Affinage

CD247

T-cell surface glycoprotein CD3 zeta chain · UniProt P20963

Length
164 aa
Mass
18.7 kDa
Annotated
2026-06-09
100 papers in source corpus 52 papers cited in narrative 50 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD247 (CD3-zeta) is the principal signal-transducing subunit of the T cell antigen receptor that both controls assembly and surface delivery of the TCR/CD3 complex and converts receptor engagement into intracellular signals (PMID:3278811, PMID:2531776). As an ER-resident assembly checkpoint, CD3-zeta associates with the pentameric TCRαβ-CD3γδε complex to form the heptameric receptor, and in its absence the complex is retained intracellularly so that only small amounts of surface TCR are expressed (PMID:3278811, PMID:2531776); a human Q70X truncation that destabilizes the protein abolishes TCR assembly and causes T-B+NK+ SCID (PMID:16672702, PMID:17170122). Signal transduction proceeds through the CD3-zeta cytoplasmic ITAM tyrosines, whose phosphorylation creates docking sites that recruit ZAP-70 and the Lck/ZAP-70-CD4/CD8 module to the engaged receptor; this cytoplasmic domain is necessary and sufficient to couple receptor cross-linking to Ca2+ flux, tyrosine kinase activation, and IL-2 production (PMID:1351920, PMID:7539035, PMID:8814252). ITAM phosphorylation defines distinct downstream branches, including a CD3-zeta/ZAP-70-dependent route to CD95L induction and activation-induced apoptosis (PMID:9547330), though complete ITAM ablation impairs signaling only quantitatively at low antigen doses because CD3-γδε ITAMs suffice for qualitatively normal responses (PMID:10229184). CD3-zeta is a versatile signaling adaptor that partners with diverse receptors beyond the TCR — CD16/FcγRIII, NKp46, NKG2D-linked receptors, and TREM-2 in NK and T cells — with transmembrane-domain packing dictating partner-complex formation and signaling capacity (PMID:2532305, PMID:35320345, PMID:20926796, PMID:34623322). Its activity is heavily controlled post-translationally: CD45 dephosphorylates phospho-CD3-zeta to terminate signaling (PMID:7526385), LAPTM5 routes intracellular CD3-zeta to lysosomal degradation (PMID:18619870, PMID:24638062), caspase-3 cleavage degrades it under disease and tumor conditions (PMID:16116236, PMID:20926796, PMID:26595239), and L-arginine availability governs its mRNA stability (PMID:11950832, PMID:15210820). CD3-zeta also accumulates as a phosphorylated endosomal pool that sustains signaling after receptor internalization (PMID:21135224) and adopts a compact, protease-resistant conformation upon triggering (PMID:18320063). Beyond immunity, CD3-zeta is expressed in hippocampal and retinal ganglion neurons where it acts through ITAM-based mechanisms as a negative regulator of dendritic development and is required for normal retinal synaptic activity and eye-specific axonal segregation (PMID:18367546, PMID:20188655).

Mechanistic history

Synthesis pass · year-by-year structured walk · 32 steps
  1. 1988 High

    Established that CD3-zeta governs the intracellular fate and surface expression of the TCR while still permitting transmembrane signaling, defining it as more than a passive structural chain.

    Evidence Chemical mutagenesis of a T cell hybridoma to generate a CD3-zeta-deficient variant with PI hydrolysis and IL-2 readouts

    PMID:3278811

    Open questions at the time
    • Did not resolve which assembly step CD3-zeta controls
    • Cytoplasmic signaling determinants not yet mapped
  2. 1988 High

    Showed that different zeta-chain dimers (zeta-zeta vs zeta-eta) couple differentially to downstream signaling, revealing TCR isoform heterogeneity in signal output.

    Evidence Isogenic T cell hybridoma variants compared for PI hydrolysis and kinase activity

    PMID:2845582

    Open questions at the time
    • Molecular basis of differential coupling unresolved
    • In vivo relevance of isoforms unclear
  3. 1989 High

    Defined CD3-zeta as the subunit required for ER-to-Golgi export of the assembled heptameric TCR and as a promiscuous signaling partner for non-TCR receptors such as CD16.

    Evidence Assembly/fractionation in CD3-zeta-deficient Jurkat cells; Co-IP from NK cells with COS-7 reconstitution of CD16

    PMID:2531776 PMID:2532305

    Open questions at the time
    • Structural basis of TCR association not determined
    • Mechanism of CD16 partner selection unknown
  4. 1990 High

    Demonstrated that CD3-eta arises by alternative splicing of the same gene, explaining the origin of distinct zeta-chain dimers.

    Evidence Protein microsequencing, cDNA cloning, and genomic exon analysis in human and mouse

    PMID:2139725 PMID:2150596

    Open questions at the time
    • Functional significance of the missing Tyr-132 in eta not yet tested
    • Regulation of splice choice unknown
  5. 1991 High

    Showed that FcεRIγ homodimers can substitute for CD3-zeta and that zeta-specific tyrosine phosphorylation distinguishes zeta from eta, refining the signaling division of labor among related chains.

    Evidence Reconstitution of FcεRIγ and CD3-zeta/eta cDNAs in deficient T cell hybridomas with functional readouts

    PMID:1708889 PMID:1714902

    Open questions at the time
    • Why zeta but not eta is phosphorylated not mechanistically defined
    • Physiological role of zeta-specific phosphorylation unclear
  6. 1992 High

    Mapped signaling sufficiency to the CD3-zeta cytoplasmic domain and identified specific tyrosines and kinase associations underlying phosphorylation, establishing it as an autonomous signaling module.

    Evidence CD8α-CD3zeta chimeras, site-directed tyrosine mutagenesis, and Co-IP in defined T cell variants

    PMID:1346934 PMID:1351920 PMID:1531339 PMID:1532798

    Open questions at the time
    • Order and hierarchy of ITAM phosphorylation incomplete
    • Direct kinase responsible for each site not fully assigned
  7. 1993 High

    Knockout mice established the in vivo requirement for CD3-zeta in conventional thymocyte development and TCR surface expression, while showing it is dispensable for γδ IEL maturation.

    Evidence CD3-zeta/eta-null and CD3-zeta-specific knockout mice analyzed by flow cytometry and proliferation assays

    PMID:8223444 PMID:8223445 PMID:8223495

    Open questions at the time
    • Did not isolate signaling from assembly contributions to the phenotype
    • Compensation by FcεRIγ in IELs not fully quantified
  8. 1994 High

    Identified CD45 as a phosphatase that binds and selectively dephosphorylates phospho-CD3-zeta, providing a mechanism for terminating TCR signals.

    Evidence GST-CD45 pulldowns with active-site mutant trapping and in vitro phosphatase assays with specificity controls

    PMID:7526385

    Open questions at the time
    • In vivo timing of CD45 action on CD3-zeta not established
    • Site specificity among the six tyrosines not resolved
  9. 1995 High

    Showed that ZAP-70/Syk phosphorylation recruits Lck-bound CD4/CD8 coreceptors to the activated complex and that CD3-zeta turns over independently of the rest of the TCR, linking phosphorylation to coreceptor assembly and receptor dynamics.

    Evidence Co-IP, phosphopeptide competition, co-capping, and pulse-chase metabolic labeling in human T cells

    PMID:7539035 PMID:7796297

    Open questions at the time
    • Quantitative contribution of independent zeta turnover to surface TCR unclear
    • Trafficking route of exchanging zeta not defined
  10. 1995 High

    Demonstrated functional redundancy between CD3-epsilon and CD3-zeta cytoplasmic domains for development and effector function in vivo, and showed CD3-eta is dispensable for selection.

