Affinage

CD3E

T-cell surface glycoprotein CD3 epsilon chain · UniProt P07766

Length
207 aa
Mass
23.1 kDa
Annotated
2026-06-09
100 papers in source corpus 36 papers cited in narrative 36 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

CD3ε is an essential signal-transducing subunit of the TCR/CD3 complex, present in two copies per receptor that assemble as CD3εγ and CD3εδ heterodimers and contact the TCRαβ heterodimer (PMID:2144901, PMID:1824636, PMID:8046335, PMID:9485181). Its extracellular C2-set Ig-like domains pair with CD3γ or CD3δ through a side-to-side hydrophobic interface, generating a conformational epitope recognized by therapeutic anti-CD3 antibodies (PMID:11439187, PMID:15534202, PMID:15136729, PMID:1717585), and a membrane-proximal stalk CXXC motif is required for productive signaling and T cell development (PMID:19956738). Surface delivery is gated by a tyrosine/serine-based ER-retention helix-turn motif in the CD3ε cytoplasmic tail that is masked only upon full complex assembly (PMID:1535117, PMID:7774584). In resting T cells the CD3ε ITAM tyrosines insert into the inner leaflet of the plasma membrane through electrostatic interactions between a basic-rich stretch (BRS) and acidic phospholipids; TCR ligation triggers a conformational change that releases the cytoplasmic tail and reduces local phosphatidylserine, exposing the ITAM to Src-family kinases (PMID:19013279, PMID:19542373, PMID:23166358, PMID:18320063). Ligation also exposes a proline-rich PxxDY motif that recruits the adaptor Nck before kinase activation and a receptor-kinase (RK) motif that binds the Lck SH3 domain to locally augment Lck activity, while Y166 phosphorylation acts as a switch toggling CD3ε between SH3- and SH2-domain partners (PMID:12110186, PMID:17617578, PMID:18555270, PMID:32690949). Src-kinase-dependent phosphorylation of the dual-tyrosine ITAM then recruits the tandem SH2 domains of ZAP-70 and the p85 subunit of PI 3-kinase, whereas a mono-phosphorylated ITAM subpopulation recruits the inhibitory kinase Csk, making CD3ε both an activating and self-restraining signaling hub (PMID:7686857, PMID:8366117, PMID:9312149, PMID:32730808). The BRS additionally binds phosphoinositides to support thymocyte development and peripheral T cell function and to promote CAR-T persistence via p85 (PMID:19542373, PMID:24899501, PMID:32730808). The extracellular protein ITPRIPL1 acts as an inhibitory ligand of CD3ε that suppresses calcium influx and ZAP70 phosphorylation (PMID:38614099).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1989 Medium

    Established which part of CD3ε is needed for receptor assembly versus signaling by asking whether the cytoplasmic tail is required at all.

    Evidence Truncation of 49 of 55 cytoplasmic residues with IL-2 readout in a T cell hybridoma

    PMID:2528731

    Open questions at the time
    • Did not identify which cytoplasmic motifs drive downstream phosphorylation
    • Antibody-driven signal may not reflect physiological pMHC triggering
  2. 1990 High

    Resolved the subunit stoichiometry of the complex by showing two CD3ε chains co-exist in one receptor.

    Evidence Co-IP and 2D gels from transgenic mice and hybridomas co-expressing human and mouse CD3ε

    PMID:1824636 PMID:2144901

    Open questions at the time
    • Did not define how the two CD3ε copies are arranged relative to TCRαβ
  3. 1992 Medium

    Demonstrated the CD3ε cytoplasmic tail is itself signaling-competent and biochemically distinct from the ζ chain, and that it carries an ER-retention signal controlling assembly.

    Evidence Chimeric receptor activation assays and deletion/chimera surface-expression assays

    PMID:1532456 PMID:1535117

    Open questions at the time
    • The distinct phosphorylation pattern was not mapped to specific effectors
    • ER-retention mechanism of masking upon assembly not structurally defined
  4. 1993 Medium

    Identified the proximal effector logic of the ITAM by mapping dual-tyrosine phosphorylation and ZAP-70 tandem-SH2 binding.

    Evidence In vivo phosphorylation site mapping and GST-ZAP-70 SH2 pull-downs from activated T cells

    PMID:7686857 PMID:8366117

    Open questions at the time
    • Single-method pull-down for ZAP-70 binding
    • Kinase responsible for ITAM phosphorylation not resolved here
  5. 1995 High

    Defined the structural basis of the ER-retention/endocytosis motif, linking CD3ε trafficking to tyrosine-based sorting signals.

    Evidence NMR of the retention motif plus chimeric internalization assays

    PMID:7774584

    Open questions at the time
    • How complete complex assembly physically masks the motif not shown
  6. 1999 Medium

    Expanded the CD3ε interactome to additional proximal partners and established CD3ε-intrinsic endocytosis signals for receptor downregulation.

    Evidence GST pull-downs/Co-IP for CAST, PDE4B2, GRK2 (2007), TopoIIβ and mutagenesis-based internalization assays

    PMID:10373416 PMID:10384095 PMID:17420248 PMID:8626450 PMID:9973473

    Open questions at the time
    • Several partners rest on single-lab Co-IP without reciprocal/in vivo validation
    • Functional role of nuclear CD3ε–TopoIIβ interaction unclear
  7. 2001 High

    Determined the ectodomain architecture, showing CD3εγ/CD3εδ pairing through a conserved Ig-domain interface and conformation-dependent antibody epitopes.

