":false},{"year":1992,"finding":"CD7 augments T cell proliferation via the IL-2 autocrine pathway by increasing IL-2 production and IL-2Rα (CD25) expression through both PKC and PTK signaling pathways; inhibitors H-7 (PKC) and genistein (PTK) suppress CD7-mediated co-mitogenesis.","method":"PBMC proliferation assays, IL-2 measurement, IL-2Rα expression analysis, PKC/PTK inhibitor treatment","journal":"Cellular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — defined pathway mechanism with pharmacological dissection; single lab","pmids":["1372842"],"is_preprint":false},{"year":1994,"finding":"CD7 cross-linking on NK cells induces rapid cytoplasmic calcium elevation, upregulation of CD25, CD71, HLA-DR, CD69, and CD54, IFN-γ secretion, NK cell proliferation, enhanced cytotoxicity against K562 targets, and augmented adhesion to fibronectin; however CD7 does not transduce a direct lytic signal.","method":"Anti-CD7 mAb cross-linking, calcium flux, flow cytometry, thymidine incorporation, cytotoxicity assay, fibronectin adhesion assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional readouts with rigorous controls; replicated across different assays","pmids":["7506726"],"is_preprint":false},{"year":1994,"finding":"CD7 exists in an oligomeric complex (homodimer) physically associated with CD3 and CD45 on human T cells; this complex contains a tyrosine kinase whose major substrate is CD45.","method":"Co-immunoprecipitation, Western blotting, fluorescence resonance energy transfer (FRET), in vitro phosphorylation assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — association confirmed by three orthogonal methods (Co-IP, Western blot, FRET); single lab","pmids":["7523512"],"is_preprint":false},{"year":1994,"finding":"CD7 cross-linking mediates rapid tyrosine phosphorylation and upregulates β1 and β2 integrin-mediated T cell adhesion; this effect is completely blocked by the tyrosine kinase inhibitor herbimycin A, and CD7 immunoprecipitates contain in vitro kinase activity phosphorylating an 80 kDa substrate on tyrosine, serine, and threonine residues.","method":"Anti-CD7 antibody cross-linking, adhesion assay, herbimycin A inhibition, anti-phosphotyrosine immunoblotting, in vitro kinase assay, phosphoamino acid analysis","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with mutagenesis controls plus multiple functional readouts","pmids":["7525296"],"is_preprint":false},{"year":1995,"finding":"CD7 cross-linking leads to association with phosphoinositide 3-kinase (PI3K) and production of D-3 phosphoinositides including phosphatidylinositol 3,4,5-trisphosphate (PIP3); this is accompanied by phosphatidic acid formation in the absence of phosphatidylinositol-4,5-bisphosphate metabolism.","method":"Co-precipitation of CD7 with PI3K, phosphoinositide lipid analysis, comparison with CD3 and CD28 stimulation","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — biochemical co-precipitation and lipid product measurement; multiple controls","pmids":["7533088"],"is_preprint":false},{"year":1996,"finding":"The cytoplasmic tail of CD7 interacts with the p85 adaptor subunit of PI3-kinase via a pTyr-X-X-Met (YEDM) motif; CD7 cross-linking markedly increases the amount of PI3-kinase activity associated with CD7.","method":"Co-precipitation with anti-CD7 mAb, recombinant p85 SH2-GST fusion protein pulldown, peptide competition, PI3-kinase activity assay","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical interaction defined by peptide competition and domain mapping plus enzymatic activity measurement","pmids":["8918688"],"is_preprint":false},{"year":1997,"finding":"CD7-deficient mice show normal lymphocyte development but have transient increases in thymocyte numbers at 3 months of age and reduced antigen-specific MHC class I-restricted CTL activity, demonstrating a role for CD7 in regulating intrathymic T cell development and CTL effector function.","method":"Targeted gene disruption (CD7 knockout mice), thymocyte enumeration at multiple timepoints, antigen-specific CTL assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with defined cellular phenotypes; replicated across age groups","pmids":["9637484"],"is_preprint":false},{"year":1997,"finding":"Targeted disruption of murine CD7 results in mice with normal lymphocyte populations, normal serum Ig levels, normal mitogenic responses, and normal NK cytotoxicity, indicating CD7 is dispensable for normal lymphoid development under steady-state conditions.","method":"Targeted gene disruption, lymphocyte subset analysis, mitogen proliferation assays, NK cytotoxicity assay","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with comprehensive immunological characterization","pmids":["9466315"],"is_preprint":false},{"year":1999,"finding":"CD7-deficient mice are resistant to LPS-induced shock; they show decreased serum IFN-γ and TNF-α levels after LPS/D-galactosamine challenge, and have reduced numbers of liver NK1.1+/CD3+ NKT cells, establishing CD7 as a key molecule in the inflammatory response leading to LPS-induced shock through regulation of NKT cell numbers and cytokine production.","method":"CD7 knockout mice, LPS/D-gal challenge survival assay, cytokine ELISA, liver mRNA analysis, liver mononuclear cell phenotyping by flow cytometry","journal":"Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple mechanistic readouts (cytokines, cell populations, survival); strong preponderance of evidence","pmids":["10075985"],"is_preprint":false},{"year":2000,"finding":"K12 (SECTM1) is identified as a cognate ligand of CD7; K12-Fc fusion protein binds specifically to T and NK cells and precipitates an ~40 kDa protein from NK cell lysates identified as CD7. Mouse K12 inhibits ConA-induced but not anti-TCR-induced T cell proliferation, and human K12-Fc stimulates upregulation of CD25, CD54, and CD69 on human NK cells.","method":"K12-Fc fusion protein flow cytometry binding, immunoprecipitation from 35S-radiolabeled NK cells, cDNA expression library screening, NK cell activation assay, T cell proliferation inhibition assay","journal":"Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — receptor-ligand identification by multiple methods including expression library screen, precipitation, and functional assays","pmids":["10652336"],"is_preprint":false},{"year":2003,"finding":"Galectin-3 binds CD7 and CD29 (β1 integrin) on the T cell surface and induces type II (mitochondrial) apoptosis including cytochrome c release and caspase-3 activation but not caspase-8 activation; this occurs through carbohydrate-dependent interactions.","method":"Identification of Gal-3 cell surface receptors, lactose inhibition assay, caspase activity measurement, cytochrome c release assay, Gal-3 transfection","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — receptor identified with functional downstream signaling validated by multiple biochemical readouts","pmids":["14678989"],"is_preprint":false},{"year":2003,"finding":"CD7 expression is necessary but not sufficient for galectin-1-induced apoptosis of Sezary T cells; cell surface glycosylation (sialylated core 1 