    Evidence Tac-CD3 chimeric transgenes in RAG2-/- mice and CD3-eta-specific knockout mice with selection crosses

    PMID:7719942 PMID:8112294

    Open questions at the time
    • Quantitative versus qualitative roles not separated
    • Specialized branches unique to zeta not addressed here
  11. 1996 Medium

    Connected defective CD3-zeta association to a selective loss of activation-induced apoptosis, suggesting a dedicated CD3-zeta-dependent death-signaling branch.

    Evidence TCRβ transmembrane mutant abolishing zeta association in Jurkat cells with apoptosis and activation readouts; CD8/p56lck recruitment via ZAP-70

    PMID:8814252 PMID:8940006

    Open questions at the time
    • Single transmembrane-mutant model; not independently confirmed
    • Molecular separation of apoptosis from IL-2 pathways incomplete
  12. 1997 High

    Established lysosomal degradation as the fate of internalized triggered TCR-CD3 complexes, defining a post-activation downmodulation route for CD3-zeta.

    Evidence FACS on T-APC conjugates, Western blot, lysosomal inhibitors, and Lamp1 immunofluorescence

    PMID:9151711

    Open questions at the time
    • Ubiquitin/adaptor machinery not yet identified
    • Quantitative recycling versus degradation balance unknown
  13. 1998 Medium

    Linked impaired ZAP-70 recruitment to CD3-zeta with selective failure of apoptosis signaling, reinforcing a membrane-recruitment requirement for the death branch.

    Evidence Co-IP and subcellular fractionation in apoptosis-deficient TCRβ-TM mutant Jurkat cells

    PMID:9547330

    Open questions at the time
    • Single lab and mutant system
    • Downstream death effectors not mapped
  14. 1998 High

    Defined an additional developmental role for CD3-zeta/eta modules in TCR-beta allelic exclusion, distinct from V(D)J initiation.

    Evidence Genetic epistasis in CD3-epsilon- and CD3-zeta/eta-deficient mice carrying a TCR-beta transgene

    PMID:9419216

    Open questions at the time
    • Signaling output mediating exclusion not defined
    • Role of individual ITAMs untested
  15. 1999 High

    Showed that complete CD3-zeta ITAM ablation impairs signaling only quantitatively at suboptimal ligand, establishing CD3-γδε ITAMs as sufficient for qualitatively normal responses.

    Evidence In vivo genetic ITAM substitution in P14 TCR transgenic mice; tyrosine-to-phenylalanine mutants in antagonism assays

    PMID:10229184 PMID:10395646

    Open questions at the time
    • Threshold-tuning mechanism by zeta ITAMs not detailed
    • Context-dependence in primary cells incompletely explored
  16. 2000 High

    Visualized the spatial dynamics of CD3-zeta and CD4 clustering at the T cell-APC interface, linking receptor reorganization to early calcium signaling.

    Evidence GFP chimeras and 3D live-cell video microscopy of T cell-APC conjugates

    PMID:10958781

    Open questions at the time
    • Molecular drivers of central cluster stabilization not identified
    • Relationship to phosphorylation kinetics not resolved
  17. 2002 High

    Identified L-arginine availability as a metabolic control of CD3-zeta abundance acting through mRNA half-life, later shown to be exploited by H. pylori arginase.

    Evidence L-Arg depletion in Jurkat cells with mRNA stability, transcription rate, and cycloheximide assays; isogenic arginase-mutant bacteria

    PMID:11950832 PMID:15210820

    Open questions at the time
    • Identity of the labile regulatory protein unknown
    • RNA element/binding factor controlling stability not defined
  18. 2003 High

    Revealed that SIV Nef directly binds the CD3-zeta cytoplasmic tail and cooperates with AP-2 to drive TCR endocytosis, defining a viral immune-evasion mechanism targeting CD3-zeta.

    Evidence CD8-CD3zeta chimera with Nef in Jurkat cells; AP-2 colocalization and in vitro recombinant binding assays

    PMID:12829850

    Open questions at the time
    • Structural basis of the composite Nef/zeta/AP-2 surface not solved
    • Relevance to HIV-1 Nef not addressed
  19. 2004 Medium

    Showed that PD-1 engagement inhibits ZAP-70 phosphorylation and its association with CD3-zeta, placing CD3-zeta at the receiving end of an inhibitory checkpoint.

    Evidence PD-1 engagement assays with phospho-Western blots, Co-IP, and in vitro ITSM/ITIM peptide-SHP binding

    PMID:15358536

    Open questions at the time
    • Direct phosphatase action on CD3-zeta versus ZAP-70 not separated
    • Single lab
  20. 2006 High

    Linked a human CD3-zeta truncation mutation directly to SCID via failed TCR assembly and protein instability, with somatic reversion partially rescuing surface TCR.

    Evidence Patient genetics with retroviral reconstitution in CD3-zeta-deficient hybridoma, metabolic labeling, and flow cytometry

    PMID:16672702 PMID:17170122

    Open questions at the time
    • Genotype-phenotype variability across patients not fully explained
    • Basis of mutant instability not structurally defined
  21. 2008 High

    Defined multiple disease-relevant control points of CD3-zeta abundance — PP2A/Elf-1 transcriptional control and caspase-3 degradation in lupus, and LAPTM5-mediated lysosomal degradation.

    Evidence PP2A and Elf-1 manipulation with promoter-binding assays in SLE T cells; caspase-3 inhibition; LAPTM5 Co-IP, KO, and domain mutants

    PMID:16116236 PMID:18619870 PMID:18714041

    Open questions at the time
    • Relative contribution of transcriptional versus degradative control in vivo unclear
    • LAPTM5 recognition determinant on CD3-zeta not mapped
  22. 2008 Medium

    Provided biochemical evidence that TCR triggering imposes a compact, protease-resistant conformation on the CD3-zeta cytoplasmic tail, suggesting allosteric coupling of engagement to the tail.

    Evidence Protease-sensitivity assay of CD3-epsilon and CD3-zeta tails after TCR triggering

    PMID:18320063

    Open questions at the time
    • Single biochemical method; structural model lacking
    • Functional consequence of conformational change untested
  23. 2008 Medium

    Extended CD3-zeta function beyond immunity, identifying it as an ITAM-dependent negative regulator of dendritic development in hippocampal neurons.

    Evidence siRNA knockdown, ITAM-mutant overexpression, and antibody activation with immunofluorescence in neurons

    PMID:18367546

    Open questions at the time
    • Neuronal upstream receptor and kinase not identified
    • Single lab
  24. 2010 High

    Established neuronal requirement for CD3-zeta in retinal dendritic motility, synaptic activity, and eye-specific axon segregation, and revealed an endosomal phospho-CD3-zeta pool sustaining signaling after internalization.

    Evidence CD3-zeta knockout mice with imaging, electrophysiology, and tracing; FRET phosphorylation biosensors with live-cell imaging

    PMID:20188655 PMID:21135224

    Open questions at the time
    • Neuronal ligand and signaling cascade undefined
    • Functional role of the endosomal phospho-pool not directly perturbed
  25. 2010 Medium

    Showed that the CD3-zeta transmembrane domain mediates CAR association with endogenous TCR and that NKG2D-triggered caspase activity degrades CD3-zeta to impair multiple shared receptors.

    Evidence CAR TM-domain mutagenesis with functional readouts; NKG2D stimulation with caspase assays and multi-receptor functional analysis

    PMID:20483753 PMID:20926796

    Open questions at the time
    • Single labs; cell-line models
    • Generality of TM-mediated complex formation across CAR designs limited
  26. 2012 Medium

    Identified SAP as a direct membrane-proximal ITAM-binding partner of CD3-zeta required for full downstream TCR signaling.