    Evidence NMR and X-ray structures of CD3εγ and CD3εδ ectodomains with mutagenesis and antibody complexes

    PMID:11439187 PMID:15136729 PMID:15534202 PMID:1717585

    Open questions at the time
    • How ectodomain conformation couples to cytoplasmic ITAM release not directly addressed
  8. 2002 High

    Showed that TCR ligation exposes a proline-rich Nck-binding sequence prior to and independent of kinase activation, revealing a non-phosphorylation triggering step.

    Evidence Pull-downs, in vivo interference with Nck–CD3ε, and synapse imaging

    PMID:12110186

    Open questions at the time
    • Physical mechanism linking pMHC binding to PRS exposure not defined here
  9. 2008 High

    Provided the structural mechanism of ITAM masking: CD3ε ITAM tyrosines bury in the membrane via basic-residue/acidic-lipid interactions and must unbind for Src-kinase access.

    Evidence NMR of lipid-bound cytoplasmic domain, live-cell FRET, and basic-residue mutagenesis; protease-resistance conformational assay

    PMID:18320063 PMID:19013279

    Open questions at the time
    • What triggers membrane dissociation in vivo not resolved in this study
  10. 2007 High

    Defined the Y166 molecular switch within an atypical PxxDY motif that toggles CD3ε between SH3 partners (Nck/Eps8L1) and SH2 partners upon phosphorylation.

    Evidence Phage display, recombinant binding, NMR of Nck SH3.1–CD3ε, in vitro kinase inhibition, and primary-cell TCR downregulation

    PMID:17617578 PMID:18555270

    Open questions at the time
    • Quantitative timing of switch relative to ITAM phosphorylation in vivo not established
  11. 2009 High

    Established the BRS as a phosphoinositide-binding module required in vivo for thymocyte development and peripheral T cell function, tying lipid engagement to physiology.

    Evidence Lipid-binding assays and BRS-mutant knock-in/transgenic mouse developmental and infection studies; CXXC stalk knock-in

    PMID:19542373 PMID:19956738 PMID:24899501

    Open questions at the time
    • Distinct contributions of membrane sequestration versus active lipid signaling by BRS not fully separated
  12. 2012 High

    Demonstrated in living cells that pMHC triggering dissociates the CD3ε tail and locally reduces phosphatidylserine, placing the lipid switch upstream of or parallel to kinase activation.

    Evidence Live-cell PS imaging in TCR microclusters with Src-kinase inhibitor epistasis; conformational MD modeling and mutants

    PMID:19671929 PMID:23166358

    Open questions at the time
    • Direct force/ligand mechanism driving the charge change not defined
  13. 2020 High

    Revealed CD3ε as a dual activating/inhibitory tuner: an RK motif locally boosts Lck activity while mono-phosphorylated ITAMs recruit inhibitory Csk, with BRS-p85 supporting persistence.

    Evidence SH3-binding assays and knock-in/CAR mouse studies; quantitative phospho-MS, Co-IP, and CAR-T functional assays

    PMID:32690949 PMID:32730808

    Open questions at the time
    • How the balance between RK-Lck activation and Csk inhibition is set per receptor not quantified
  14. 2024 High

    Identified an extracellular inhibitory ligand of CD3ε, defining a new checkpoint that suppresses early T cell activation.

    Evidence ITPRIPL1–CD3ε binding assays, calcium and ZAP70 phosphorylation readouts, and in vivo tumor models with neutralizing antibody

