Affinage

CD3E

T-cell surface glycoprotein CD3 epsilon chain · UniProt P07766

Length
207 aa
Mass
23.1 kDa
Annotated
2026-04-28
100 papers in source corpus 38 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD3ε is an essential signal-transducing subunit of the T cell receptor (TCR)/CD3 complex, present in two copies per complex as part of CD3εγ and CD3εδ heterodimers, where it couples antigen recognition to intracellular signaling cascades that govern thymocyte development, T cell activation, and immune synapse formation (PMID:2144901, PMID:7588594, PMID:12110186). The CD3ε cytoplasmic tail contains at least four sequentially regulated functional elements: a basic residue-rich stretch (BRS) that anchors the ITAM tyrosines in the plasma membrane inner leaflet via electrostatic interactions with acidic phospholipids in resting T cells; a proline-rich sequence (PRS) exposed upon ligand engagement to recruit the adaptor Nck independently of kinase activity; a receptor kinase (RK) motif that binds the Lck SH3 domain in a ligand-dependent manner to locally recruit and amplify Src-family kinase activity; and the ITAM itself, whose dual phosphorylation recruits ZAP-70 via tandem SH2 domains while mono-phosphorylation recruits inhibitory Csk to self-limit signaling (PMID:19013279, PMID:12110186, PMID:32690949, PMID:32730808, PMID:8366117). Structurally, NMR and crystallographic studies define a unique side-by-side Ig-domain interface in CD3εγ and CD3εδ heterodimers, with a membrane-proximal CXXC stalk motif required for signal transmission but not surface assembly (PMID:11439187, PMID:15136729, PMID:19956738). CD3ε loss-of-function arrests thymocyte development at the CD25⁺ DN3 stage, demonstrating its non-redundant role in pre-TCR–mediated β-selection (PMID:7588594, PMID:9843989).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1989 Medium

    Early mutagenesis established that the CD3ε cytoplasmic domain is dispensable for TCR surface assembly, redirecting attention to the transmembrane and extracellular domains as the primary assembly determinants and to the cytoplasmic tail as a dedicated signaling module.

    Evidence Cytoplasmic truncation mutant transfected into T cells retaining surface TCR expression and IL-2 production

    PMID:2528731

    Open questions at the time
    • Single study with overexpression system; does not address whether residual 6 amino acids contribute
    • Quantitative signaling was not measured
  2. 1990 High

    Demonstration that the TCR complex contains two CD3ε subunits resolved the stoichiometry question and established the dimeric framework (εγ + εδ) that organizes all subsequent structural and signaling studies.

    Evidence Non-reducing/reducing 2D gel electrophoresis, CNBr peptide sequencing, and transgenic mouse co-expression

    PMID:2144290 PMID:2144901

    Open questions at the time
    • Exact arrangement of two CD3ε copies relative to TCRαβ was not resolved until later cryo-EM studies
  3. 1992 High

    Identification of a 22-amino-acid activation domain in CD3ε and a transferable ER retention signal defined the cytoplasmic tail as a multifunctional signaling cassette with built-in quality-control for unassembled chains.

    Evidence Chimeric receptor T cell activation assays (PMID:1532456); deletion mutagenesis and gain-of-function ER retention transfer to CD4 (PMID:1535117)

    PMID:1532456 PMID:1535117

    Open questions at the time
    • Identity of the kinase directly phosphorylating CD3ε was not established
    • ER retention receptor/machinery not identified
  4. 1993 High

    Demonstration that ZAP-70 requires both tandem SH2 domains to engage doubly phosphorylated CD3ε ITAM established the mechanistic logic of dual-tyrosine signaling and explained why both ITAM tyrosines must be phosphorylated for productive signaling.

    Evidence GST-fusion pulldowns from activated Jurkat lysates with single vs. tandem SH2 constructs; site-specific phosphorylation mapping

    PMID:7686857 PMID:8366117

    Open questions at the time
    • Relative contribution of CD3ε vs. CD3ζ ITAMs to total ZAP-70 recruitment was unclear
    • In vivo confirmation awaited genetic models
  5. 1995 High

    Gene knockout in mice demonstrated that CD3ε is non-redundantly required for pre-TCR–mediated β-selection, arresting thymocyte development at the DN3 stage and establishing CD3ε as the critical signaling bottleneck in early T cell development.