O-glycans) additionally determines susceptibility, as CD7-positive Sezary cells with this glycotype resist galectin-1-mediated death.","method":"Galectin-1 apoptosis assay, CD7 expression analysis, cell surface glycosylation analysis of Sezary cell lines and primary lesions, in vivo galectin-1 detection by IHC","journal":"Modern pathology","confidence":"Medium","confidence_rationale":"Tier 2 — functional apoptosis assay with glycosylation analysis; single lab","pmids":["12808059"],"is_preprint":false},{"year":2003,"finding":"CD7 expression on CD8+ T cells marks distinct differentiation subsets with different functional properties: CD7-high cells contain naive and memory cells; CD7-low and CD7-negative cells contain effector cells that can be further divided into cytokine-secreting and lytic effector subsets.","method":"Multi-parameter flow cytometry, functional cytokine secretion assays, cytotoxicity assays on sorted CD7hi/lo/neg CD8+ T cell subsets","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct sorting and functional comparison of defined subsets; single lab","pmids":["12594257"],"is_preprint":false},{"year":2007,"finding":"Progressive restriction in lymphoid/myeloid lineage potential in human thymic progenitors correlates with increasing CD7 expression: CD7-negative CD34+ thymocytes retain full lympho-myeloid potential and express HSC genes; CD7-intermediate cells produce B, T, and NK cells; CD7-high cells produce only T and NK cells.","method":"Fluorescence-activated cell sorting by CD7 expression level, multi-lineage in vitro differentiation assays (B, T, NK, myelo-erythroid), gene expression analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — clonal-level differentiation assays with sorted populations; multiple lineages tested","pmids":["17959857"],"is_preprint":false},{"year":2009,"finding":"CD7 co-expression with CD56 distinguishes functional NK cells from CD56+ monocyte/DC-like cells; only CD7+CD56+ NK cells secrete IFN-γ and degranulate after IL-12/IL-18 or K562 stimulation, while CD7-negative CD56+ myeloid cells stimulate allogeneic responses but lack NK effector functions.","method":"Multi-color flow cytometry, IFN-γ secretion assay, degranulation (CD107a) assay, allogeneic stimulation assay, K562 cytotoxicity assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — functional discrimination of subsets by multiple orthogonal assays","pmids":["19805616"],"is_preprint":false},{"year":2009,"finding":"Twist2 transcription factor downregulates CD7 gene promoter activity in T cells through its C-terminal domain and possibly via histone deacetylation; ectopic Twist2 expression reduces CD7 surface levels and decreases galectin-1-induced apoptosis.","method":"Twist2 ectopic expression, CD7 promoter activity assay, C-terminal deletion mutant analysis, HDAC inhibitor treatment (TSA, sodium butyrate), galectin-1 apoptosis assay","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 — promoter assay with deletion mapping and functional consequence; single lab","pmids":["19937140"],"is_preprint":false},{"year":2013,"finding":"SECTM1 (K12) produced by tumor cells binds CD7 on monocytes and significantly increases monocyte migration via activation of the PI3K pathway; CD7 is expressed on human monocytes and macrophages and its expression decreases upon M-CSF-induced differentiation.","method":"SECTM1-CD7 binding assay, monocyte migration assay, PI3K pathway analysis, flow cytometry for CD7 expression on monocytes/macrophages, conditioned medium experiments","journal":"Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — receptor-ligand interaction validated with functional migration assay and pathway identification; single lab","pmids":["24157461"],"is_preprint":false},{"year":2017,"finding":"Targeted genomic disruption of the CD7 gene in T cells prevents fratricide when a CD7-specific CAR is expressed; CD7-edited CAR T cells expand normally, retain cytotoxic function against malignant T-cell lines and primary tumors, and are protective in a mouse xenograft model of T-ALL.","method":"CRISPR/Cas9 gene editing, CAR T cell expansion and fratricide assays, cytotoxicity assays, xenograft mouse model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — genetic disruption with multiple functional readouts and in vivo validation","pmids":["28539325"],"is_preprint":false},{"year":2022,"finding":"Naturally selected CD7-CAR T cells overcome fratricide because the CD7-targeting CAR masks or sequesters CD7 molecules on the T cell surface, minimizing accessible CD7 epitopes without requiring genetic knockout; this approach yields a higher proportion of central memory CD8+ T cells compared to sorted CD7-negative or CD7-knocked-out CAR T cells.","method":"Flow cytometry of CD7 surface expression, comparison of CD7-masked vs CD7-KO vs CD7-negative CAR T cell products, central memory phenotype analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic demonstration of CAR-mediated CD7 masking with functional comparisons; single lab","pmids":["35500125"],"is_preprint":false},{"year":1996,"finding":"CD7 expression is transcriptionally regulated and absent CD7 expression in a subset of CD4+ memory T cells represents a stable, separate differentiation state: once naive T cells differentiate into CD7-negative memory cells through repeated stimulation, sorted CD7-negative cells do not re-express CD7 and show no CD7 mRNA.","method":"Serial stimulation of sorted naive CD4+ T cells, RT-PCR for CD7 mRNA, cell sorting and re-culture of CD7+ and CD7- populations, surface phenotyping","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptional regulation and stable phenotype confirmed by sorting and re-culture; single lab","pmids":["8958052"],"is_preprint":false}],"current_model":"CD7 is a 40 kDa type I transmembrane Ig-superfamily glycoprotein expressed on T and NK cells that functions as a co-stimulatory/accessory signaling receptor: upon cross-linking it associates with CD3/CD45 and recruits a tyrosine kinase activity and PI3-kinase (via its cytoplasmic YEDM motif) to generate PIP3, elevate intracellular calcium, activate both PKC and PTK pathways, and promote IL-2 production, IL-2Rα upregulation, integrin-mediated adhesion, and cytokine secretion; its natural ligand SECTM1/K12 (expressed by thymic epithelial cells and tumor cells) engages CD7 to modulate T/NK cell activation and monocyte migration via PI3K; CD7 also serves as a galectin-3/galectin-1 receptor mediating mitochondrial apoptosis, and its level of expression marks progressive stages of T cell lineage commitment in the thymus and functional differentiation of peripheral CD8+ T cells."