    PMID:38614099

    Open questions at the time
    • Structural basis of ITPRIPL1–CD3ε engagement not resolved
    • Physiological contexts of endogenous ITPRIPL1 signaling unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How extracellular ligation is mechanically transmitted across the membrane to drive CD3ε ITAM release and the precise order of conformational, lipid, and kinase events remain incompletely defined.
  • No unified structural model coupling ectodomain conformation to cytoplasmic ITAM exposure
  • Quantitative kinetics of membrane dissociation versus phosphorylation in vivo unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0060090 molecular adaptor activity 4 GO:0008289 lipid binding 3 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 5 R-HSA-1266738 Developmental Biology 3
Partners
CD3DCD3GCSKITPRIPL1LCKNCK1PIK3R1ZAP70
Complex memberships
CD3εγ heterodimerCD3εδ heterodimerTCR/CD3 complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 A 22-amino acid region of the CD3ε cytoplasmic tail independently activates T cells, producing a quantitatively distinct pattern of tyrosine phosphorylation compared to that induced by the TCR ζ chain cytoplasmic tail, indicating activation of different biochemical pathways. Chimeric receptor expression and T cell activation assay with tyrosine phosphorylation readout Science Medium 1532456
2002 Ligand engagement of the TCR-CD3 complex induces a conformational change in CD3ε that exposes a proline-rich sequence (PRS), enabling recruitment of the adaptor protein Nck. This occurs earlier than and independently of tyrosine kinase activation and is critical for immune synapse maturation and T cell activation. Pull-down assay, in vivo interference with Nck–CD3ε association, immunological synapse imaging Cell High 12110186
2008 The CD3ε cytoplasmic ITAM tyrosines insert deeply into the hydrophobic core of the plasma membrane inner leaflet via electrostatic interactions between basic CD3ε residues and acidic phospholipids; receptor ligation must cause unbinding of the CD3ε ITAM from the membrane to render these tyrosines accessible to Src kinases. NMR structure of lipid-bound cytoplasmic domain, live-cell FRET imaging, mutagenesis of basic residues Cell High 19013279
1993 The tandem SH2 domains of ZAP-70 specifically bind to tyrosine-phosphorylated CD3ε (and TCR ζ) from activated T cells; neither the N-terminal nor C-terminal SH2 domain alone is sufficient for this interaction. GST fusion protein pull-down from activated Jurkat T cell lysates The Journal of biological chemistry Medium 8366117
2004 Crystal structure of the human CD3εγ heterodimer (2.1 Å) in complex with therapeutic mAb OKT3 reveals the mode of CD3εγ dimerization, maps candidate TCR docking sites including a duplicated acidic-residue-rich region unique to human CD3ε, and shows OKT3 binds to an atypically small area of CD3ε. X-ray crystallography at 2.1 Å resolution Proceedings of the National Academy of Sciences of the United States of America High 15136729
2001 The solution NMR structure of the CD3εγ ectodomain heterodimer reveals a unique side-to-side hydrophobic interface between two C2-set Ig-like domains with parallel pairing of C-terminal β-strands; mutational analysis confirms the importance of this interface and the membrane-proximal stalk motif (RxCxxCxE) for domain-domain association. NMR structure determination combined with mutagenesis Cell High 11439187
2004 Crystal structure of human CD3εδ ectodomain heterodimer at 1.9 Å in complex with UCHT1 scFv reveals a conserved interface between CD3εδ and CD3εγ (parallel G-strand packing), with CD3δ having a more electronegative and compact Ig fold than CD3γ, and UCHT1 binding near an acidic region of CD3ε opposite the dimer interface. X-ray crystallography at 1.9 Å resolution Proceedings of the National Academy of Sciences of the United States of America High 15534202
1993 TCR-stimulated CD3ε undergoes tyrosine phosphorylation in vivo specifically at both tyrosine residues within its C-terminal ITAM signal transduction motif, with kinetics similar to ζ chain phosphorylation but strictly dependent on cell-surface expression of CD3ε. In vivo phosphorylation assay, chemical and proteolytic cleavage combined with peptide-specific Western blotting European journal of immunology Medium 7686857
1992 A 10-amino acid sequence (residues 171–180) in the CD3ε cytosolic tail functions as an endoplasmic reticulum retention signal; the tyrosine and serine within this sequence are critical for retention, and this signal is hidden upon complete TCR complex assembly to allow surface expression. Deletion mutagenesis, chimeric protein expression (CD3ε retention sequence appended to CD4), cell surface expression assay Nature High 1535117
1995 NMR spectroscopy and mutagenesis show the CD3ε ER-retention motif (involving Tyr177, Leu180, Arg183) forms an elongated α-helix followed by a β-turn; this motif is functionally homologous to tyrosine-based endocytosis signals and can substitute for the transferrin receptor internalization sequence. NMR spectroscopy, mutagenesis, chimeric protein internalization assay The EMBO journal High 7774584
1990 The mature TCR/CD3 complex contains two CD3ε polypeptide chains, as demonstrated by co-expression of human and mouse CD3ε in the same complex in both transfected hybridomas and transgenic mice, with the two CD3ε subunits forming direct contact via disulfide-linked homodimers. Immunoprecipitation from transgenic thymocytes/T cells and transfected hybridomas; two-dimensional gel electrophoresis Proceedings of the National Academy of Sciences of the United States of America High 2144901