    Evidence Targeted gene disruption in mice with flow cytometric phenotyping; NMR of ER retention helix-turn motif

    PMID:7588594 PMID:7774584 PMID:9843989

    Open questions at the time
    • Whether CD3ε signals through the pre-TCR via the same cytoplasmic motifs as the mature TCR was not tested
  6. 1998 High

    Biochemical dissection of TCR assembly revealed that CD3εγ and CD3εδ dimers associate simultaneously and indiscriminately with TCRα and TCRβ, with CD3ζ cross-linking two hemicomplexes, resolving the assembly pathway and refuting ordered-assembly models.

    Evidence Co-immunoprecipitation and 2D gel electrophoresis from Jurkat cells and thymocytes

    PMID:9485181

    Open questions at the time
    • Structural basis of TCRα/β selectivity for εγ vs. εδ not resolved
  7. 2001 High

    The NMR structure of the CD3εγ ectodomain heterodimer revealed a unique side-by-side Ig-domain interface and identified the RxCxxCxE stalk motif as critical for heterodimer association and TCR assembly, providing the first atomic-resolution view of CD3 architecture.

    Evidence Solution NMR structure determination with site-directed mutagenesis validation

    PMID:11439187

    Open questions at the time
    • Structure of the full TCR/CD3 complex was not available
    • Role of the CXXC motif in signaling vs. assembly not separated
  8. 2002 High

    Discovery that TCR engagement exposes a proline-rich sequence (PRS) in CD3ε to recruit Nck prior to and independently of kinase activation established the first example of a conformational-change-driven, phosphorylation-independent signaling event in TCR biology.

    Evidence Nck pulldown assays, live-cell imaging of immune synapse formation, dominant-negative interference in vivo

    PMID:12110186

    Open questions at the time
    • How mechanical force or ligand binding triggers PRS exposure was not defined
    • Whether Nck recruitment is strictly required for all TCR signaling outputs was debated
  9. 2004 High

    Crystal structures of human CD3εγ (2.1 Å) and CD3εδ (1.9 Å) completed the ectodomain structural catalog, revealing conserved parallel G-strand packing but distinct electrostatic surfaces that likely contribute to differential TCRα/β interactions.

    Evidence X-ray crystallography of CD3εγ–OKT3 and CD3εδ–UCHT1 scFv complexes

    PMID:15136729 PMID:15534202

    Open questions at the time
    • How ectodomains contact TCRαβ remained unresolved without a full complex structure
  10. 2007 High

    Identification of the PxxDY phospho-switch in CD3ε showed that Tyr166 phosphorylation by Lck reciprocally toggles the tail from SH3-mediated Nck/Eps8L1 recruitment to SH2-mediated ZAP-70 engagement, establishing a temporal logic for early vs. late signaling.

    Evidence SH3 phage display, phosphopeptide binding assays, Lck cotransfection in Jurkat cells

    PMID:17617578

    Open questions at the time
    • Kinetics of the switch in living T cells not resolved
    • Contribution of Eps8L1 to TCR signaling not functionally tested in vivo
  11. 2008 High

    NMR and FRET studies revealed that in resting T cells the CD3ε ITAM tyrosines are buried in the lipid bilayer via BRS-mediated electrostatic interactions with acidic phospholipids, establishing a 'safety-catch' mechanism that prevents spurious kinase access and explaining how signaling is kept silent until receptor ligation.

    Evidence NMR structure of lipid-bound CD3ε cytoplasmic domain, FRET live-cell imaging, electrostatic mutagenesis; Nck–CD3ε NMR co-structure plus in vitro kinase inhibition

    PMID:18555270 PMID:19013279

    Open questions at the time
    • Identity of the force or biochemical event that physically extracts the tail from the membrane remained debated (mechanical pulling vs. local lipid rearrangement)
  12. 2009 High

    Knock-in mouse models targeting the BRS and CXXC stalk motifs separately demonstrated that BRS-mediated membrane association tunes signaling strength during thymocyte selection, while the CXXC motif is required for signal transduction but not surface assembly, functionally dissecting two structural elements.