},"narrative":{"teleology":[{"year":1984,"claim":"Establishing CD7 as a post-translationally modified transmembrane glycoprotein resolved the basic molecular identity of this lymphocyte-surface antigen and its biosynthetic route through the secretory pathway.","evidence":"Biosynthetic labeling, tunicamycin/endo-H/endo-F glycosylation analysis, phosphoamino acid analysis in human T cells","pmids":["6609985"],"confidence":"High","gaps":["Three-dimensional structure undetermined","Functional significance of serine phosphorylation and acylation unknown"]},{"year":1992,"claim":"Demonstrating that CD7 cross-linking delivers a co-stimulatory signal that promotes IL-2 production, IL-2Rα upregulation, calcium flux, and cytokine induction through both PKC and PTK pathways established CD7 as an activating accessory receptor on T and γδ T cells.","evidence":"Anti-CD7 mAb co-stimulation assays on PBMCs and γδ T cell lines with PKC/PTK inhibitor dissection, calcium flux, and cytokine measurement","pmids":["2459196","1709867","1372842"],"confidence":"Medium","gaps":["Proximal signaling complex not yet identified","Basis for differential activation of γδ versus αβ T cells unclear"]},{"year":1994,"claim":"Identifying CD7 as a homodimer physically associated with CD3 and CD45 that co-precipitates tyrosine kinase activity, and showing that CD7 cross-linking drives integrin-mediated adhesion and NK cell activation, defined the signaling complex and broadened CD7 function beyond T cell co-stimulation.","evidence":"Co-IP, FRET, in vitro kinase assays on T cells; anti-CD7 cross-linking on NK cells with calcium flux, activation marker upregulation, cytotoxicity and adhesion assays","pmids":["7523512","7525296","7506726"],"confidence":"High","gaps":["Identity of the 80 kDa kinase substrate unknown","Specific tyrosine kinase(s) in the CD7 complex not identified"]},{"year":1996,"claim":"Mapping the PI3K recruitment site to the cytoplasmic YEDM motif of CD7 and showing that cross-linking triggers PIP3 generation provided the first direct biochemical mechanism linking CD7 engagement to lipid second-messenger signaling.","evidence":"Co-precipitation with anti-CD7, GST-p85 SH2 pulldown, peptide competition, PI3K enzymatic activity assay, D-3 phosphoinositide lipid analysis","pmids":["8918688","7533088"],"confidence":"High","gaps":["Downstream effectors of PIP3 in CD7 signaling (e.g., Akt activation) not directly demonstrated","Relative contribution of PI3K vs PKC/PTK arms to functional outcomes undefined"]},{"year":1997,"claim":"CD7-knockout mice revealed that CD7 is dispensable for steady-state lymphoid development but contributes to thymocyte homeostasis and antigen-specific CTL function, separating developmental from effector roles.","evidence":"Two independent targeted gene disruptions in mice; thymocyte enumeration, mitogenic responses, NK cytotoxicity, and MHC class I-restricted CTL assays","pmids":["9637484","9466315"],"confidence":"High","gaps":["Redundancy with other co-stimulatory receptors not dissected","Mechanism of reduced CTL activity not resolved"]},{"year":1999,"claim":"The finding that CD7-deficient mice resist LPS-induced shock and have reduced hepatic NKT cells linked CD7 to innate inflammatory responses and NKT cell homeostasis in vivo.","evidence":"CD7 KO mice challenged with LPS/D-galactosamine; survival, serum cytokine ELISA, liver mononuclear cell phenotyping","pmids":["10075985"],"confidence":"High","gaps":["Whether CD7 directly regulates NKT cell development or survival is unclear","Cell-intrinsic vs cell-extrinsic mechanism not distinguished"]},{"year":2000,"claim":"Identification of SECTM1 (K12) as the cognate ligand of CD7 that activates NK cells and inhibits ConA-driven T cell proliferation resolved a long-standing search for CD7's natural binding partner.","evidence":"K12-Fc fusion binding, immunoprecipitation of ~40 kDa protein from NK cells, cDNA expression library screening, functional NK activation and T cell inhibition assays","pmids":["10652336"],"confidence":"High","gaps":["Structural basis of SECTM1–CD7 interaction undetermined","Whether SECTM1 is the sole physiological ligand unknown"]},{"year":2003,"claim":"Demonstrating that galectin-1 and galectin-3 bind CD7 to trigger mitochondrial apoptosis (cytochrome c release, caspase-3 activation) established CD7 as a death receptor for galectin family members, with glycosylation state as a susceptibility determinant.","evidence":"Galectin-3 receptor identification, lactose inhibition, caspase/cytochrome c assays; galectin-1 apoptosis on Sézary T cells with glycosylation analysis","pmids":["14678989","12808059"],"confidence":"High","gaps":["Mechanism coupling galectin–CD7 binding to mitochondrial pathway not elucidated","Whether the YEDM/PI3K signaling axis is involved in galectin-induced death unknown"]},{"year":2007,"claim":"Correlating graded CD7 expression with progressive lineage restriction in thymic progenitors and with effector differentiation in peripheral CD8+ T cells established CD7 level as a functional marker of T cell commitment and differentiation state.","evidence":"Sorted CD7-neg/int/high CD34+ thymocytes in multi-lineage differentiation assays; sorted CD7hi/lo/neg CD8+ T cell functional analysis; serial stimulation and re-culture of CD4+ T cells","pmids":["17959857","12594257","8958052"],"confidence":"High","gaps":["Transcription factors upstream of CD7 regulation during lineage commitment largely undefined beyond Twist2","Whether CD7 signaling actively drives commitment or is merely a marker unclear"]},{"year":2013,"claim":"Extending CD7 function to monocytes by showing that tumor-derived SECTM1 promotes PI3K-dependent monocyte migration via CD7 broadened the receptor's role to myeloid innate immunity and tumor microenvironment biology.","evidence":"SECTM1–CD7 binding on monocytes, transwell migration assay with PI3K pathway analysis, flow cytometry during M-CSF differentiation","pmids":["24157461"],"confidence":"Medium","gaps":["In vivo relevance of CD7-dependent monocyte migration not tested","Other signaling intermediates downstream of PI3K in monocytes not identified"]},{"year":2017,"claim":"CRISPR/Cas9 disruption of CD7 in CAR T cells eliminated fratricide and enabled effective anti-CD7 CAR T therapy against T-ALL in xenograft models, validating CD7 as both a therapeutic target and an expendable molecule in engineered T cells.","evidence":"CRISPR/Cas9 CD7 KO, CAR T expansion/fratricide assays, cytotoxicity against T-ALL lines and primary tumors, xenograft model","pmids":["28539325"],"confidence":"High","gaps":["Long-term consequences of CD7 loss on engineered T cell fitness in patients unknown","Whether CD7 loss alters galectin-mediated apoptotic regulation of CAR T cells untested"]},{"year":null,"claim":"Key open questions include the structural basis of CD7–SECTM1 and CD7–galectin interactions, the identity of the tyrosine kinase(s) directly recruited to the CD7–CD3–CD45 complex, the signaling mechanism linking CD7-galectin binding to mitochondrial apoptosis, and whether CD7 actively instructs lineage commitment or passively marks it.