1991 The mature TCR/CD3 complex contains two CD3ε subunits; FRET and immunoprecipitation from transgenic mice expressing both human and mouse CD3ε show both species present in the same complex, and antigen comodulation supports stochastic incorporation of CD3ε during assembly. Immunoprecipitation, fluorescence resonance energy transfer (FRET), antigen comodulation The Journal of experimental medicine High 1824636
1994 Each TCR/CD3 complex on the surface of thymocytes and mature T cells contains precisely one TCRα, one TCRβ, and two CD3ε chains, as determined by quantitative immunofluorescence in double TCR-transgenic mice. Quantitative flow cytometry in double-TCR-transgenic mice with biochemically distinguishable TCR chains The Journal of experimental medicine High 8046335
2020 A subpopulation of CD3ε ITAMs is mono-phosphorylated due to Lck kinase selectivity and specifically recruits the inhibitory kinase Csk to attenuate TCR signaling, making TCR a self-restrained signaling machinery. The CD3ε BRS (basic residue-rich sequence) promotes CAR-T cell persistence via p85 recruitment. Quantitative mass spectrometry phosphorylation profiling of all CD3 chains, Co-IP, CAR-T cell functional assays Cell High 32730808
2020 A previously unknown receptor-kinase (RK) motif in the CD3ε cytoplasmic tail interacts with the Lck SH3 domain in a noncanonical mode; this motif is accessible only upon TCR ligation, and its binding to Lck results in local augmentation of Lck activity, CD3 phosphorylation, T cell activation, and thymocyte development. Binding motif identification, SH3 domain interaction assays, knock-in mouse functional studies, in vitro and in vivo CAR experiments Nature immunology High 32690949
1998 CD3εγ and CD3εδ dimers associate indistinctly with both TCRα and TCRβ chains (not in a preferential asymmetric manner), as shown in Jurkat cells and human thymocytes; CD3ζ homodimer mediates the interaction between both TCRαβ heterodimers in a double-TCR complex model. Immunoprecipitation combined with two-dimensional gel electrophoresis; analysis of TCRα-negative MOLT-4 cells and Jurkat mutant with point mutation in TCRβ transmembrane domain European journal of immunology Medium 9485181
1997 Tyrosine phosphorylation of CD3ε recruits the p85α subunit of PI 3-kinase in a T cell activation-dependent manner; both Tyr170 and Tyr181 within the CD3ε ITAM are required for efficient p85α binding, whereas these mutations do not affect Fyn binding, suggesting differential effector recruitment from a single ITAM. Stable transfection of CD8–CD3ε chimera in Jurkat cells, Ab-induced phosphorylation, mutagenesis in COS-7 co-transfection system, Co-IP of PI 3-kinase activity The Journal of biological chemistry Medium 9312149
1996 Topoisomerase IIβ (TopoIIβ) specifically interacts with CD3ε via its N-terminal 12-amino acid basic cluster motif; this interaction is also found for FcRγ (which has a similar motif) but not CD3η. CD3ε is present in the nuclear fraction of thymocytes (increasing upon T cell activation), and co-immunoprecipitation from nuclear fractions confirms the TopoIIβ–CD3ε interaction in cells. GST pull-down cloning screen, Co-immunoprecipitation from nuclear fractions, deletion mutagenesis The Journal of biological chemistry Medium 8626450
1999 CAST (a novel protein) specifically binds in vivo and in vitro to CD3ε (but not CD3ζ or FcRγ) via a unique membrane-proximal region; CAST undergoes tyrosine phosphorylation upon TCR stimulation, and dominant-negative CAST suppresses NFAT activation and IL-2 production. GST pull-down cloning, Co-immunoprecipitation, dominant-negative overexpression, NFAT reporter assay The Journal of biological chemistry Medium 10373416
1999 PDE4B2 (but not PDE4B1) isoform specifically associates with CD3ε via its N-terminal myristoylation sites; only the TCR-associated PDE4B2 undergoes tyrosine phosphorylation following CD3 ligation, suggesting receptor-association determines selective enzyme activation. Co-immunoprecipitation from peripheral blood T cells, isoform-specific phosphorylation analysis Journal of immunology Medium 9973473
2007 A PxxDY motif in the CD3ε proline-rich region (sharing Tyr166 with the ITAM) is the binding site for SH3 domains of Nck and Eps8L1; phosphorylation of Y166 abolishes SH3 binding and is induced by TCR ligation in Jurkat cells, constituting a molecular switch that toggles CD3ε between SH3- and SH2-domain binding partners. SH3 domain phage display library screening, recombinant protein binding assays, peptide spot filter assays, co-transfection with dominant-active Lck, endogenous protein interaction in Jurkat cells Journal of immunology High 17617578
2008 NMR structure of the Nck SH3.1–CD3ε PxxDY complex shows how Nck binds the atypical CD3ε motif; Nck binding inhibits phosphorylation of the CD3ε ITAM by Fyn and Lck in vitro, and CD3ε–Nck interaction downregulates TCR surface expression upon physiological stimulation in primary mouse lymph node cells. NMR structure determination, in vitro kinase phosphorylation inhibition assay, TCR surface expression assay in primary lymph node cells Journal of molecular biology High 18555270
2007 G protein-coupled receptor kinase 2 (GRK2) constitutively associates with the membrane-proximal portion of the CD3ε cytoplasmic domain, as identified by mass spectrometry and verified by co-IP and transient transfection assays. Mass spectrometry of CD3ε-associated proteins, transient transfection assay, Western blot Co-IP The Journal of biological chemistry Medium 17420248