    Evidence BRS-mutant and CXXC-mutant knock-in mice with flow cytometry, T cell activation assays, and influenza infection model

    PMID:19542373 PMID:19956738 PMID:24899501

    Open questions at the time
    • How BRS release is coordinated with PRS exposure and RK motif accessibility was not integrated into a single mechanistic model
  13. 2014 High

    Knock-in mice with a conservative PRS mutation abolishing Nck recruitment showed impaired TCR signaling, reduced antigen-driven T cell activation, partial protection from EAE, and impaired antitumor responses, providing in vivo genetic proof that the conformational Nck-recruitment step is functionally essential.

    Evidence PRS knock-in mouse, pulldown assays, EAE and tumor vaccination models, inhibitory peptide in vivo

    PMID:24470497

    Open questions at the time
    • Nck-independent functions of PRS exposure not excluded
    • Relative contribution of Nck vs. other SH3 partners in vivo not resolved
  14. 2020 High

    Two discoveries completed the functional map of the CD3ε cytoplasmic tail: identification of a receptor kinase (RK) motif that recruits Lck SH3 upon TCR ligation, and quantitative phosphoproteomics showing that mono-phosphorylated CD3ε recruits inhibitory Csk, establishing CD3ε as an integrated signal amplifier and attenuator.

    Evidence Peptide binding assays, mutagenesis, primary T cell and thymocyte assays, CAR-T tumor models (PMID:32690949); quantitative MS of all CD3 ITAMs, Csk co-IP, CAR-T functional assays (PMID:32730808)

    PMID:32690949 PMID:32730808

    Open questions at the time
    • Structural basis of the RK-Lck SH3 interaction not determined at atomic resolution
    • How mono- vs. dual-phosphorylated ITAMs are dynamically balanced in vivo is not quantified
    • Whether Csk recruitment to CD3ε dominates over CD3ζ-based feedback is unclear
  15. 2024 High

    Identification of ITPRIPL1 as an inhibitory extracellular ligand for CD3ε revealed a previously unknown immune checkpoint acting directly on the TCR signaling complex, with therapeutic implications demonstrated by neutralizing antibody-mediated tumor restriction.

    Evidence Binding assays, calcium flux and ZAP70 phosphorylation measurement, neutralizing antibody in vivo tumor models

    PMID:38614099

    Open questions at the time
    • Binding site on CD3ε not mapped at residue resolution
    • Whether ITPRIPL1 competes with pMHC-TCR interaction or acts allosterically is unknown
    • Physiological role of ITPRIPL1-CD3ε axis in normal immune homeostasis not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified structural and dynamic model integrating all four CD3ε cytoplasmic motifs (BRS, PRS, RK, ITAM) within the context of the full TCR/CD3 complex, and delineation of how mechanical force, lipid remodeling, and kinase access are temporally coordinated upon ligand engagement, remains unresolved.
  • Full-length TCR/CD3 complex structure with cytoplasmic domains in membrane context not available
  • Quantitative temporal ordering of BRS release → PRS exposure → RK exposure → ITAM phosphorylation not measured in single cells
  • Relative signaling contributions of CD3ε vs. CD3ζ ITAMs in physiological antigen recognition not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 3 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 7 R-HSA-1266738 Developmental Biology 4
Partners
CSKGRK2ITPRIPL1LCKNCK1PIK3R1ZAP70
Complex memberships
TCR/CD3 complex