    Evidence Co-IP with domain mapping and shRNA knockdown with downstream signaling and cytokine readouts

    PMID:22912825

    Open questions at the time
    • Single lab; no reciprocal in vivo validation
    • Competition with ZAP-70 for the same ITAM not resolved
  27. 2013 Medium

    Defined LAT as a negative feedback regulator constraining CD3-zeta and ZAP-70 phosphorylation, refining the kinetics of proximal signaling.

    Evidence Quantitative phosphoproteomics in isogenic LAT-sufficient and LAT-deficient Jurkat cells

    PMID:24204825

    Open questions at the time
    • Mechanism of feedback (phosphatase recruitment vs kinase sequestration) not defined
    • Single method
  28. 2014 Medium

    Resolved the substrate specificity of LAPTM5 to intracellular Golgi-localized CD3-zeta, independent of ITAM phosphorylation and genetically distinct from SLAP/c-Cbl.

    Evidence Subcellular fractionation, Golgi-localizing and ITAM-null CD3-zeta mutants, and genetic epistasis with SLAP/c-Cbl

    PMID:24638062

    Open questions at the time
    • Recognition motif on CD3-zeta unmapped
    • Single lab
  29. 2013 High

    Demonstrated, via a defined rat knockout, that CD3-zeta-dependent T cells are required for full salt-sensitive hypertension, extending CD3-zeta function to cardiovascular disease.

    Evidence Zinc-finger nuclease frameshift in rat CD247 with protein confirmation, flow cytometry, blood pressure, and renal histology

    PMID:24343121

    Open questions at the time
    • Causal T cell subset not identified
    • Renal antigen/signaling driving infiltration unknown
  30. 2021 Medium

    Showed that TREM-2 in CD4+ T cells signals through the CD3-zeta-ZAP-70 complex rather than DAP12, driving Th1 differentiation, expanding the repertoire of CD3-zeta-coupled receptors.

    Evidence Co-IP of TREM-2 with CD3-zeta/ZAP-70 and conditional TREM-2 knockout with Rag2-/- reconstitution

    PMID:34623322

    Open questions at the time
    • Structural basis of TREM-2/CD3-zeta coupling unknown
    • Single lab
  31. 2022 High

    Established the CD3-zeta transmembrane domain as the structural determinant of CD16 complex formation and NK signaling capacity through species-swap rescue experiments.

    Evidence Systematic TM mutagenesis, reconstituted CD16-CD3-zeta complexes, NK functional assays, and structural modeling

    PMID:35320345

    Open questions at the time
    • Atomic-resolution TM packing not experimentally solved
    • Generalization to other zeta-partner receptors not tested
  32. 2024 Medium

    Showed that CD28 costimulation builds a platform recruiting LCK and ZAP-70 to CD3-zeta to augment CAR-NK cytotoxicity and persistence, applying CD3-zeta proximal signaling logic to engineered cells.

    Evidence CAR-NK cells with varied costimulatory domains, Co-IP of LCK/ZAP-70 with CD3-zeta, cytotoxicity assays, and xenograft models

    PMID:38900051

    Open questions at the time
    • Whether CD28 acts on CD3-zeta directly or via complex remodeling unclear
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CD3-zeta transmembrane and cytoplasmic conformational states are coupled to ITAM phosphorylation order, partner-receptor selection, and the balance among its many degradation pathways remains unresolved at structural and quantitative levels.
  • No atomic structure linking TM packing to signaling-competent complexes
  • Quantitative hierarchy among CD45, caspase-3, LAPTM5, and arginine-controlled regulation in vivo undefined
  • Neuronal upstream ligands and effectors of CD3-zeta unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0060090 molecular adaptor activity 4 GO:0005198 structural molecule activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005764 lysosome 2 GO:0005794 Golgi apparatus 2 GO:0005768 endosome 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3
Partners
CD16CD4CD45LAPTM5LCKSAPTREM-2ZAP-70
Complex memberships
TCR/CD3 complex