2009 The CD3ε cytoplasmic tail contains a basic-rich stretch (BRS) that complexes acidic phospholipids including PI(4,5)P2 and PI(3,4,5)P3; BRS mutations in transgenic mice cause T cell developmental defects, decreased TCR surface expression, reduced TCR signaling responses, and delayed CD3ε localization to the immunological synapse. Phospholipid-binding assays, transgenic mouse T cell functional analysis, TCR surface expression and signaling assays, immune synapse imaging Journal of immunology High 19542373
2012 TCR triggering by peptide-MHC induces dissociation of the CD3ε cytoplasmic domain from the plasma membrane, accompanied by a focal reduction in negative charge and available phosphatidylserine (PS) in TCR microclusters; this lipid change occurs even when TCR signaling is blocked by a Src kinase inhibitor, placing it upstream of or parallel to kinase activation. Live-cell imaging of PS distribution, TCR microcluster analysis, pharmacological Src kinase inhibition The Journal of experimental medicine High 23166358
2009 Molecular dynamics modeling of CD3 ectodomain conformational change shows a stiffening effect funneled to the base of CD3ε; mutation of two key residues blocks transmission of the conformational change and inhibits T cell differentiation and activation even in the presence of excess endogenous CD3ε, suggesting cooperativity between TCR complexes. Molecular dynamics modeling, CD3ε conformational mutants, T cell activation and differentiation assays Science signaling Medium 19671929
1999 CD3ε contains endocytosis signals in its cytoplasmic tail; deletion and point-mutant analysis of CD3ε expressed at the cell surface independently of other TCR-CD3 subunits demonstrated that these signals mediate internalization, implicating CD3ε in TCR downregulation. Deletion and point mutagenesis of CD3ε, cell surface expression and internalization assays Journal of immunology Medium 10384095
1998 One of the two CD3ε chains in the TCR complex is located in close proximity to the TCR Cbeta FG loop, as demonstrated by FRET inhibition experiments using mAbs to TCR-β and CD3ε in primary T cells and transgenic mice expressing human and mouse CD3ε. Monoclonal antibody steric/FRET-based proximity assay in transgenic T cells The Journal of experimental medicine Medium 9565644
2008 TCR triggering causes the cytoplasmic tails of CD3ε and CD3ζ to adopt a compact, protease-resistant conformation, suggesting the conformational change induced by TCR ligation is transmitted to the cytoplasmic tails of at least CD3ε and CD3ζ. Protease-sensitivity assay of CD3ε and CD3ζ cytoplasmic tails upon TCR triggering PloS one Medium 18320063
1991 A conformational epitope on CD3ε, expressed only when CD3ε is associated with either CD3γ or CD3δ, is the main target for widely used anti-CD3 mAbs (OKT3, UCHT1, Leu-4, WT31); isolated CD3ε is not recognized by these mAbs but is recognized by mAbs raised against denatured CD3ε. COS cell transfection with individual and combined CD3 genes, immunofluorescence and immunoprecipitation Journal of immunology Medium 1717585
2009 The conserved CXXC motif in the extracellular stalk of CD3ε is critical for T cell development and TCR signaling; mice expressing CXXC→SXSC mutant CD3ε show incorporation into the TCR complex and surface TCR rescue but impaired T cell development and activation at all TCR-dependent stages. Knock-in mouse with Cys→Ser mutations, T cell development analysis, T cell activation assays PLoS biology High 19956738
2014 Membrane association of the CD3ε BRS (basic-rich stretch) is required for optimal thymocyte development and peripheral T cell function; BRS-mutant knock-in mice have reduced thymic cellularity, enhanced DN4 TCR signaling causing increased cell death, impaired positive selection, and substantially reduced T cell responsiveness to influenza infection. Knock-in mouse model with BRS mutations, thymocyte subset analysis, T cell selection and functional assays, influenza infection model Journal of immunology High 24899501
2005 CD3ε phosphorylation requires Src family kinase (SFK) activity, whereas CD3ζ phosphorylation and ZAP70 recruitment do not absolutely require Lck or other PP2-inhibitable SFK; this differential requirement indicates distinct pathways for CD3ζ and CD3ε ITAM phosphorylation. Anti-CD3-stimulated mouse CTLs with SFK inhibitor PP2, Western blot analysis of phosphorylation, ZAP70 Co-IP Journal of immunology Medium 15944285
1989 Deletion of 49 of the 55 cytoplasmic amino acid residues of CD3ε does not prevent assembly of a functional surface TCR complex or signal transduction triggered by antibody binding to the external domain, indicating the CD3ε cytoplasmic domain is dispensable for TCR assembly and for signals delivered to the external region. Transfection of truncated CD3ε cDNA into T cell hybridoma, IL-2 production assay Proceedings of the National Academy of Sciences of the United States of America Medium 2528731
2024 ITPRIPL1 functions as an inhibitory ligand of CD3ε; binding of ITPRIPL1 extracellular domain to CD3ε on T cells significantly decreases calcium influx and ZAP70 phosphorylation, impeding initial T cell activation; a neutralizing antibody against ITPRIPL1 restrained tumor growth and promoted T cell infiltration in mouse models. Co-IP/binding assays, calcium influx measurement, ZAP70 phosphorylation assay, in vivo tumor models with neutralizing antibody Cell High 38614099
2001 A single MHC class I molecule brings TCR and CD8 into close proximity by serving as a docking molecule for both; FRET experiments directly demonstrate that CD3ε is brought into close proximity with CD8 upon TCR/CD8 association mediated by class I MHC, independently of phosphorylation events. Fluorescence resonance energy transfer (FRET) with MHC class I, CD8, TCR, and CD3ε fluorescent reporters Journal of immunology Medium 11441088