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure for CD7 or its ligand complexes","Specific kinase(s) in the CD7 complex remain unidentified","Active vs passive role of CD7 in thymic lineage commitment unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,2,5,8,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5,6,13,14]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,5,10,12,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[14,15]}],"complexes":["CD7–CD3–CD45 complex"],"partners":["CD3E","PTPRC","PIK3R1","SECTM1","LGALS3","LGALS1","ITGB1"],"other_free_text":[]},"mechanistic_narrative":"CD7 is a type I transmembrane immunoglobulin-superfamily glycoprotein that functions as an accessory signaling receptor on T cells, NK cells, and monocytes, modulating activation, differentiation, and apoptotic susceptibility. Upon cross-linking, CD7 forms homodimers that associate with CD3 and CD45, recruit a tyrosine kinase activity, and engage PI3-kinase via a cytoplasmic YEDM motif to generate PIP3, elevate intracellular calcium, activate PKC and PTK pathways, and promote IL-2 production, IL-2Rα upregulation, integrin-mediated adhesion, and cytokine secretion [PMID:7523512, PMID:8918688, PMID:7533088, PMID:7525296]. Its cognate ligand SECTM1 (K12) binds CD7 on T, NK, and monocytic cells to modulate proliferation and drive PI3K-dependent monocyte migration, while galectin-1 and galectin-3 engage CD7 to trigger mitochondrial apoptosis through cytochrome c release and caspase-3 activation [PMID:10652336, PMID:24157461, PMID:14678989, PMID:12808059]. Progressive upregulation of CD7 marks lineage restriction during thymic T cell development—from multipotent CD7-negative progenitors to T/NK-committed CD7-high cells—and graded CD7 loss on peripheral CD8+ T cells delineates naive, memory, and effector subsets [PMID:17959857, PMID:12594257, PMID:8958052]."},"prefetch_data":{"uniprot":{"accession":"P09564","full_name":"T-cell antigen CD7","aliases":["GP40","T-cell leukemia antigen","T-cell surface antigen Leu-9","TP41"],"length_aa":240,"mass_kda":25.4,"function":"Transmembrane glycoprotein expressed by T-cells and natural killer (NK) cells and their precursors (PubMed:7506726). Plays a costimulatory role in T-cell activation upon binding to its ligand K12/SECTM1 (PubMed:10652336). In turn, mediates the production of cytokines such as IL-2 (PubMed:1709867). On resting NK-cells, CD7 activation results in a significant induction of interferon-gamma levels (PubMed:7506726)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P09564/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD7","classification":"Not Classified","n_dependent_lines":18,"n_total_lines":1208,"dependency_fraction":0.014900662251655629},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD7","total_profiled":1310},"omim":[{"mim_id":"602602","title":"SECRETED AND TRANSMEMBRANE 1; SECTM1","url":"https://www.omim.org/entry/602602"},{"mim_id":"314200","title":"THYROXINE-BINDING GLOBULIN OF SERUM; TBG","url":"https://www.omim.org/entry/314200"},{"mim_id":"254400","title":"MYCOSIS FUNGOIDES","url":"https://www.omim.org/entry/254400"},{"mim_id":"186940","title":"CD4 ANTIGEN; 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8918688","citation_count":25,"is_preprint":false},{"pmid":"12186891","id":"PMC_12186891","title":"C-Terminal gp40 peptide analogs inhibit feline immunodeficiency virus: cell fusion and virus spread.","date":"2002","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/12186891","citation_count":24,"is_preprint":false},{"pmid":"37215124","id":"PMC_37215124","title":"Targeted CD7 CAR T-cells for treatment of T-Lymphocyte leukemia and lymphoma and acute myeloid leukemia: recent advances.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37215124","citation_count":24,"is_preprint":false},{"pmid":"36735547","id":"PMC_36735547","title":"Single-Cell Transcriptomics Reveals Immune Reconstitution in Patients with R/R T-ALL/LBL Treated with Donor-Derived CD7 CAR-T Therapy.","date":"2023","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/36735547","citation_count":24,"is_preprint":false},{"pmid":"9720718","id":"PMC_9720718","title":"CD7 positive hematopoietic progenitors and acute myeloid leukemia and other minimally differentiated leukemia.","date":"1998","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/9720718","citation_count":22,"is_preprint":false},{"pmid":"22126605","id":"PMC_22126605","title":"Autoimmune enteropathy with a CD8+ CD7- T-cell small bowel intraepithelial lymphocytosis: case report and literature review.","date":"2011","source":"BMC gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/22126605","citation_count":22,"is_preprint":false},{"pmid":"10671214","id":"PMC_10671214","title":"CD7 expression distinguishes subsets of CD4(+) T cells with distinct functional properties and ability to support replication of HIV-1.","date":"2000","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10671214","citation_count":22,"is_preprint":false},{"pmid":"1283077","id":"PMC_1283077","title":"Biological characteristics of CD7 positive acute myelogenous leukaemia.","date":"1992","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/1283077","citation_count":22,"is_preprint":false},{"pmid":"35317521","id":"PMC_35317521","title":"Feasibility study of a novel preparation strategy for anti-CD7 CAR-T cells with a recombinant anti-CD7 blocking antibody.","date":"2022","source":"Molecular therapy oncolytics","url":"https://pubmed.ncbi.nlm.nih.gov/35317521","citation_count":22,"is_preprint":false},{"pmid":"1704842","id":"PMC_1704842","title":"CD4 and CD7 molecules as targets for drug delivery from antibody bearing liposomes.","date":"1991","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/1704842","citation_count":22,"is_preprint":false},{"pmid":"19937140","id":"PMC_19937140","title":"Twist2 regulates CD7 expression and galectin-1-induced apoptosis in mature T-cells.","date":"2009","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/19937140","citation_count":21,"is_preprint":false},{"pmid":"15055863","id":"PMC_15055863","title":"The importance of CD7 and CD56 antigens in acute leukaemias.","date":"2004","source":"International journal of clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/15055863","citation_count":21,"is_preprint":false},{"pmid":"17275106","id":"PMC_17275106","title":"Stable expression of Cryptosporidium parvum glycoprotein gp40/15 in Toxoplasma gondii.","date":"2007","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/17275106","citation_count":20,"is_preprint":false},{"pmid":"37391486","id":"PMC_37391486","title":"Inserting EF1α-driven CD7-specific CAR at CD7 locus reduces fratricide and enhances tumor rejection.","date":"2023","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/37391486","citation_count":20,"is_preprint":false},{"pmid":"15742156","id":"PMC_15742156","title":"Expression of the CD7 ligand K-12 in human thymic epithelial cells: regulation by IFN-gamma.","date":"2005","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15742156","citation_count":19,"is_preprint":false},{"pmid":"12894562","id":"PMC_12894562","title":"CD7 expression in reactive and malignant human skin T-lymphocytes.","date":"2003","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/12894562","citation_count":18,"is_preprint":false},{"pmid":"33965880","id":"PMC_33965880","title":"Chimeric antigen receptor T cells targeting CD7 in a child with high-risk T-cell acute lymphoblastic