Evidence

Reading pass · 50 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 CD3-zeta is required for normal intracellular trafficking and cell surface expression of the TCR/CD3 complex; in its absence only small amounts of surface TCR are expressed, but direct cross-linking of the partial receptor can still induce phosphatidylinositol hydrolysis and IL-2 production, demonstrating that CD3-zeta determines the normal intracellular fate of the TCR and plays an important role in physiologically relevant transmembrane signaling. Chemical mutagenesis of T cell hybridoma to generate CD3-zeta-deficient variant; functional assays (PI hydrolysis, IL-2 production, antigen response) Cell High 3278811
1988 The CD3-zeta eta heterodimer form of the TCR complex shows greater coupling to phosphatidylinositol hydrolysis and serine kinase activation than the CD3-zeta homodimer form, indicating differential signal transduction by TCR isoforms containing different zeta-chain dimers. Isolation of T cell hybridoma variants expressing CD3-zeta2 without CD3-zeta-eta; comparison of signaling outputs (PI hydrolysis, serine kinase, tyrosine kinase activity) Science High 2845582
1989 CD3-zeta specifically co-associates with CD16 (FcγRIII) on human NK cells; co-transfection of CD3-zeta cDNA into COS-7 cells permits surface expression of a transmembrane-linked CD16 complex, demonstrating that CD3-zeta can partner with diverse membrane receptors for signal transduction. Co-immunoprecipitation from NK cell lysates; co-transfection of CD3-zeta cDNA with CD16 in COS-7 cells Nature High 2532305
1989 CD3-zeta is required for export of the TCR/CD3 complex from the endoplasmic reticulum to the Golgi apparatus; it associates with the pentameric TCR complex (TCRαβ-CD3γδε) in the ER to form the heptameric complex, and without it the complex is retained intracellularly. Biochemical fractionation and assembly studies in CD3-zeta-deficient Jurkat T cells; analysis of intracellular processing stages Journal of immunology High 2531776
1990 CD3-eta is produced by alternative splicing from the same gene as CD3-zeta; CD3-eta and CD3-zeta share identical sequences through amino acid 122 but diverge at their C-terminal regions, with CD3-eta lacking one of six cytoplasmic tyrosine residues (Tyr-132) present in CD3-zeta. Protein microsequencing and cDNA cloning; genomic analysis confirming alternative splicing from a single locus Proceedings of the National Academy of Sciences High 2139725
1990 CD3-eta is produced by alternative splicing of the same gene as CD3-zeta; exon VIII of CD3-eta is located 4 kb downstream of exon VIII of CD3-zeta and is reached via an alternative splicing acceptor site. Genomic analysis of murine CD3-eta gene; identification of exon structure and splicing signals International immunology High 2150596
1991 FcεRIγ homodimers can functionally substitute for CD3-zeta in T cells lacking CD3-zeta and CD3-eta: FcεRIγ associates with TCR components to upregulate TCR surface expression and restores coupling of antigen recognition to IL-2 production. Transfection of FcεRIγ cDNA into CD3-zeta/eta-deficient T cell hybridoma; surface expression and functional assays Journal of Biological Chemistry High 1714902
1991 Differential signal transduction by TCR isoforms: tyrosine phosphorylation of CD3-zeta but not CD3-eta follows TCR stimulation; both zeta-containing and eta-containing isoforms transmit Ca2+ mobilization, PI turnover, and IL-2 signals, but zeta-specific phosphorylation likely plays a regulatory role. Stable transfection of CD3-zeta and/or CD3-eta cDNAs into a CD3-zeta/eta-deficient T cell hybridoma; comparison of signaling readouts and tyrosine phosphorylation Proceedings of the National Academy of Sciences High 1708889
1992 The CD3-zeta cytoplasmic domain is necessary and sufficient to couple CD2 stimulation to intracellular signaling (Ca2+ flux, protein tyrosine kinase activation, IL-2 secretion), as demonstrated by a CD8α/CD3-zeta chimeric receptor in CD2+CD3- T cells. Transfection of CD8α-CD3ζ cytoplasmic domain chimeric receptor into CD2+CD3- Jurkat variant; functional assays after CD2 cross-linking Journal of Experimental Medicine High 1351920
1992 CD2-mediated signaling in T lymphocytes and NK cells depends on the CD3-zeta subunit; in T cells, transfection of transmembrane CD16 (which associates with CD3-zeta homodimers) into TCR-negative Jurkat cells restores CD2 signaling; a truncated CD3-zeta incapable of transducing signals abrogates CD2 signaling. Transfection of CD16 cDNA into TCR-negative Jurkat cells; transfection of CD2 into T hybridomas bearing full-length or truncated CD3-zeta; co-immunoprecipitation; functional assays Proceedings of the National Academy of Sciences High 1346934
1992 CD3-zeta phosphorylation at Tyr-132 is required for formation of pp21 (the hyperphosphorylated form); multiple tyrosine residues including Tyr-121 contribute to pp21; p59fyn (but not p56lck or p62yes) associates with all TCR isoforms through TCR components distinct from CD3-zeta or CD3-eta. Site-directed mutagenesis of CD3-zeta tyrosine residues; in vitro and in vivo phosphorylation assays; co-immunoprecipitation Journal of Biological Chemistry High 1531339
1992 CD3-zeta surface expression enhances CD4-p56lck-mediated upregulation of TCR-CD3 signaling; in mutant cells where CD3-zeta is not properly associated with the TCR-CD3 complex, CD4 cross-linking with CD3 has weaker effects on calcium mobilization, CD3-zeta tyrosine phosphorylation, and PLCγ1 tyrosine phosphorylation. Analysis of HPB-ALL T cell mutants with defective CD3-zeta association; calcium flux measurement; tyrosine phosphorylation assays after CD3/CD4 co-cross-linking Journal of Biological Chemistry Medium 1532798
1993 CD3-zeta/eta gene products are required for efficient generation and/or survival of CD4+CD8+ thymocytes and for normal intrathymic T cell differentiation; CD3-zeta/eta-deficient mice have profound reduction in surface TCR levels and almost no mature single-positive thymocytes, whereas gut intraepithelial lymphocytes use FcεRIγ homodimers as TCR-associated subunits. Gene targeting (homologous recombination) to generate CD3-zeta/eta-null mice; flow cytometry of thymic and peripheral T cell populations EMBO Journal High 8223444 8223445 8223495
1993 CD3-zeta-deficient mice have impaired T cell development (greatly reduced thymocytes, 5-fold lower TCR expression on peripheral T cells, impaired proliferative response), while TCRγδ+ intestinal intraepithelial lymphocytes are unaffected, indicating CD3-zeta has a critical role in conventional T cell development and signaling but is dispensable for extrathymic IEL maturation. Gene targeting in ES cells to generate CD3-zeta-specific knockout mice (preserving CD3-eta expression); flow cytometry; proliferation assays EMBO Journal High 8223445
1994 CD45 protein-tyrosine phosphatase specifically binds to tyrosine-phosphorylated CD3-zeta chain through its catalytic domain, and preferentially dephosphorylates CD3-zeta under conditions that do not significantly affect other cellular proteins, suggesting CD45 terminates T cell responses via CD3-zeta dephosphorylation. GST-CD45 fusion protein pulldown (including catalytically inactive C828S mutant); in vitro phosphatase assay with purified substrates; specificity controls with LAR PTPase and CD45-LAR hybrids Proceedings of the National Academy of Sciences High 7526385
1994 CD3-eta is not required for thymic positive or negative selection, alloproliferative responses, or CTL function, as demonstrated in CD3-eta-specific knockout mice generated by insertion of a neomycin resistance gene into exon 9 (leaving CD3-zeta intact). Gene targeting to disrupt CD3-eta only; analysis of T cell development and function; crossing with anti-HY TCR transgenic mice EMBO Journal High 8112294