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1992 Activation of T cells by a tyrosine kinase activation domain in the cytoplasmic tail of CD3 epsilon. Science (New York, N.Y.) 433 1532456
2002 Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Cell 365 12110186
2008 Regulation of T cell receptor activation by dynamic membrane binding of the CD3epsilon cytoplasmic tyrosine-based motif. Cell 363 19013279
1995 Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene. The EMBO journal 357 7588594
1993 Tandem SH2 domains of ZAP-70 bind to T cell antigen receptor zeta and CD3 epsilon from activated Jurkat T cells. The Journal of biological chemistry 255 8366117
1992 Ontogeny of human natural killer (NK) cells: fetal NK cells mediate cytolytic function and express cytoplasmic CD3 epsilon,delta proteins. The Journal of experimental medicine 246 1372642
1994 A block in both early T lymphocyte and natural killer cell development in transgenic mice with high-copy numbers of the human CD3E gene. Proceedings of the National Academy of Sciences of the United States of America 195 7937778
1993 Restoration of early thymocyte differentiation in T-cell receptor beta-chain-deficient mutant mice by transmembrane signaling through CD3 epsilon. Proceedings of the National Academy of Sciences of the United States of America 190 8248261
1994 CD3 epsilon-mediated signals rescue the development of CD4+CD8+ thymocytes in RAG-2-/- mice in the absence of TCR beta chain expression. International immunology 182 7947468
1998 Rapid death and regeneration of NKT cells in anti-CD3epsilon- or IL-12-treated mice: a major role for bone marrow in NKT cell homeostasis. Immunity 181 9768754
1989 Monoclonal antibodies to murine CD3 epsilon define distinct epitopes, one of which may interact with CD4 during T cell activation. Journal of immunology (Baltimore, Md. : 1950) 181 2470817
2020 Multiple Signaling Roles of CD3ε and Its Application in CAR-T Cell Therapy. Cell 158 32730808
2004 Crystal structure of the human T cell receptor CD3 epsilon gamma heterodimer complexed to the therapeutic mAb OKT3. Proceedings of the National Academy of Sciences of the United States of America 147 15136729
1992 Expression of cytoplasmic CD3 epsilon proteins in activated human adult natural killer (NK) cells and CD3 gamma, delta, epsilon complexes in fetal NK cells. Implications for the relationship of NK and T lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 147 1387664
2001 Mechanisms contributing to T cell receptor signaling and assembly revealed by the solution structure of an ectodomain fragment of the CD3 epsilon gamma heterodimer. Cell 146 11439187
1991 Cloning of murine TCF-1, a T cell-specific transcription factor interacting with functional motifs in the CD3-epsilon and T cell receptor alpha enhancers. The Journal of experimental medicine 137 1827138
1991 Structure of the T cell antigen receptor (TCR): two CD3 epsilon subunits in a functional TCR/CD3 complex. The Journal of experimental medicine 130 1824636
2004 Crystal structure of a human CD3-epsilon/delta dimer in complex with a UCHT1 single-chain antibody fragment. Proceedings of the National Academy of Sciences of the United States of America 124 15534202
1990 Structure of the T-cell antigen receptor: evidence for two CD3 epsilon subunits in the T-cell receptor-CD3 complex. Proceedings of the National Academy of Sciences of the United States of America 122 2144901
2020 Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function. Nature immunology 97 32690949
1998 Specific requirement for CD3epsilon in T cell development. Proceedings of the National Academy of Sciences of the United States of America 97 9843989
2012 Local changes in lipid environment of TCR microclusters regulate membrane binding by the CD3ε cytoplasmic domain. The Journal of experimental medicine 92 23166358
1993 Regulation of thymocyte development through CD3. I. Timepoint of ligation of CD3 epsilon determines clonal deletion or induction of developmental program. The Journal of experimental medicine 87 8382254
2008 The proline-rich sequence of CD3epsilon controls T cell antigen receptor expression on and signaling potency in preselection CD4+CD8+ thymocytes. Nature immunology 85 18408722
2009 Cooperativity between T cell receptor complexes revealed by conformational mutants of CD3epsilon. Science signaling 84 19671929
1988 CD3-negative lymphokine-activated cytotoxic cells express the CD3 epsilon gene. Journal of immunology (Baltimore, Md. : 1950) 84 2894394
1997 Restoration of thymopoiesis in pT alpha-/- mice by anti-CD3epsilon antibody treatment or with transgenes encoding activated Lck or tailless pT alpha. Immunity 83 9208843
1991 A conformational epitope expressed upon association of CD3-epsilon with either CD3-delta or CD3-gamma is the main target for recognition by anti-CD3 monoclonal antibodies. Journal of immunology (Baltimore, Md. : 1950) 82 1717585
1994 Stoichiometry of the T cell antigen receptor (TCR) complex: each TCR/CD3 complex contains one TCR alpha, one TCR beta, and two CD3 epsilon chains. The Journal of experimental medicine 74 8046335
1995 CD3 epsilon and CD3 zeta cytoplasmic domains can independently generate signals for T cell development and function. Immunity 71 7719942
1993 Independent mutations of the human CD3-epsilon gene resulting in a T cell receptor/CD3 complex immunodeficiency. Nature genetics 71 8490660
1996 Specific interaction of topoisomerase II beta and the CD3 epsilon chain of the T cell receptor complex. The Journal of biological chemistry 70 8626450