leukemia.","date":"2021","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33965880","citation_count":18,"is_preprint":false},{"pmid":"18718658","id":"PMC_18718658","title":"Aggressive characteristics of myeloblasts expressing CD7 in myelodysplastic syndromes.","date":"2008","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/18718658","citation_count":18,"is_preprint":false},{"pmid":"36517851","id":"PMC_36517851","title":"Naturally selected CD7 CAR-T therapy without genetic editing demonstrates significant antitumour efficacy against relapsed and refractory acute myeloid leukaemia (R/R-AML).","date":"2022","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36517851","citation_count":17,"is_preprint":false},{"pmid":"7678579","id":"PMC_7678579","title":"Isolation and characterization of mouse CD7 cDNA.","date":"1993","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/7678579","citation_count":17,"is_preprint":false},{"pmid":"16417922","id":"PMC_16417922","title":"Evaluation of CD7 and terminal deoxynucleotidyl transferase (TdT) expression in CD34+ myeloblasts from patients with myelodysplastic syndrome.","date":"2006","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/16417922","citation_count":16,"is_preprint":false},{"pmid":"7513604","id":"PMC_7513604","title":"Clinical and biologic characteristics of CD7+ acute myeloid leukemia. Our experience and literature review.","date":"1994","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/7513604","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53207,"output_tokens":5512,"usd":0.12115},"stage2":{"model":"claude-opus-4-6","input_tokens":9133,"output_tokens":3119,"usd":0.18546},"total_usd":0.30661,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1984,\n      \"finding\": \"CD7 (gp40) is a monomeric transmembrane glycoprotein of Mr=40,000 that is asymmetrically inserted into the rough endoplasmic reticulum as a transmembrane structure, undergoes N-linked glycosylation (two high-mannose type glycans processed to complex oligosaccharides during transport), also contains O-linked glycans, covalently associated fatty acid, and is phosphorylated on phosphoserine.\",\n      \"method\": \"Biosynthetic labeling, tunicamycin inhibition, endo-F/endo-H cleavage, gal-NAc oligosaccharidase digestion, 32P phosphate labeling, phosphoamino acid analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal biochemical methods in a single rigorous study\",\n      \"pmids\": [\"6609985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Immobilized anti-CD7 monoclonal antibody delivers a co-mitogenic signal to T cells in conjunction with suboptimal anti-CD3 stimulation, promoting IL-2 production and IL-2 receptor expression; this co-mitogenic effect can be replicated by PMA but not by calcium ionophore.\",\n      \"method\": \"Co-mitogenic proliferation assay with solid-phase antibodies, IL-2 and IL-2R measurement, PKC/PTK pharmacological dissection\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean functional assay with multiple stimulation conditions; single lab\",\n      \"pmids\": [\"2459196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"CD7 cross-linking on TCRγ/δ+ T cell lines causes rapid cytoplasmic free calcium elevation, IL-2 production, and induction of TNF-α, TNF-β, and GM-CSF mRNAs, directly activating these cells; the same anti-CD7 antibody fails to activate TCRα/β+ T cells.\",\n      \"method\": \"Calcium flux measurement, cytokine ELISA, mRNA induction assay, proliferation assay with anti-CD7 mAb stimulation\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional evidence with multiple readouts; single lab\",\n      \"pmids\": [\"1709867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"CD7 gene transcription is selectively induced by calcium flux (ionomycin) in a cyclosporin A-sensitive, extracellular calcium-dependent, tyrosine-kinase-independent manner; transcriptional induction peaks at 1 hour and precedes surface upregulation.\",\n      \"method\": \"Ionomycin stimulation, CD7 mRNA half-life measurement, transcriptional run-on analysis, pharmacological inhibitors, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — transcriptional mechanism defined by run-on assay and multiple inhibitor controls\",\n      \"pmids\": [\"1717576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"CD7 augments T cell proliferation via the IL-2 autocrine pathway by increasing IL-2 production and IL-2Rα (CD25) expression through both PKC and PTK signaling pathways; inhibitors H-7 (PKC) and genistein (PTK) suppress CD7-mediated co-mitogenesis.\",\n      \"method\": \"PBMC proliferation assays, IL-2 measurement, IL-2Rα expression analysis, PKC/PTK inhibitor treatment\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined pathway mechanism with pharmacological dissection; single lab\",\n      \"pmids\": [\"1372842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"CD7 cross-linking on NK cells induces rapid cytoplasmic calcium elevation, upregulation of CD25, CD71, HLA-DR, CD69, and CD54, IFN-γ secretion, NK cell proliferation, enhanced cytotoxicity against K562 targets, and augmented adhesion to fibronectin; however CD7 does not transduce a direct lytic signal.\",\n      \"method\": \"Anti-CD7 mAb cross-linking, calcium flux, flow cytometry, thymidine incorporation, cytotoxicity assay, fibronectin adhesion assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional readouts with rigorous controls; replicated across different assays\",\n      \"pmids\": [\"7506726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"CD7 exists in an oligomeric complex (homodimer) physically associated with CD3 and CD45 on human T cells; this complex contains a tyrosine kinase whose major substrate is CD45.\",\n      \"method\": \"Co-immunoprecipitation, Western blotting, fluorescence resonance energy transfer (FRET), in vitro phosphorylation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — association confirmed by three orthogonal methods (Co-IP, Western blot, FRET); single lab\",\n      \"pmids\": [\"7523512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"CD7 cross-linking mediates rapid tyrosine phosphorylation and upregulates β1 and β2 integrin-mediated T cell adhesion; this effect is completely blocked by the tyrosine kinase inhibitor herbimycin A, and CD7 immunoprecipitates contain in vitro kinase activity phosphorylating an 80 kDa substrate on tyrosine, serine, and threonine residues.\",\n      \"method\": \"Anti-CD7 antibody cross-linking, adhesion assay, herbimycin A inhibition, anti-phosphotyrosine immunoblotting, in vitro kinase assay, phosphoamino acid analysis\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with mutagenesis controls plus multiple functional readouts\",\n      \"pmids\": [\"7525296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CD7 cross-linking leads to association with phosphoinositide 3-kinase (PI3K) and production of D-3 phosphoinositides including phosphatidylinositol 3,4,5-trisphosphate (PIP3); this is accompanied by phosphatidic acid formation in the absence of phosphatidylinositol-4,5-bisphosphate metabolism.