Evidence

Reading pass · 34 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 can independently activate T cells, producing a distinct pattern of tyrosine phosphorylation from that produced by the TCRζ chain, indicating it activates different biochemical pathways and contains a tyrosine kinase activation domain. Chimeric receptor expression and T cell activation assays with tyrosine phosphorylation readout Science High 1532456
1993 The tandem SH2 domains of ZAP-70 bind to tyrosine-phosphorylated CD3ε (and TCRζ) from activated T cells; neither single SH2 domain alone is sufficient, demonstrating that dual SH2 engagement of the CD3ε ITAM is required for ZAP-70 recruitment. GST-fusion protein pulldown from activated Jurkat T cell lysates; domain-mapping with individual vs. tandem SH2 constructs The Journal of Biological Chemistry High 8366117
1993 CD3ε is tyrosine-phosphorylated on both ITAM tyrosines upon TCR/CD3 engagement in human T cells, with kinetics similar to TCRζ phosphorylation; phosphorylation is strictly dependent on cell-surface expression of CD3ε. In vivo phosphorylation, chemical/proteolytic cleavage, peptide-specific Western blotting European Journal of Immunology High 7686857
1995 Targeted disruption of the CD3ε gene in mice arrests thymocyte development at the CD44-/lowCD25+ triple-negative stage (same as RAG-deficient mice), establishing an essential and non-redundant role for CD3ε in pre-TCR-mediated β-selection. Gene targeting (knockout mouse), flow cytometric phenotyping, TCR gene rearrangement analysis The EMBO Journal High 7588594
1990 The TCR/CD3 complex contains two CD3ε subunits; disulfide-linked CD3ε homodimers exist in a fraction of TCR complexes from both human and murine T lymphocytes, as shown by non-reducing two-dimensional gel electrophoresis and amino acid sequence analysis. Immunoprecipitation, non-reducing/reducing 2D gel electrophoresis, CNBr peptide sequencing, transgenic mouse co-expression Proceedings of the National Academy of Sciences High 1824636 2144290 2144901 8046335
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 membrane-proximal stalk motif (RxCxxCxE) is critical for domain-domain association and TCR assembly. NMR structure determination; site-directed mutagenesis with biochemical functional validation Cell High 11439187
2002 Ligand engagement of TCR-CD3 induces a conformational change in CD3ε that exposes a proline-rich sequence (PRS), resulting in recruitment of the adaptor protein Nck. This occurs earlier than and independently of tyrosine kinase activation. Interference with Nck-CD3ε association impairs immune synapse maturation and T cell activation. Pulldown assay for Nck-CD3ε interaction, live-cell imaging, dominant-negative interference in vivo Cell High 12110186
2004 Crystal structure of the human CD3εγ heterodimer at 2.1-Å resolution complexed with OKT3 reveals the structural basis for CD3 assembly, maps candidate TCR docking sites including an acidic region unique to human CD3ε, and shows OKT3 binds a small area of CD3ε. X-ray crystallography at 2.1-Å resolution Proceedings of the National Academy of Sciences High 15136729
2004 Crystal structure of the human CD3εδ ectodomain heterodimer at 1.9-Å resolution (complexed with UCHT1 scFv) reveals a conserved interface with parallel G-strand packing shared with CD3εγ; CD3δ has a more electronegative and compact Ig fold than CD3γ, giving the two heterodimers distinct molecular surfaces. X-ray crystallography at 1.9-Å resolution Proceedings of the National Academy of Sciences High 15534202
2008 In resting T cells, the CD3ε cytoplasmic ITAM is sequestered by electrostatic interactions with acidic phospholipids in the inner leaflet of the plasma membrane; NMR structure of the lipid-bound state shows the two key ITAM tyrosines are buried deep in the hydrophobic bilayer core, rendering them inaccessible to Src kinases until receptor ligation displaces the domain from the membrane. FRET live-cell imaging, NMR structure determination of lipid-bound cytoplasmic domain, electrostatic mutagenesis Cell High 19013279
2012 TCR triggering by peptide-MHC induces dissociation of the CD3ε cytoplasmic domain from the plasma membrane, accompanied by focal reduction in phosphatidylserine and negative surface charge in TCR microclusters; this lipid compositional change occurs even when Src kinase signaling is blocked, indicating it is upstream of kinase activation. Live-cell imaging of lipid composition, PS sensors, Src kinase inhibitor treatment The Journal of Experimental Medicine High 23166358
1992 Amino acids 171–180 in the CD3ε cytoplasmic tail constitute an ER retention signal; deletion of this sequence allows surface expression of the isolated CD3ε chain, and appending it to CD4 (a plasma membrane protein) causes ER retention, demonstrating it is a transferable retention motif. Deletion mutagenesis, COS cell transfection, cell surface vs. ER localization assay Nature High 1535117