2009 The cytoplasmic tail of the T cell receptor CD3 epsilon subunit contains a phospholipid-binding motif that regulates T cell functions. Journal of immunology (Baltimore, Md. : 1950) 68 19542373
2008 Tumor-educated tolerogenic dendritic cells induce CD3epsilon down-regulation and apoptosis of T cells through oxygen-dependent pathways. Journal of immunology (Baltimore, Md. : 1950) 64 18713979
2007 Reciprocal regulation of SH3 and SH2 domain binding via tyrosine phosphorylation of a common site in CD3epsilon. Journal of immunology (Baltimore, Md. : 1950) 64 17617578
1992 An endoplasmic reticulum retention signal in the CD3 epsilon chain of the T-cell receptor. Nature 63 1535117
1998 Assembly of the TCR/CD3 complex: CD3 epsilon/delta and CD3 epsilon/gamma dimers associate indistinctly with both TCR alpha and TCR beta chains. Evidence for a double TCR heterodimer model. European journal of immunology 62 9485181
1995 A tyrosine-containing motif mediates ER retention of CD3-epsilon and adopts a helix-turn structure. The EMBO journal 62 7774584
1998 One of the CD3epsilon subunits within a T cell receptor complex lies in close proximity to the Cbeta FG loop. The Journal of experimental medicine 60 9565644
1989 An enhancer located in a CpG-island 3' to the TCR/CD3-epsilon gene confers T lymphocyte-specificity to its promoter. The EMBO journal 59 2583122
2005 The CD3epsilon proline-rich sequence, and its interaction with Nck, is not required for T cell development and function. Journal of immunology (Baltimore, Md. : 1950) 58 15972658
2000 Function of CD3 epsilon-mediated signals in T cell development. The Journal of experimental medicine 58 10993922
2011 Characterization of an anti-rainbow trout (Oncorhynchus mykiss) CD3ε monoclonal antibody. Veterinary immunology and immunopathology 57 22188783
1989 Most anti-human CD3 monoclonal antibodies are directed to the CD3 epsilon subunit. European journal of immunology 55 2472280
1993 Regulation of thymocyte development through CD3. II. Expression of T cell receptor beta CD3 epsilon and maturation to the CD4+8+ stage are highly correlated in individual thymocytes. The Journal of experimental medicine 54 7504052
2018 Engineering a bispecific antibody with a common light chain: Identification and optimization of an anti-CD3 epsilon and anti-GPC3 bispecific antibody, ERY974. Methods (San Diego, Calif.) 49 30326272
2007 Characterization of the CD3zeta, CD3gammadelta and CD3epsilon subunits of the T cell receptor complex in Atlantic salmon. Developmental and comparative immunology 49 17532043
1999 Signals transduced by CD3epsilon, but not by surface pre-TCR complexes, are able to induce maturation of an early thymic lymphoma in vitro. Journal of immunology (Baltimore, Md. : 1950) 46 10452996
1988 Human CD3-epsilon gene contains three miniexons and is transcribed from a non-TATA promoter. Proceedings of the National Academy of Sciences of the United States of America 46 3267235
2008 The proline-rich sequence of CD3epsilon as an amplifier of low-avidity TCR signaling. Journal of immunology (Baltimore, Md. : 1950) 45 18566390
2024 ITPRIPL1 binds CD3ε to impede T cell activation and enable tumor immune evasion. Cell 44 38614099
1999 Unexpectedly late expression of intracellular CD3epsilon and TCR gammadelta proteins during adult thymus development. International immunology 44 10508182
1995 Over-expression of CD3 epsilon transgenes blocks T lymphocyte development. International immunology 44 7794823
2007 Notch signaling induces cytoplasmic CD3 epsilon expression in human differentiating NK cells. Blood 43 17630354
1999 CAST, a novel CD3epsilon-binding protein transducing activation signal for interleukin-2 production in T cells. The Journal of biological chemistry 43 10373416
2015 Resimmune, an anti-CD3ε recombinant immunotoxin, induces durable remissions in patients with cutaneous T-cell lymphoma. Haematologica 42 25795722
1998 Establishment of an IL-2-dependent cell line derived from 'nasal-type' NK/T-cell lymphoma of CD2+, sCD3-, CD3epsilon+, CD56+ phenotype and associated with the Epstein-Barr virus. British journal of haematology 42 9858215
1993 The T cell receptor associated CD3-epsilon protein is phosphorylated upon T cell activation in the two tyrosine residues of a conserved signal transduction motif. European journal of immunology 40 7686857
2014 TCRs genetically linked to CD28 and CD3ε do not mispair with endogenous TCR chains and mediate enhanced T cell persistence and anti-melanoma activity. Journal of immunology (Baltimore, Md. : 1950) 39 25320284
2009 A conserved CXXC motif in CD3epsilon is critical for T cell development and TCR signaling. PLoS biology 39 19956738
2001 Reduced T-cell receptor CD3zeta-chain protein and sustained CD3epsilon expression at the site of mycobacterial infection. Immunology 39 11722641
1999 The CD3 epsilon subunit of the TCR contains endocytosis signals. Journal of immunology (Baltimore, Md. : 1950) 39 10384095
2008 Structural and functional evidence that Nck interaction with CD3epsilon regulates T-cell receptor activity. Journal of molecular biology 38 18555270
1997 Tyrosine phosphorylation of the CD3-epsilon subunit of the T cell antigen receptor mediates enhanced association with phosphatidylinositol 3-kinase in Jurkat T cells. The Journal of biological chemistry 38 9312149
1995 Compared TCR and CD3 epsilon expression on alpha beta and gamma delta T cells. Evidence for the association of two TCR heterodimers with three CD3 epsilon chains in the TCR/CD3 complex. Journal of immunology (Baltimore, Md. : 1950) 37 7706721
2014 Relevance of Nck-CD3 epsilon interaction for T cell activation in vivo. Journal of immunology (Baltimore, Md. : 1950) 36 24470497