\",\n      \"method\": \"Co-precipitation of CD7 with PI3K, phosphoinositide lipid analysis, comparison with CD3 and CD28 stimulation\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical co-precipitation and lipid product measurement; multiple controls\",\n      \"pmids\": [\"7533088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The cytoplasmic tail of CD7 interacts with the p85 adaptor subunit of PI3-kinase via a pTyr-X-X-Met (YEDM) motif; CD7 cross-linking markedly increases the amount of PI3-kinase activity associated with CD7.\",\n      \"method\": \"Co-precipitation with anti-CD7 mAb, recombinant p85 SH2-GST fusion protein pulldown, peptide competition, PI3-kinase activity assay\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical interaction defined by peptide competition and domain mapping plus enzymatic activity measurement\",\n      \"pmids\": [\"8918688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CD7-deficient mice show normal lymphocyte development but have transient increases in thymocyte numbers at 3 months of age and reduced antigen-specific MHC class I-restricted CTL activity, demonstrating a role for CD7 in regulating intrathymic T cell development and CTL effector function.\",\n      \"method\": \"Targeted gene disruption (CD7 knockout mice), thymocyte enumeration at multiple timepoints, antigen-specific CTL assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined cellular phenotypes; replicated across age groups\",\n      \"pmids\": [\"9637484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Targeted disruption of murine CD7 results in mice with normal lymphocyte populations, normal serum Ig levels, normal mitogenic responses, and normal NK cytotoxicity, indicating CD7 is dispensable for normal lymphoid development under steady-state conditions.\",\n      \"method\": \"Targeted gene disruption, lymphocyte subset analysis, mitogen proliferation assays, NK cytotoxicity assay\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with comprehensive immunological characterization\",\n      \"pmids\": [\"9466315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD7-deficient mice are resistant to LPS-induced shock; they show decreased serum IFN-γ and TNF-α levels after LPS/D-galactosamine challenge, and have reduced numbers of liver NK1.1+/CD3+ NKT cells, establishing CD7 as a key molecule in the inflammatory response leading to LPS-induced shock through regulation of NKT cell numbers and cytokine production.\",\n      \"method\": \"CD7 knockout mice, LPS/D-gal challenge survival assay, cytokine ELISA, liver mRNA analysis, liver mononuclear cell phenotyping by flow cytometry\",\n      \"journal\": \"Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple mechanistic readouts (cytokines, cell populations, survival); strong preponderance of evidence\",\n      \"pmids\": [\"10075985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"K12 (SECTM1) is identified as a cognate ligand of CD7; K12-Fc fusion protein binds specifically to T and NK cells and precipitates an ~40 kDa protein from NK cell lysates identified as CD7. Mouse K12 inhibits ConA-induced but not anti-TCR-induced T cell proliferation, and human K12-Fc stimulates upregulation of CD25, CD54, and CD69 on human NK cells.\",\n      \"method\": \"K12-Fc fusion protein flow cytometry binding, immunoprecipitation from 35S-radiolabeled NK cells, cDNA expression library screening, NK cell activation assay, T cell proliferation inhibition assay\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — receptor-ligand identification by multiple methods including expression library screen, precipitation, and functional assays\",\n      \"pmids\": [\"10652336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Galectin-3 binds CD7 and CD29 (β1 integrin) on the T cell surface and induces type II (mitochondrial) apoptosis including cytochrome c release and caspase-3 activation but not caspase-8 activation; this occurs through carbohydrate-dependent interactions.\",\n      \"method\": \"Identification of Gal-3 cell surface receptors, lactose inhibition assay, caspase activity measurement, cytochrome c release assay, Gal-3 transfection\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — receptor identified with functional downstream signaling validated by multiple biochemical readouts\",\n      \"pmids\": [\"14678989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD7 expression is necessary but not sufficient for galectin-1-induced apoptosis of Sezary T cells; cell surface glycosylation (sialylated core 1 O-glycans) additionally determines susceptibility, as CD7-positive Sezary cells with this glycotype resist galectin-1-mediated death.\",\n      \"method\": \"Galectin-1 apoptosis assay, CD7 expression analysis, cell surface glycosylation analysis of Sezary cell lines and primary lesions, in vivo galectin-1 detection by IHC\",\n      \"journal\": \"Modern pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional apoptosis assay with glycosylation analysis; single lab\",\n      \"pmids\": [\"12808059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD7 expression on CD8+ T cells marks distinct differentiation subsets with different functional properties: CD7-high cells contain naive and memory cells; CD7-low and CD7-negative cells contain effector cells that can be further divided into cytokine-secreting and lytic effector subsets.\",\n      \"method\": \"Multi-parameter flow cytometry, functional cytokine secretion assays, cytotoxicity assays on sorted CD7hi/lo/neg CD8+ T cell subsets\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct sorting and functional comparison of defined subsets; single lab\",\n      \"pmids\": [\"12594257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Progressive restriction in lymphoid/myeloid lineage potential in human thymic progenitors correlates with increasing CD7 expression: CD7-negative CD34+ thymocytes retain full lympho-myeloid potential and express HSC genes; CD7-intermediate cells produce B, T, and NK cells; CD7-high cells produce only T and NK cells.\",\n      \"method\": \"Fluorescence-activated cell sorting by CD7 expression level, multi-lineage in vitro differentiation assays (B, T, NK, myelo-erythroid), gene expression analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clonal-level differentiation assays with sorted populations; multiple lineages tested\",\n      \"pmids\": [\"17959857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD7 co-expression with CD56 distinguishes functional NK cells from CD56+ monocyte/DC-like cells; only CD7+CD56+ NK cells secrete IFN-γ and degranulate after IL-12/IL-18 or K562 stimulation, while CD7-negative CD56+ myeloid cells stimulate allogeneic responses but lack NK effector functions.\",\n      \"method\": \"Multi-color flow cytometry, IFN-γ secretion assay, degranulation (CD107a) assay, allogeneic stimulation assay, K562 cytotoxicity assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional discrimination of subsets by multiple orthogonal assays\",\n      \"pmids\": [\"19805616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Twist2 transcription factor downregulates CD7 gene promoter activity in T cells through its C-terminal domain and possibly via histone deacetylation; ectopic Twist2 expression reduces CD7 surface levels and decreases galectin-1-induced apoptosis.