1995 Syk and ZAP-70 mediate recruitment of CD4/p56lck to the activated TCR/CD3/zeta complex: tyrosine-phosphorylated ZAP-70 and Syk bind to the SH2 domain of p56lck, and this interaction enables CD4 to associate with antigen-stimulated TCR complexes. Co-immunoprecipitation after CD3 stimulation of Jurkat cells; phosphopeptide competition assays; co-capping experiments in human T lymphoblasts Journal of Experimental Medicine High 7539035
1995 CD3-zeta undergoes rapid turnover independently from the rest of the TCR-CD3 complex in normal T cells; newly synthesized zeta chain exchanges with complex-associated zeta, and the TCR complex may be transported to the surface via the zeta turnover pathway. Metabolic pulse-chase labeling in normal T cells; biochemical analysis of surface TCR complex components Immunity Medium 7796297
1995 Both CD3-epsilon and CD3-zeta cytoplasmic domains can independently generate signals sufficient for T cell development (release of DN to DP block) and function (thymocyte death, mature T cell proliferation) in vivo, with no qualitative differences observed between them. Tac-CD3epsilon and Tac-CD3zeta transgenes introduced into normal and RAG2-/- mice; in vivo and in vitro cross-linking; functional assays Immunity High 7719942
1996 p56lck SH2 domain mediates recruitment of CD8/p56lck to the activated TCR/CD3/zeta complex via interaction with tyrosine-phosphorylated ZAP-70; this mechanism operates for both CD8αα and CD8αβ isoforms. Co-immunoprecipitation after CD3 stimulation; phosphopeptide competition for p56lck SH2 domain binding; in vivo co-precipitation of TCR with CD8 European Journal of Immunology Medium 8814252
1996 A mutation in the transmembrane domain of TCR-beta (Tyr to Leu at TM11) causes loose association of CD3-zeta resulting in defective TCR/CD3 assembly, and selectively abolishes activation-induced apoptosis and CD95-L expression without affecting IL-2, CD25/CD69 induction, or TCR downregulation, suggesting a specific CD3-zeta-dependent apoptosis pathway. Mutagenesis of TCRβ TM domain; transfection into TCRβ-negative Jurkat cells; co-immunoprecipitation; functional assays including apoptosis, IL-2, CD25/CD69 Journal of Biological Chemistry Medium 8940006
1997 Triggered TCR-CD3 complexes are internalized and rapidly degraded in the lysosomal compartment; lysosomal function inhibitors (bafilomycin A1, folimycin) markedly reduce CD3-zeta degradation and cause accumulation in Lamp1+ vesicles. FACS on fixed/permeabilized T-APC conjugates; Western blot on cell lysates; pharmacological inhibition of lysosomes; immunofluorescence for Lamp1 Journal of Experimental Medicine High 9151711
1998 Impaired association of ZAP-70 with CD3-zeta (despite normal ZAP-70 phosphorylation and normal Ca2+ fluxes) is specifically associated with failure to induce CD95-L and apoptosis upon TCR triggering, suggesting CD3-zeta is required for ZAP-70 recruitment to the membrane leading to a specific apoptosis-signaling pathway. Co-immunoprecipitation of ZAP-70 with CD3-zeta in apoptosis-deficient TCRβ-TM mutant Jurkat cells; subcellular fractionation; tyrosine phosphorylation assays; Ca2+ flux measurement Journal of Experimental Medicine Medium 9547330
1998 CD3-zeta/eta modules are each essential for allelic exclusion at the TCR-beta locus (demonstrated using TCR-beta transgenic mice lacking CD3-epsilon and/or CD3-zeta/eta), but CD3 gene products are dispensable for initiation of V(D)J recombination at TCR loci. Genetic epistasis using CD3-epsilon- and CD3-zeta/eta-deficient mice harboring TCR-beta transgene; analysis of TCR rearrangement and allelic exclusion Journal of Experimental Medicine High 9419216
1999 Absence of all functional CD3-zeta ITAMs does not qualitatively impair TCR signaling or T cell effector functions; CD3-gammadeltaepsilon ITAMs are sufficient for qualitatively normal TCR signaling; CD3-zeta ITAMs only make a quantitative difference at suboptimal peptide concentrations. Genetic substitution of CD3-zeta chains lacking all or part of ITAMs in P14 TCR transgenic mice; analysis of T cell activation and effector functions Immunity High 10229184
1999 Differential CD3-zeta phosphorylation (pp21 vs pp23 forms) is not required for T cell antagonism by altered peptide ligands; CD3-zeta is required for full agonist responses but not for antagonist responses. CD3-zeta tyrosine-to-phenylalanine mutants expressed in T cells; agonist and antagonist peptide stimulation assays; IL-2 production measurement Journal of immunology Medium 10395646
2000 CD4 and TCR-associated CD3-zeta cluster together at the T cell-APC interface coincident with intracellular Ca2+ increases; subsequently, signaling-, costimulation-, and cytoskeleton-dependent processes stabilize CD3-zeta in a single central cluster while CD4 moves to the periphery. GFP-tagged chimeras; three-dimensional video microscopy; live-cell imaging of T cell-APC conjugates Science High 10958781
2001 CD38 signaling in T cells does not require the CD3-zeta ITAM cytoplasmic domains; in T cells expressing CD3-zeta lacking the cytoplasmic domain, CD38 cross-linking still induces tyrosine phosphorylation of ZAP-70, LAT, Shc, and activates PKB/Akt and Erk. CD38 is constitutively associated with lipid rafts containing Lck and CD3-zeta; full CD3-zeta phosphorylation occurs only in rafts. T cells expressing cytoplasmic-domain-truncated CD3-zeta; Western blotting; lipid raft fractionation; methyl-β-cyclodextrin depletion Journal of Biological Chemistry Medium 11689561
2002 L-Arginine depletion causes decreased CD3-zeta expression in Jurkat T cells through a shorter CD3-zeta mRNA half-life (not decreased transcription rate), reversible by L-Arg replenishment but not other amino acids; the mechanism is sensitive to cycloheximide, suggesting involvement of a labile protein. Culture of Jurkat cells in L-Arg-free medium; flow cytometry; Western blot; RT-PCR; mRNA stability assays with cycloheximide; transcription rate measurements Journal of Biological Chemistry High 11950832
2003 SIV Nef directly binds the CD3-zeta cytoplasmic domain and cooperates with AP-2 clathrin adaptor to induce TCR-CD3 endocytosis; SIV Nef and CD3-zeta cooperate to bind AP-2 via a novel interaction surface distinct from Nef's canonical AP-2-binding determinants. Co-expression of SIV Nef with CD8-CD3zeta chimera in Jurkat cells; flow cytometry for endocytosis; colocalization with AP-2 by fluorescence microscopy; in vitro binding assays with recombinant proteins Journal of Virology High 12829850
2004 PD-1 signaling inhibits TCR-mediated phosphorylation of ZAP-70 and its association with CD3-zeta, and attenuates PKCtheta activation; phosphorylated PD-1 ITSM peptide acts as a docking site for SHP-2 and SHP-1 in vitro, while the ITIM peptide associates only with SHP-2. T cell stimulation assays with PD-1 engagement; phospho-specific Western blotting for ZAP-70 and PKCtheta; co-immunoprecipitation of ZAP-70/CD3-zeta; in vitro peptide-protein binding assays FEBS Letters Medium 15358536
2004 H. pylori arginase (RocF) depletes L-arginine from the T cell microenvironment and thereby reduces CD3-zeta expression; the arginase mutant rocF(-) neither depletes L-arginine nor reduces CD3-zeta expression, and arginase inhibitors reverse these events. Co-culture of Jurkat and normal T cells with wild-type vs. arginase-mutant H. pylori; flow cytometry for CD3-zeta; L-arginine measurement; arginase inhibitor experiments Journal of Immunology Medium 15210820
2005 Increased caspase-3 expression and activity in SLE T cells contributes to CD3-zeta degradation; caspase-3 inhibition with Z-DEVD-FMK reduces CD3-zeta proteolysis, restores CD3-zeta expression and its association with lipid rafts, reverses abnormal lipid raft preclustering, and reduces FcRgamma expression in SLE T cells. Caspase-3 inhibitor treatment of SLE T cells; Western blot for CD3-zeta; lipid raft fractionation; calcium flux measurement; flow cytometry Journal of Immunology Medium 16116236