1995 The CD3ε ER retention motif forms a helix-turn structure determined by NMR; Tyr177, Leu180, and Arg183 are critical residues; the tyrosine-leucine arrangement mimics endocytosis signals and can functionally substitute for the transferrin receptor internalization sequence. Site-directed mutagenesis, NMR spectroscopy, chimeric protein endocytosis assay The EMBO Journal High 7774584
1998 Genetic deletion of CD3ε exon 5, but not CD3εγδζ collectively, arrests T cell development at the CD44-CD25+ DN stage; NK cell development and function are unaffected, demonstrating CD3ε has a specific, non-redundant role in pre-TCR assembly and T-lineage development not shared by other CD3 chains or required for NK development. Targeted gene disruption (exon 5 deletion), flow cytometry, in vitro/in vivo NK assays Proceedings of the National Academy of Sciences High 7638228 9843989
1996 Topoisomerase IIβ specifically binds the membrane-proximal basic amino acid cluster (N-terminal 12 amino acids) of the CD3ε cytoplasmic domain; CD3ε co-immunoprecipitates with topoIIβ from the nuclear fraction of T cells, and this association increases upon T cell activation. GST-fusion pulldown cloning, co-immunoprecipitation from nuclear fraction, domain mapping The Journal of Biological Chemistry Medium 8626450
1997 Tyrosine phosphorylation of CD3ε on both ITAM tyrosines (Tyr170 and Tyr181) recruits the p85α subunit of PI 3-kinase; both tyrosines are required for efficient p85α binding, and ligation of CD3ε induces PI 3-kinase enzymatic activity associated with the chain. CD8-CD3ε chimera transfection, immunoprecipitation, kinase assay, mutagenesis of ITAM tyrosines in COS-7 cells The Journal of Biological Chemistry High 9312149
1999 The novel protein CAST specifically interacts in vivo and in vitro with the membrane-proximal region of CD3ε (but not CD3ζ or FcRγ), undergoes tyrosine phosphorylation upon TCR stimulation, and dominant-negative CAST suppresses NFAT activation and IL-2 production, identifying a CD3ε-specific signaling pathway. GST-pulldown cloning, co-immunoprecipitation, dominant-negative overexpression, NFAT reporter assay The Journal of Biological Chemistry Medium 10373416
1999 The PDE4B2 isoform (but not PDE4B1) associates specifically with CD3ε in T cells; only the TCR-associated PDE4B2 is tyrosine-phosphorylated after CD3 ligation, and the kinetics correlate with changes in cAMP levels, suggesting isoform-selective TCR regulation of cAMP hydrolysis. Co-immunoprecipitation, Western blotting, cAMP measurement Journal of Immunology Medium 9973473
1999 CD3ε contains endocytosis signals in its cytoplasmic tail; deletion/point mutants expressed at the cell surface independently of other TCR-CD3 subunits demonstrate that these sequences mediate internalization, contributing to TCR downregulation after activation. Deletion and point mutant expression in transfected cells, internalization assay Journal of Immunology Medium 10384095
2007 Phosphorylation of Tyr166 in the CD3ε PxxDY motif acts as a molecular switch: in the unphosphorylated state this tyrosine is within the SH3-binding site for Nck and Eps8L1, enabling their recruitment; phosphorylation by Lck abolishes SH3 binding and shifts CD3ε to SH2-domain (ZAP-70) engagement, providing reciprocal regulation of SH3 vs. SH2 signaling. SH3 phage-display library screening, recombinant protein binding assays, phosphopeptide spot assays, dominant-active Lck cotransfection, Jurkat TCR ligation experiments Journal of Immunology High 17617578
2007 The membrane-proximal portion of CD3ε constitutively associates with the serine/threonine kinase GRK2 (G protein-coupled receptor kinase 2) in T cells, identified by mass spectrometry of CD3ε-associated proteins and confirmed by co-immunoprecipitation and transfection assays. Mass spectrometry of CD3ε immunoprecipitate, co-immunoprecipitation, transient transfection The Journal of Biological Chemistry Medium 17420248
2008 Structural and biochemical analysis shows Nck binds the CD3ε PxxDY/ITAM motif via its SH3 domain; Nck binding inhibits phosphorylation of the CD3ε ITAM by Fyn and Lck in vitro, and the CD3ε-Nck interaction downregulates TCR surface expression upon physiological stimulation in primary T cells. NMR structure of Nck SH3-CD3ε peptide complex, in vitro kinase assay with mutagenesis, primary T cell TCR downregulation assay Journal of Molecular Biology High 18555270
2008 Upon TCR triggering, the cytoplasmic tails of CD3ε and CD3ζ become fully protease-resistant, indicating they adopt a compact, locked conformation; this conformational change is transmitted from the ectodomain to the cytoplasmic tails. Protease-sensitivity assay on triggered T cells PLoS ONE Medium 18320063
2009 The basic residue-rich stretch (BRS) of the CD3ε cytoplasmic tail mediates binding to acidic phospholipids (PI(3)P, PI(4)P, PI(5)P, PI(3,4,5)P3, PI(4,5)P2); BRS mutations in transgenic mice cause T cell developmental defects, reduced TCR surface expression, impaired TCR signaling, and delayed CD3ε localization to the immunological synapse. Phospholipid binding assay, transgenic knock-in mouse with BRS mutations, flow cytometry, signaling assay, confocal microscopy Journal of Immunology High 19542373