\",\n      \"method\": \"Twist2 ectopic expression, CD7 promoter activity assay, C-terminal deletion mutant analysis, HDAC inhibitor treatment (TSA, sodium butyrate), galectin-1 apoptosis assay\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter assay with deletion mapping and functional consequence; single lab\",\n      \"pmids\": [\"19937140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SECTM1 (K12) produced by tumor cells binds CD7 on monocytes and significantly increases monocyte migration via activation of the PI3K pathway; CD7 is expressed on human monocytes and macrophages and its expression decreases upon M-CSF-induced differentiation.\",\n      \"method\": \"SECTM1-CD7 binding assay, monocyte migration assay, PI3K pathway analysis, flow cytometry for CD7 expression on monocytes/macrophages, conditioned medium experiments\",\n      \"journal\": \"Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor-ligand interaction validated with functional migration assay and pathway identification; single lab\",\n      \"pmids\": [\"24157461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Targeted genomic disruption of the CD7 gene in T cells prevents fratricide when a CD7-specific CAR is expressed; CD7-edited CAR T cells expand normally, retain cytotoxic function against malignant T-cell lines and primary tumors, and are protective in a mouse xenograft model of T-ALL.\",\n      \"method\": \"CRISPR/Cas9 gene editing, CAR T cell expansion and fratricide assays, cytotoxicity assays, xenograft mouse model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic disruption with multiple functional readouts and in vivo validation\",\n      \"pmids\": [\"28539325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Naturally selected CD7-CAR T cells overcome fratricide because the CD7-targeting CAR masks or sequesters CD7 molecules on the T cell surface, minimizing accessible CD7 epitopes without requiring genetic knockout; this approach yields a higher proportion of central memory CD8+ T cells compared to sorted CD7-negative or CD7-knocked-out CAR T cells.\",\n      \"method\": \"Flow cytometry of CD7 surface expression, comparison of CD7-masked vs CD7-KO vs CD7-negative CAR T cell products, central memory phenotype analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic demonstration of CAR-mediated CD7 masking with functional comparisons; single lab\",\n      \"pmids\": [\"35500125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CD7 expression is transcriptionally regulated and absent CD7 expression in a subset of CD4+ memory T cells represents a stable, separate differentiation state: once naive T cells differentiate into CD7-negative memory cells through repeated stimulation, sorted CD7-negative cells do not re-express CD7 and show no CD7 mRNA.\",\n      \"method\": \"Serial stimulation of sorted naive CD4+ T cells, RT-PCR for CD7 mRNA, cell sorting and re-culture of CD7+ and CD7- populations, surface phenotyping\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptional regulation and stable phenotype confirmed by sorting and re-culture; single lab\",\n      \"pmids\": [\"8958052\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD7 is a 40 kDa type I transmembrane Ig-superfamily glycoprotein expressed on T and NK cells that functions as a co-stimulatory/accessory signaling receptor: upon cross-linking it associates with CD3/CD45 and recruits a tyrosine kinase activity and PI3-kinase (via its cytoplasmic YEDM motif) to generate PIP3, elevate intracellular calcium, activate both PKC and PTK pathways, and promote IL-2 production, IL-2Rα upregulation, integrin-mediated adhesion, and cytokine secretion; its natural ligand SECTM1/K12 (expressed by thymic epithelial cells and tumor cells) engages CD7 to modulate T/NK cell activation and monocyte migration via PI3K; CD7 also serves as a galectin-3/galectin-1 receptor mediating mitochondrial apoptosis, and its level of expression marks progressive stages of T cell lineage commitment in the thymus and functional differentiation of peripheral CD8+ T cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CD7 is a type I transmembrane immunoglobulin-superfamily glycoprotein that functions as an accessory signaling receptor on T cells, NK cells, and monocytes, modulating activation, differentiation, and apoptotic susceptibility. Upon cross-linking, CD7 forms homodimers that associate with CD3 and CD45, recruit a tyrosine kinase activity, and engage PI3-kinase via a cytoplasmic YEDM motif to generate PIP3, elevate intracellular calcium, activate PKC and PTK pathways, and promote IL-2 production, IL-2Rα upregulation, integrin-mediated adhesion, and cytokine secretion [PMID:7523512, PMID:8918688, PMID:7533088, PMID:7525296]. Its cognate ligand SECTM1 (K12) binds CD7 on T, NK, and monocytic cells to modulate proliferation and drive PI3K-dependent monocyte migration, while galectin-1 and galectin-3 engage CD7 to trigger mitochondrial apoptosis through cytochrome c release and caspase-3 activation [PMID:10652336, PMID:24157461, PMID:14678989, PMID:12808059]. Progressive upregulation of CD7 marks lineage restriction during thymic T cell development—from multipotent CD7-negative progenitors to T/NK-committed CD7-high cells—and graded CD7 loss on peripheral CD8+ T cells delineates naive, memory, and effector subsets [PMID:17959857, PMID:12594257, PMID:8958052].\",\n  \"teleology\": [\n    {\n      \"year\": 1984,\n      \"claim\": \"Establishing CD7 as a post-translationally modified transmembrane glycoprotein resolved the basic molecular identity of this lymphocyte-surface antigen and its biosynthetic route through the secretory pathway.\",\n      \"evidence\": \"Biosynthetic labeling, tunicamycin/endo-H/endo-F glycosylation analysis, phosphoamino acid analysis in human T cells\",\n      \"pmids\": [\"6609985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Three-dimensional structure undetermined\", \"Functional significance of serine phosphorylation and acylation unknown\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Demonstrating that CD7 cross-linking delivers a co-stimulatory signal that promotes IL-2 production, IL-2Rα upregulation, calcium flux, and cytokine induction through both PKC and PTK pathways established CD7 as an activating accessory receptor on T and γδ T cells.\",\n      \"evidence\": \"Anti-CD7 mAb co-stimulation assays on PBMCs and γδ T cell lines with PKC/PTK inhibitor dissection, calcium flux, and cytokine measurement\",\n      \"pmids\": [\"2459196\", \"1709867\", \"1372842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Proximal signaling complex not yet identified\", \"Basis for differential activation of γδ versus αβ T cells unclear\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Identifying CD7 as a homodimer physically associated with CD3 and CD45 that co-precipitates tyrosine kinase activity, and showing that CD7 cross-linking drives integrin-mediated adhesion and NK cell activation, defined the signaling complex and broadened CD7 function beyond T cell co-stimulation.