2006 Homozygous Q70X mutation in CD3-zeta causes T-B+NK+ SCID in humans by preventing normal TCR assembly and surface expression; mutant CD3-zeta protein is unstable and rapidly degraded; somatic reversion mutations in CD3-zeta can partially rescue surface TCR expression on a subset of T cells. Patient genetic analysis; retroviral transduction of mutant CD3-zeta into MA5.8 CD3-zeta-deficient murine T hybridoma; Western blot; metabolic labeling; flow cytometry New England Journal of Medicine / Blood High 16672702 17170122
2008 PP2A dephosphorylates Elf-1 at Thr-231 in lupus T cells, leading to decreased nuclear 98-kDa Elf-1 form and its reduced binding to the CD3-zeta promoter, thereby suppressing CD3-zeta gene expression; PP2A suppression restores CD3-zeta and corrects aberrant TCR signaling. PP2A knockdown/overexpression in SLE T cells; Elf-1 phosphorylation analysis; promoter binding assays; Western blot; flow cytometry Journal of Immunology Medium 18714041
2008 LAPTM5 negatively regulates surface TCR expression by specifically interacting with CD3-zeta and promoting its lysosomal degradation without affecting CD3-epsilon, CD3-delta, or CD3-gamma; TCR downmodulation requires the polyproline-tyrosine motifs and ubiquitin-interacting motif of LAPTM5. Co-immunoprecipitation; LAPTM5 knockout/overexpression; Western blot; flow cytometry for surface TCR; mutational analysis of LAPTM5 motifs Immunity High 18619870
2008 TCR engagement causes the cytoplasmic tails of CD3-epsilon and CD3-zeta to adopt a compact, protease-resistant conformation, suggesting that the conformational change induced upon TCR triggering is transmitted to CD3-zeta cytoplasmic tails. Protease-sensitivity assay of CD3-epsilon and CD3-zeta cytoplasmic tails upon TCR triggering in T cells PLoS ONE Medium 18320063
2008 CD3-zeta is expressed in hippocampal neurons predominantly in the somatodendritic compartment, particularly at dendritic filopodia and growth cones; siRNA-mediated knockdown of CD3-zeta or expression of ITAM-mutant CD3-zeta increases dendritic arborization, while CD3-zeta antibody-mediated activation reduces it, establishing CD3-zeta as a negative regulator of dendritic development through ITAM-based mechanisms. siRNA knockdown; overexpression of loss-of-function ITAM mutant; antibody-mediated activation; immunofluorescence; biochemical fractionation of rat brain Molecular Biology of the Cell Medium 18367546
2010 CD3-zeta is expressed in retinal ganglion cells (RGCs); CD3-zeta-deficient mice have reduced RGC dendritic motility, increased RGC dendritic density, selectively defective glutamate-receptor-mediated synaptic activity in the retina, and failure of eye-specific segregation of RGC axon projections to the CNS. CD3-zeta knockout mice; live-cell imaging of dendritic motility; electrophysiology; anatomical tracing of retinal projections Neuron High 20188655
2010 Tyrosine-phosphorylated CD3-zeta accumulates on endosomal vesicles distinct from lysosomes after TCR activation, in addition to plasma membrane phosphorylation; genetically encoded live-cell reporters revealed this intracellular phospho-CD3-zeta pool that may sustain TCR signaling after receptor internalization. Genetically encoded FRET-based phosphorylation reporters for CD3-zeta; live-cell fluorescence microscopy; pharmacological kinase/phosphatase manipulation Proceedings of the National Academy of Sciences High 21135224
2010 CARs containing the CD3-zeta transmembrane domain form a complex with the endogenous TCR; receptor dimerization and interaction with the endogenous TCR complex are required for optimal CAR function; mutations of the CAR TM domain that abrogate these interactions reduce functional capacity. TM domain mutant CARs expressed in Jurkat cells; cytokine production assays after antigen stimulation; biochemical analysis of complex formation Journal of Immunology Medium 20483753
2010 NKG2D signaling in T and NK cells initiates Fas ligand/Fas-mediated caspase-3/-7 activation, which causes CD3-zeta degradation and impairs function of TCR, CD16, NKp30, and NKp46 receptors that all signal through CD3-zeta. NKG2D stimulation of T and NK cells; caspase activation assays; Western blot for CD3-zeta; functional assays for multiple CD3-zeta-dependent receptors; ex vivo analysis of tumor-infiltrating lymphocytes Journal of Immunology Medium 20926796
2012 SAP directly associates with CD3-zeta through the first ITAM of CD3-zeta proximal to the membrane; SAP knockdown reduces Erk, Akt, and PLCγ1 activation and IL-2/IL-4 mRNA induction downstream of TCR-CD3 complex triggering. Co-immunoprecipitation; direct binding assay; shRNA-mediated SAP knockdown; Western blot for downstream signaling; RT-PCR for cytokine mRNA PLoS ONE Medium 22912825
2013 LAT acts as a negative feedback regulator of CD3-zeta and ZAP-70 tyrosine phosphorylation; in LAT-deficient Jurkat cells, CD3-zeta and ZAP-70 phosphorylation is augmented and more persistent despite loss of ERK and PLCγ1 activation. MS-based quantitative phosphoproteomics comparing LAT-sufficient and LAT-deficient Jurkat T cells after TCR stimulation PLoS ONE Medium 24204825
2013 CD247 (CD3-zeta) deficiency in Dahl salt-sensitive rats causes >99% reduction in circulating CD3+ T cells, significantly blunts renal T cell infiltration after high-salt diet, and reduces mean arterial blood pressure, establishing that functional CD3-zeta-dependent T cells are required for full development of salt-sensitive hypertension. Zinc-finger nuclease-mediated 11-bp frameshift deletion in CD247 in rat; Western blot confirmation of protein absence; flow cytometry; blood pressure measurement; renal immunohistology Hypertension High 24343121
2014 LAPTM5 promotes lysosomal degradation of intracellular (Golgi-localized) CD3-zeta but not of cell-surface CD3-zeta associated with the mature TCR complex; ITAM tyrosine phosphorylation of CD3-zeta is dispensable for LAPTM5-mediated degradation; LAPTM5 and SLAP/c-Cbl function in distinct genetic pathways to negatively regulate TCR expression. Subcellular fractionation; Golgi-localizing mutant CD3-zeta; CD3-zeta YF mutant (all 6 ITAM tyrosines mutated); Western blot; genetic epistasis with SLAP/c-Cbl knockdown Immunology and Cell Biology Medium 24638062
2015 Extracellular OAS2 secreted by oral tumors induces caspase-3 activation in T cells, which results in CD3-zeta chain down-regulation; caspase-3 inhibition or OAS2 knockdown restores CD3-zeta expression. Proteomic identification of OAS2; OAS2 overexpression in HEK293 cells; recombinant OAS2 treatment of T cells; caspase-3 activity assays; caspase-3 inhibitor and siRNA rescue experiments Immunology Medium 26595239
2021 TREM-2 expressed on CD4+ T cells interacts with the CD3-zeta-ZAP70 complex (unlike in myeloid cells where it signals through DAP12); this interaction leads to STAT1/4 activation and T-bet transcription, promoting Th1 responses against M. tuberculosis. Co-immunoprecipitation of TREM-2 with CD3-zeta and ZAP-70; TREM-2 conditional knockout in CD4+ T cells; Rag2-/- reconstitution with TREM-2-KO vs. WT cells; signaling assays Journal of Clinical Investigation Medium 34623322
2022 Residues in the transmembrane domain of mouse CD3-zeta prevent efficient complex formation with mouse CD16, dampening CD16-mediated NK cell signaling; mutating these mouse CD3-zeta TM residues to those encoded by human CD3-zeta rescues CD16 receptor function, demonstrating that CD3-zeta TM domain structure determines CD16 signaling capacity. Systematic TM domain mutagenesis; reconstitution of CD16-CD3-zeta complexes; functional NK cell assays; structural modeling of TM domain packing Journal of Experimental Medicine High 35320345
2024 CD28 costimulation enhances CAR-NK cell function by creating a platform that recruits LCK and ZAP-70 to CD3-zeta, initiating a signaling cascade; this LCK/CD3-zeta/ZAP-70 axis augments NK cell cytotoxicity and persistence in vivo. CAR-NK cells with various costimulatory domains; co-immunoprecipitation of LCK and ZAP-70 with CD3-zeta; in vitro cytotoxicity assays; multiple xenograft tumor models Cancer Discovery Medium 38900051