2009 Molecular dynamics modeling plus mutagenesis of CD3ε ectodomains shows ligand-induced conformational change is funneled to the base of CD3ε, stiffening CD3 dimers; mutations blocking this transmission prevent T cell differentiation and activation in a dominant-negative manner, revealing cooperativity between TCR complexes. Molecular dynamics modeling, site-directed mutagenesis, T cell activation and differentiation assays Science Signaling Medium 19671929
2009 The conserved CXXC motif in the CD3ε ectodomain stalk is required for TCR signaling and T cell development; knock-in mice expressing CXXC→SXSXS CD3ε can assemble surface TCR complexes but show impaired TCR-dependent activation at all developmental stages, arguing against a simple receptor aggregation model and implicating the stalk in signal transmission. Knock-in mouse generation, surface TCR expression analysis, T cell activation assays PLoS Biology High 19956738
2014 The CD3ε BRS-mediated membrane association is required for optimal thymocyte DN3→DN4 transition and positive selection; BRS-mutant knock-in mice show enhanced TCR signaling in DN4 cells leading to increased cell death, TCR downregulation, impaired positive selection, and reduced peripheral T cell responses including to influenza. Knock-in mouse, flow cytometry of thymic subsets, functional T cell assays, influenza infection model Journal of Immunology High 24899501
2014 The Nck-CD3ε PRS interaction is required for efficient T cell activation in vivo; knock-in mice with a conservative PRS mutation that abolishes Nck recruitment show deficient TCR signaling (including CD3ζ phosphorylation), reduced antigen-induced T cell activation, partial protection from experimental autoimmune encephalitis, and impaired antitumor responses. Knock-in mouse, pulldown assay, flow cytometric signaling readout, EAE model, tumor vaccination model, inhibitory peptide in vivo Journal of Immunology High 24470497
1998 Assembly of the TCR/CD3 complex involves indiscriminate association of both CD3εγ and CD3εδ dimers with both TCRα and TCRβ chains simultaneously, inconsistent with an ordered assembly model; CD3ζ homodimer cross-links two TCR hemicomplexes, each containing either CD3εγ or CD3εδ, supporting a double TCR heterodimer stoichiometry. Co-immunoprecipitation, 2D gel electrophoresis from Jurkat cells and human thymocytes, TCRα-negative cell line analysis European Journal of Immunology High 9485181
2005 Src family kinase (SFK) activity is absolutely required for CD3ε ITAM phosphorylation but not for CD3ζ phosphorylation or ZAP-70 recruitment upon TCR stimulation; this demonstrates a differential SFK requirement distinguishing CD3ε from CD3ζ phosphorylation. Anti-CD3 stimulation of CTLs in presence/absence of SFK inhibitor PP2, immunoprecipitation, Western blotting, Lck-deficient Jurkat cells Journal of Immunology Medium 15944285
2020 A subpopulation of CD3ε ITAMs is mono-phosphorylated due to Lck kinase selectivity, and this mono-phosphorylated CD3ε specifically recruits the inhibitory kinase Csk to attenuate TCR signaling; the CD3ε BRS promotes CAR-T persistence via p85 recruitment; these findings establish CD3ε as a built-in multifunctional signal tuner containing both activating and inhibitory motifs. Quantitative mass spectrometry phospho-proteomics of all CD3 ITAMs, Csk co-immunoprecipitation, CAR-T cell functional assays in vitro and in vivo Cell High 32730808
2020 A previously unknown receptor kinase (RK) motif in the CD3ε cytoplasmic tail binds the Lck SH3 domain in a non-canonical mode; this motif is exposed only upon TCR ligation, providing a mechanism for ligand-dependent Lck recruitment, local augmentation of Lck activity, CD3 phosphorylation, and T cell activation. Peptide binding assays, mutagenesis, primary T cell activation assays, thymocyte development assays, CAR-T in vitro and in vivo tumor assays Nature Immunology High 32690949
2024 ITPRIPL1 functions as an inhibitory ligand for CD3ε; binding of the ITPRIPL1 extracellular domain to CD3ε on T cells decreases calcium influx and ZAP70 phosphorylation, impeding initial T cell activation ('signal one'); neutralizing antibody against ITPRIPL1 restores T cell function and restricts tumor growth in mouse models. Binding assays, calcium flux measurement, ZAP70 phosphorylation assay, neutralizing antibody in vivo tumor models Cell High 38614099
1989 Deletion of 49 of 55 cytoplasmic amino acid residues of CD3ε does not prevent assembly of a functional surface TCR or transduction of a stimulus delivered to the ectodomain, indicating that the CD3ε cytoplasmic domain is not required for TCR assembly but that transmembrane/extracellular interactions with other TCR chains are sufficient for surface expression and receptor assembly. cDNA transfection of cytoplasmic-truncation mutant, surface TCR expression assay, IL-2 production assay Proceedings of the National Academy of Sciences Medium 2528731