\",\n      \"evidence\": \"Co-IP, FRET, in vitro kinase assays on T cells; anti-CD7 cross-linking on NK cells with calcium flux, activation marker upregulation, cytotoxicity and adhesion assays\",\n      \"pmids\": [\"7523512\", \"7525296\", \"7506726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the 80 kDa kinase substrate unknown\", \"Specific tyrosine kinase(s) in the CD7 complex not identified\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Mapping the PI3K recruitment site to the cytoplasmic YEDM motif of CD7 and showing that cross-linking triggers PIP3 generation provided the first direct biochemical mechanism linking CD7 engagement to lipid second-messenger signaling.\",\n      \"evidence\": \"Co-precipitation with anti-CD7, GST-p85 SH2 pulldown, peptide competition, PI3K enzymatic activity assay, D-3 phosphoinositide lipid analysis\",\n      \"pmids\": [\"8918688\", \"7533088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of PIP3 in CD7 signaling (e.g., Akt activation) not directly demonstrated\", \"Relative contribution of PI3K vs PKC/PTK arms to functional outcomes undefined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"CD7-knockout mice revealed that CD7 is dispensable for steady-state lymphoid development but contributes to thymocyte homeostasis and antigen-specific CTL function, separating developmental from effector roles.\",\n      \"evidence\": \"Two independent targeted gene disruptions in mice; thymocyte enumeration, mitogenic responses, NK cytotoxicity, and MHC class I-restricted CTL assays\",\n      \"pmids\": [\"9637484\", \"9466315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy with other co-stimulatory receptors not dissected\", \"Mechanism of reduced CTL activity not resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"The finding that CD7-deficient mice resist LPS-induced shock and have reduced hepatic NKT cells linked CD7 to innate inflammatory responses and NKT cell homeostasis in vivo.\",\n      \"evidence\": \"CD7 KO mice challenged with LPS/D-galactosamine; survival, serum cytokine ELISA, liver mononuclear cell phenotyping\",\n      \"pmids\": [\"10075985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD7 directly regulates NKT cell development or survival is unclear\", \"Cell-intrinsic vs cell-extrinsic mechanism not distinguished\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of SECTM1 (K12) as the cognate ligand of CD7 that activates NK cells and inhibits ConA-driven T cell proliferation resolved a long-standing search for CD7's natural binding partner.\",\n      \"evidence\": \"K12-Fc fusion binding, immunoprecipitation of ~40 kDa protein from NK cells, cDNA expression library screening, functional NK activation and T cell inhibition assays\",\n      \"pmids\": [\"10652336\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of SECTM1–CD7 interaction undetermined\", \"Whether SECTM1 is the sole physiological ligand unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating that galectin-1 and galectin-3 bind CD7 to trigger mitochondrial apoptosis (cytochrome c release, caspase-3 activation) established CD7 as a death receptor for galectin family members, with glycosylation state as a susceptibility determinant.\",\n      \"evidence\": \"Galectin-3 receptor identification, lactose inhibition, caspase/cytochrome c assays; galectin-1 apoptosis on Sézary T cells with glycosylation analysis\",\n      \"pmids\": [\"14678989\", \"12808059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling galectin–CD7 binding to mitochondrial pathway not elucidated\", \"Whether the YEDM/PI3K signaling axis is involved in galectin-induced death unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Correlating graded CD7 expression with progressive lineage restriction in thymic progenitors and with effector differentiation in peripheral CD8+ T cells established CD7 level as a functional marker of T cell commitment and differentiation state.\",\n      \"evidence\": \"Sorted CD7-neg/int/high CD34+ thymocytes in multi-lineage differentiation assays; sorted CD7hi/lo/neg CD8+ T cell functional analysis; serial stimulation and re-culture of CD4+ T cells\",\n      \"pmids\": [\"17959857\", \"12594257\", \"8958052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factors upstream of CD7 regulation during lineage commitment largely undefined beyond Twist2\", \"Whether CD7 signaling actively drives commitment or is merely a marker unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extending CD7 function to monocytes by showing that tumor-derived SECTM1 promotes PI3K-dependent monocyte migration via CD7 broadened the receptor's role to myeloid innate immunity and tumor microenvironment biology.\",\n      \"evidence\": \"SECTM1–CD7 binding on monocytes, transwell migration assay with PI3K pathway analysis, flow cytometry during M-CSF differentiation\",\n      \"pmids\": [\"24157461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of CD7-dependent monocyte migration not tested\", \"Other signaling intermediates downstream of PI3K in monocytes not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CRISPR/Cas9 disruption of CD7 in CAR T cells eliminated fratricide and enabled effective anti-CD7 CAR T therapy against T-ALL in xenograft models, validating CD7 as both a therapeutic target and an expendable molecule in engineered T cells.\",\n      \"evidence\": \"CRISPR/Cas9 CD7 KO, CAR T expansion/fratricide assays, cytotoxicity against T-ALL lines and primary tumors, xenograft model\",\n      \"pmids\": [\"28539325\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term consequences of CD7 loss on engineered T cell fitness in patients unknown\", \"Whether CD7 loss alters galectin-mediated apoptotic regulation of CAR T cells untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of CD7–SECTM1 and CD7–galectin interactions, the identity of the tyrosine kinase(s) directly recruited to the CD7–CD3–CD45 complex, the signaling mechanism linking CD7-galectin binding to mitochondrial apoptosis, and whether CD7 actively instructs lineage commitment or passively marks it.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure for CD7 or its ligand complexes\", \"Specific kinase(s) in the CD7 complex remain unidentified\", \"Active vs passive role of CD7 in thymic lineage commitment unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 2, 5, 8, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5, 6, 13, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [8, 9, 20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 5, 10, 12, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [14, 15]}\n    ],\n    \"complexes\": [\n      \"CD7–CD3–CD45 complex\"\n    ],\n    \"partners\": [\n      \"CD3E\",\n      \"PTPRC\",\n      \"PIK3R1\",\n      \"SECTM1\",\n      \"LGALS3\",\n      \"LGALS1\",\n      \"ITGB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}