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS letters 645 15358536
1989 Co-association of CD3 zeta with a receptor (CD16) for IgG Fc on human natural killer cells. Nature 429 2532305
2003 L-arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 391 12874210
2002 Regulation of T cell receptor CD3zeta chain expression by L-arginine. The Journal of biological chemistry 389 11950832
1988 Failure to synthesize the T cell CD3-zeta chain: structure and function of a partial T cell receptor complex. Cell 379 3278811
2000 Differential clustering of CD4 and CD3zeta during T cell recognition. Science (New York, N.Y.) 295 10958781
2014 Target antigen density governs the efficacy of anti-CD20-CD28-CD3 ζ chimeric antigen receptor-modified effector CD8+ T cells. Journal of immunology (Baltimore, Md. : 1950) 253 25520398
1997 Degradation of T cell receptor (TCR)-CD3-zeta complexes after antigenic stimulation. The Journal of experimental medicine 251 9151711
1993 T cell development in mice lacking the CD3-zeta/eta gene. The EMBO journal 226 8223444
2003 T-cell apoptosis and suppression of T-cell receptor/CD3-zeta by Fas ligand-containing membrane vesicles shed from ovarian tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 223 14613988
2010 The optimal antigen response of chimeric antigen receptors harboring the CD3zeta transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex. Journal of immunology (Baltimore, Md. : 1950) 210 20483753
1993 Abnormal T cell development in CD3-zeta-/- mutant mice and identification of a novel T cell population in the intestine. The EMBO journal 184 8223495
2005 L-Arginine modulates CD3zeta expression and T cell function in activated human T lymphocytes. Cellular immunology 182 15922712
1993 Developmental and functional impairment of T cells in mice lacking CD3 zeta chains. The EMBO journal 161 8223445
1994 Specific interaction of the CD45 protein-tyrosine phosphatase with tyrosine-phosphorylated CD3 zeta chain. Proceedings of the National Academy of Sciences of the United States of America 152 7526385
2013 CD247 modulates blood pressure by altering T-lymphocyte infiltration in the kidney. Hypertension (Dallas, Tex. : 1979) 139 24343121
1988 T cell CD3-zeta eta heterodimer expression and coupling to phosphoinositide hydrolysis. Science (New York, N.Y.) 134 2845582
1995 Syk and ZAP-70 mediate recruitment of p56lck/CD4 to the activated T cell receptor/CD3/zeta complex. The Journal of experimental medicine 122 7539035
1990 Molecular cloning of the CD3 eta subunit identifies a CD3 zeta-related product in thymus-derived cells. Proceedings of the National Academy of Sciences of the United States of America 113 2139725
2000 Human immunodeficiency virus-specific circulating CD8 T lymphocytes have down-modulated CD3zeta and CD28, key signaling molecules for T-cell activation. Journal of virology 105 10906185
2001 L-Arginine regulates the expression of the T-cell receptor zeta chain (CD3zeta) in Jurkat cells. Clinical cancer research : an official journal of the American Association for Cancer Research 103 11300497
1995 Variable expression of CD3-zeta chain in tumor-infiltrating lymphocytes (TIL) derived from renal-cell carcinoma: relationship with TIL phenotype and function. International journal of cancer 103 7591205
1992 CD3 zeta dependence of the CD2 pathway of activation in T lymphocytes and natural killer cells. Proceedings of the National Academy of Sciences of the United States of America 99 1346934
2004 Helicobacter pylori arginase inhibits T cell proliferation and reduces the expression of the TCR zeta-chain (CD3zeta). Journal of immunology (Baltimore, Md. : 1950) 95 15210820
2001 CD38 is associated with lipid rafts and upon receptor stimulation leads to Akt/protein kinase B and Erk activation in the absence of the CD3-zeta immune receptor tyrosine-based activation motifs. The Journal of biological chemistry 88 11689561
1999 Crippling of CD3-zeta ITAMs does not impair T cell receptor signaling. Immunity 85 10229184
1998 An anti-CD30 chimeric receptor that mediates CD3-zeta-independent T-cell activation against Hodgkin's lymphoma cells in the presence of soluble CD30. Cancer research 85 9515791
2006 Inherited and somatic CD3zeta mutations in a patient with T-cell deficiency. The New England journal of medicine 84 16672702
1992 The CD3 zeta cytoplasmic domain mediates CD2-induced T cell activation. The Journal of experimental medicine 74 1351920
1995 CD3 epsilon and CD3 zeta cytoplasmic domains can independently generate signals for T cell development and function. Immunity 71 7719942
1995 Rapid turnover of the CD3 zeta chain independent of the TCR-CD3 complex in normal T cells. Immunity 70 7796297
2008 Human TCR that incorporate CD3zeta induce highly preferred pairing between TCRalpha and beta chains following gene transfer. Journal of immunology (Baltimore, Md. : 1950) 68 18490778
2010 Imaging T-cell receptor activation reveals accumulation of tyrosine-phosphorylated CD3ζ in the endosomal compartment. Proceedings of the National Academy of Sciences of the United States of America 65 21135224
2003 CD38 signaling in T cells is initiated within a subset of membrane rafts containing Lck and the CD3-zeta subunit of the T cell antigen receptor. The Journal of biological chemistry 65 14523017
1992 Phosphorylation of multiple CD3 zeta tyrosine residues leads to formation of pp21 in vitro and in vivo. Structural changes upon T cell receptor stimulation. The Journal of biological chemistry 64 1531339
2008 A lysosomal protein negatively regulates surface T cell antigen receptor expression by promoting CD3zeta-chain degradation. Immunity 62 18619870
2010 The immune protein CD3zeta is required for normal development of neural circuits in the retina. Neuron 61 20188655
2004 Rat NKp46 activates natural killer cell cytotoxicity and is associated with FcepsilonRIgamma and CD3zeta. Journal of leukocyte biology 59 15356098
2014 CD3ζ-based chimeric antigen receptors mediate T cell activation via cis- and trans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy. Clinical and experimental immunology 58 24116999
2006 Decreased expression of CD3zeta and nuclear transcription factor kappa B in patients with pulmonary tuberculosis: potential mechanisms and reversibility with treatment. The Journal of infectious diseases 58 17054067
1991 Differential signal transduction via T-cell receptor CD3 zeta 2, CD3 zeta-eta, and CD3 eta 2 isoforms. Proceedings of the National Academy of Sciences of the United States of America 55 1708889
2005 Increased caspase-3 expression and activity contribute to reduced CD3zeta expression in systemic lupus erythematosus T cells. Journal of immunology (Baltimore, Md. : 1950) 53 16116236
2000 CD3zeta and CD28 down-modulation on CD8 T cells during viral infection. Blood 53 10910918
2024 CD28 Costimulation Augments CAR Signaling in NK Cells via the LCK/CD3ζ/ZAP70 Signaling Axis. Cancer discovery 52 38900051
1991 The high affinity Fc epsilon receptor gamma subunit (Fc epsilon RI gamma) facilitates T cell receptor expression and antigen/major histocompatibility complex-driven signaling in the absence of CD3 zeta and CD3 eta. The Journal of biological chemistry 50 1714902
1989 Assembly, intracellular processing, and expression at the cell surface of the human alpha beta T cell receptor/CD3 complex. Function of the CD3-zeta chain. Journal of immunology (Baltimore, Md. : 1950) 50 2531776
2008 PP2A dephosphorylates Elf-1 and determines the expression of CD3zeta and FcRgamma in human systemic lupus erythematosus T cells. Journal of immunology (Baltimore, Md. : 1950) 49 18714041
2007 Characterization of the CD3zeta, CD3gammadelta and CD3epsilon subunits of the T cell receptor complex in Atlantic salmon. Developmental and comparative immunology 49 17532043
1996 The p56lck SH2 domain mediates recruitment of CD8/p56lck to the activated T cell receptor/CD3/zeta complex. European journal of immunology 49 8814252
1994 The decreased expression of CD3 zeta chains in cancer patients is not reversed by IL-2 administration. International journal of cancer 49 7989113
2001 Generation and biochemical analysis of human effector CD4 T cells: alterations in tyrosine phosphorylation and loss of CD3zeta expression. Blood 48 11389026