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 364 12110186
2008 Regulation of T cell receptor activation by dynamic membrane binding of the CD3epsilon cytoplasmic tyrosine-based motif. Cell 360 19013279
1995 Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene. The EMBO journal 355 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 153 32730808
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 145 11439187
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 144 15136729
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 129 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 123 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
1998 Specific requirement for CD3epsilon in T cell development. Proceedings of the National Academy of Sciences of the United States of America 97 9843989
2020 Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function. Nature immunology 94 32690949
2012 Local changes in lipid environment of TCR microclusters regulate membrane binding by the CD3ε cytoplasmic domain. The Journal of experimental medicine 91 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
1988 CD3-negative lymphokine-activated cytotoxic cells express the CD3 epsilon gene. Journal of immunology (Baltimore, Md. : 1950) 84 2894394
2009 Cooperativity between T cell receptor complexes revealed by conformational mutants of CD3epsilon. Science signaling 83 19671929
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
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) 67 19542373
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
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) 63 18713979
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 56 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
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
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
2015 Resimmune, an anti-CD3ε recombinant immunotoxin, induces durable remissions in patients with cutaneous T-cell lymphoma. Haematologica 42 25795722
1999 CAST, a novel CD3epsilon-binding protein transducing activation signal for interleukin-2 production in T cells. The Journal of biological chemistry 42 10373416
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
2024 ITPRIPL1 binds CD3ε to impede T cell activation and enable tumor immune evasion. Cell 39 38614099
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
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) 38 25320284
2009 A conserved CXXC motif in CD3epsilon is critical for T cell development and TCR signaling. PLoS biology 38 19956738
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) 33 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
1998 Regulation of Vbeta germline transcription in RAG-deficient mice by the CD3epsilon-mediated signals: implication of Vbeta transcriptional regulation in TCR beta allelic exclusion. International immunology 30 9645603
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
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
1995 Frequent expression of CD3 epsilon in CD3 (Leu 4)-negative nasal T-cell lymphomas. Leukemia 22 7845028
2022 Chimeric anti-GPC3 sFv-CD3ε receptor-modified T cells with IL7 co-expression for the treatment of solid tumors. Molecular therapy oncolytics 21 35572194
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
2020 Ligand-Guided Selection with Artificially Expanded Genetic Information Systems against TCR-CD3ε. Biochemistry 18 31880917
2016 Mucosal administration of CD3-specific monoclonal antibody inhibits diabetes in NOD mice and in a preclinical mouse model transgenic for the CD3 epsilon chain. Journal of autoimmunity 18 27745778