2014 Membrane association of the CD3ε signaling domain is required for optimal T cell development and function. Journal of immunology (Baltimore, Md. : 1950) 34 24899501
1995 Use of anti-CD3 epsilon F(ab')2 fragments in vivo to modulate graft-versus-host disease without loss of graft-versus-leukemia reactivity after MHC-matched bone marrow transplantation. Journal of immunology (Baltimore, Md. : 1950) 33 7730653
2000 CD3epsilon homologues in the chondrostean fish Acipenser ruthenus. Immunogenetics 32 11061286
1994 In vivo or in vitro anti-CD3 epsilon chain monoclonal antibody therapy for the prevention of lethal murine graft-versus-host disease across the major histocompatibility barrier in mice. Journal of immunology (Baltimore, Md. : 1950) 31 8144942
2009 Critical and multiple roles for the CD3epsilon intracytoplasmic tail in double negative to double positive thymocyte differentiation. Journal of immunology (Baltimore, Md. : 1950) 29 19342663
2008 T cell receptor engagement triggers its CD3epsilon and CD3zeta subunits to adopt a compact, locked conformation. PloS one 29 18320063
2002 The ontogeny of B cells in the thymus of normal, CD3 epsilon knockout (KO), RAG-2 KO and IL-7 transgenic mice. International immunology 29 11751756
1988 Characterization and expression of the murine CD3-epsilon gene. Proceedings of the National Academy of Sciences of the United States of America 28 2973066
1999 Specific CD3 epsilon association of a phosphodiesterase 4B isoform determines its selective tyrosine phosphorylation after CD3 ligation. Journal of immunology (Baltimore, Md. : 1950) 27 9973473
1996 Porcine CD3 epsilon: its characterization, expression and involvement in activation of porcine T lymphocytes. Immunology 27 8675218
2001 Anti-CD3 epsilon F(ab')2 prevents graft-versus-host disease by selectively depleting donor T cells activated by recipient alloantigens. Journal of immunology (Baltimore, Md. : 1950) 26 11313428
1997 Identification and analysis of the chicken CD3epsilon gene. European journal of immunology 26 9022018
2011 Identification of CD3ε, CD4, CD8β splice variants of Atlantic salmon. Fish & shellfish immunology 25 21821134
2001 Monomeric class I molecules mediate TCR/CD3 epsilon/CD8 interaction on the surface of T cells. Journal of immunology (Baltimore, Md. : 1950) 25 11441088
1999 Regulation of delta opioid receptor expression by anti-CD3-epsilon, PMA, and ionomycin in murine splenocytes and T cells. Journal of leukocyte biology 25 10331502
1996 Anti-graft-versus-host disease effect of DT390-anti-CD3sFv, a single-chain Fv fusion immunotoxin specifically targeting the CD3 epsilon moiety of the T-cell receptor. Blood 25 8822957
2007 The membrane-proximal portion of CD3 epsilon associates with the serine/threonine kinase GRK2. The Journal of biological chemistry 24 17420248
2005 Molecular characterization of the Japanese flounder, Paralichthys olivaceus, CD3epsilon and evolution of the CD3 cluster. Developmental and comparative immunology 24 15450752
1999 T lymphocyte development in the absence of CD3 epsilon or CD3 gamma delta epsilon zeta. Journal of immunology (Baltimore, Md. : 1950) 24 9886373
1995 Normal development and function of natural killer cells in CD3 epsilon delta 5/delta 5 mutant mice. Proceedings of the National Academy of Sciences of the United States of America 24 7638228
1990 A fraction of CD3 epsilon subunits exists as disulfide-linked dimers in both human and murine T lymphocytes. The Journal of biological chemistry 24 2144290
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
2022 Chimeric anti-GPC3 sFv-CD3ε receptor-modified T cells with IL7 co-expression for the treatment of solid tumors. Molecular therapy oncolytics 22 35572194
1995 Frequent expression of CD3 epsilon in CD3 (Leu 4)-negative nasal T-cell lymphomas. Leukemia 22 7845028
2017 Entire CD3ε, δ, and γ humanized mouse to evaluate human CD3-mediated therapeutics. Scientific reports 21 28368009
2017 Development of a monoclonal antibody against the CD3ε of olive flounder (Paralichthys olivaceus) and its application in evaluating immune response related to CD3ε. Fish & shellfish immunology 20 28433716
2005 Differential Src family kinase activity requirements for CD3 zeta phosphorylation/ZAP70 recruitment and CD3 epsilon phosphorylation. Journal of immunology (Baltimore, Md. : 1950) 20 15944285
1998 Expression of a CD3 epsilon transgene in CD3 epsilon(null) mice does not restore CD3 gamma and delta expression but efficiently rescues T cell development from a subpopulation of prothymocytes. International immunology 20 9885898
2017 Human Group 1 Innate Lymphocytes Are Negative for Surface CD3ε but Express CD5. Immunity 19 28514677
2012 Anti-CD3ε mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications. Blood 19 22723555
2004 CD4(-)c-kit(-)CD3epsilon(-)IL-2Ralpha(+) Peyer's patch cells are a novel cell subset which secrete IL-5 in response to IL-2: implications for their role in IgA production. European journal of immunology 19 15214040
2004 Downmodulation of CD3epsilon expression in CD8alpha+beta- T cells of feline immunodeficiency virus-infected cats. The Journal of general virology 19 15302952
2000 TGF-beta 1 differentially regulates IL-2 expression and [3H]-thymidine incorporation in CD3 epsilon mAb- and CD28 mAb-activated splenocytes and thymocytes. Immunopharmacology 19 10936508
1989 Deletion of the cytoplasmic region of the CD3 epsilon subunit does not prevent assembly of a functional T-cell receptor. Proceedings of the National Academy of Sciences of the United States of America 19 2528731

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