2001 Modulation of TcR/CD3-zeta chain expression by a circulating factor derived from ovarian cancer patients. British journal of cancer 48 11401315
1998 Variable expression of CD3-zeta and associated protein tyrosine kinases in lymphocytes from patients with myeloid malignancies. British journal of haematology 48 9531350
2006 T-B+NK+ severe combined immunodeficiency caused by complete deficiency of the CD3zeta subunit of the T-cell antigen receptor complex. Blood 47 17170122
2000 SOCS-1 can suppress CD3zeta- and Syk-mediated NF-AT activation in a non-lymphoid cell line. FEBS letters 47 10788618
2000 Impaired expression of the CD3-zeta chain in peripheral blood T cells of patients with chronic myeloid leukaemia results in an increased susceptibility to apoptosis. British journal of haematology 47 11122143
2000 An entirely humanized CD3 zeta-chain signaling receptor that directs peripheral blood t cells to specific lysis of carcinoembryonic antigen-positive tumor cells. International journal of cancer 45 10962448
2015 In HIV-positive patients, myeloid-derived suppressor cells induce T-cell anergy by suppressing CD3ζ expression through ELF-1 inhibition. AIDS (London, England) 44 26355672
2004 Citrulline can preserve proliferation and prevent the loss of CD3 zeta chain under conditions of low arginine. JPEN. Journal of parenteral and enteral nutrition 44 15568289
1998 The CD3-gammadeltaepsilon and CD3-zeta/eta modules are each essential for allelic exclusion at the T cell receptor beta locus but are both dispensable for the initiation of V to (D)J recombination at the T cell receptor-beta, -gamma, and -delta loci. The Journal of experimental medicine 44 9419216
2010 NKG2D initiates caspase-mediated CD3zeta degradation and lymphocyte receptor impairments associated with human cancer and autoimmune disease. Journal of immunology (Baltimore, Md. : 1950) 42 20926796
2014 Gene-modified human α/β-T cells expressing a chimeric CD16-CD3ζ receptor as adoptively transferable effector cells for anticancer monoclonal antibody therapy. Cancer immunology research 39 24778321
2010 Variation in the Cd3 zeta (Cd247) gene correlates with altered T cell activation and is associated with autoimmune diabetes. Journal of immunology (Baltimore, Md. : 1950) 39 20400699
2001 Reduced T-cell receptor CD3zeta-chain protein and sustained CD3epsilon expression at the site of mycobacterial infection. Immunology 39 11722641
2003 Cooperative interactions of simian immunodeficiency virus Nef, AP-2, and CD3-zeta mediate the selective induction of T-cell receptor-CD3 endocytosis. Journal of virology 38 12829850
2024 Integration of ζ-deficient CARs into the CD3ζ gene conveys potent cytotoxicity in T and NK cells. Blood 37 38493479
1996 Apoptosis but not other activation events is inhibited by a mutation in the transmembrane domain of T cell receptor beta that impairs CD3zeta association. The Journal of biological chemistry 37 8940006
1994 Targeted disruption within the CD3 zeta/eta/phi/Oct-1 locus in mouse. The EMBO journal 37 8112294
2022 Advances in CD247. Scandinavian journal of immunology 35 35388926
1992 CD3-zeta surface expression is required for CD4-p56lck-mediated upregulation of T cell antigen receptor-CD3 signaling in T cells. The Journal of biological chemistry 35 1532798
1998 Interleukin 2 restores CD3-zeta chain expression but fails to generate tumour-specific lytic activity in tumour-infiltrating lymphocytes derived from human colorectal hepatic metastases. British journal of cancer 33 9569042
2015 A novel thymoma-associated immunodeficiency with increased naive T cells and reduced CD247 expression. Journal of immunology (Baltimore, Md. : 1950) 31 25732729
1993 CD3 zeta/eta/theta locus is colinear with and transcribed antisense to the gene encoding the transcription factor Oct-1. Journal of immunology (Baltimore, Md. : 1950) 31 8376772
2007 Tumor-associated macrophages and CD3-zeta expression of tumor-infiltrating lymphocytes in human esophageal squamous-cell carcinoma. Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus 30 17439593
1990 CD3 zeta and eta chains are produced by alternative splicing from a common gene. International immunology 30 2150596
2022 The CD3ζ adaptor structure determines functional differences between human and mouse CD16 Fc receptor signaling. The Journal of experimental medicine 29 35320345
2008 T cell receptor engagement triggers its CD3epsilon and CD3zeta subunits to adopt a compact, locked conformation. PloS one 29 18320063
2012 CD3 ζ defects in systemic lupus erythematosus. Annals of the rheumatic diseases 28 22460144
2008 The signaling adaptor protein CD3zeta is a negative regulator of dendrite development in young neurons. Molecular biology of the cell 28 18367546
2002 Modulation of T-cell CD3-zeta chain expression during normal pregnancy. Journal of reproductive immunology 28 11839393
2019 CD247 expression is associated with differentiation and classification in ovarian cancer. Medicine 27 31861005
2015 Extracellular 2'5'-oligoadenylate synthetase 2 mediates T-cell receptor CD3-ζ chain down-regulation via caspase-3 activation in oral cancer. Immunology 27 26595239
2013 Quantitative phosphoproteome analysis unveils LAT as a modulator of CD3ζ and ZAP-70 tyrosine phosphorylation. PloS one 27 24204825
2011 Association of CD247 with systemic lupus erythematosus in Asian populations. Lupus 27 22004975
2000 DAP12 and KAP10 (DAP10)-novel transmembrane adapter proteins of the CD3zeta family. Immunologic research 27 10945225
1998 T cell receptor (TCR) engagement in apoptosis-defective, but interleukin 2 (IL-2)-producing, T cells results in impaired ZAP70/CD3-zeta association. The Journal of experimental medicine 27 9547330
2007 B and T lymphocyte attenuator interacts with CD3zeta and inhibits tyrosine phosphorylation of TCRzeta complex during T-cell activation. Immunology and cell biology 26 17607320
2001 Loss of T-cell receptor-CD3zeta and T-cell function in tumor-infiltrating lymphocytes but not in tumor-associated lymphocytes in ovarian carcinoma. Surgery 26 11391375
1999 Expression of CD3-zeta on T-cells in primary cervical carcinoma and in metastasis-positive and -negative pelvic lymph nodes. British journal of cancer 26 10098746
2021 TREM-2 promotes Th1 responses by interacting with the CD3ζ-ZAP70 complex following Mycobacterium tuberculosis infection. The Journal of clinical investigation 25 34623322
2014 SAP-regulated T Cell-APC adhesion and ligation-dependent and -independent Ly108-CD3ζ interactions. Journal of immunology (Baltimore, Md. : 1950) 25 25217164
2013 T lymphocytes from chagasic patients are activated but lack proliferative capacity and down-regulate CD28 and CD3ζ. PLoS neglected tropical diseases 25 23383358
2015 Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study. Genes and immunity 24 25569266
2004 Decreased expression of the CD3zeta chain in T cells infiltrating the synovial membrane of patients with osteoarthritis. Clinical and diagnostic laboratory immunology 24 14715568
2015 Comprehensive Survey of miRNA-mRNA Interactions Reveals That Ccr7 and Cd247 (CD3 zeta) are Posttranscriptionally Controlled in Pancreas Infiltrating T Lymphocytes of Non-Obese Diabetic (NOD) Mice. PloS one 23 26606254
2014 LAPTM5 promotes lysosomal degradation of intracellular CD3ζ but not of cell surface CD3ζ. Immunology and cell biology 23 24638062
2014 Towards neuroimmunotherapy for cancer: the neurotransmitters glutamate, dopamine and GnRH-II augment substantially the ability of T cells of few head and neck cancer patients to perform spontaneous migration, chemotactic migration and migration towards the autologous tumor, and also elevate markedly the expression of CD3zeta and CD3epsilon TCR-associated chains. Journal of neural transmission (Vienna, Austria : 1996) 23 25030361
2012 The adaptor protein SAP directly associates with CD3ζ chain and regulates T cell receptor signaling. PloS one 23 22912825
1999 Differential CD3 zeta phosphorylation is not required for the induction of T cell antagonism by altered peptide ligands. Journal of immunology (Baltimore, Md. : 1950) 23 10395646
1998 Increased Zap-70 association with CD3zeta in CD4 T cells from old mice. Cellular immunology 23 9878110

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