Affinage

CD247

T-cell surface glycoprotein CD3 zeta chain · UniProt P20963

Length
164 aa
Mass
18.7 kDa
Annotated
2026-04-28
100 papers in source corpus 49 papers cited in narrative 47 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD247 (CD3ζ) is a transmembrane signaling adapter essential for TCR assembly, surface expression, and signal transduction in T cells, and also serves as a shared signaling subunit for activating receptors on NK cells including CD16 and NKp46 (PMID:2532305, PMID:8223444). Its cytoplasmic domain contains three ITAMs whose tyrosines are phosphorylated by Lck to recruit ZAP-70, coupling antigen recognition to downstream calcium flux, MAPK, and NFAT activation; however, these ITAMs also exert an inhibitory function that suppresses responses to low-affinity ligands, thereby enabling ligand discrimination and kinetic proofreading (PMID:9295038, PMID:37945821). CD3ζ expression is regulated at multiple levels—transcriptionally by Elf-1/PP2A, post-transcriptionally by L-arginine availability controlling mRNA stability, and post-translationally by distinct LAPTM5-mediated lysosomal, SLAP/c-Cbl-dependent, and TNF-induced proteasomal degradation pathways (PMID:18714041, PMID:11950832, PMID:18619870, PMID:22798681). Homozygous loss-of-function mutations in CD247 cause T⁻B⁺NK⁺ severe combined immunodeficiency in humans (PMID:17170122).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1988 High

    Establishing that ζη heterodimers and ζζ homodimers within the TCR complex couple to distinct downstream signaling pathways resolved how a single receptor could generate qualitatively different signals.

    Evidence Biochemical fractionation and functional stimulation in parental vs. variant T cell lines with differential ζη/ζζ dimer content

    PMID:2845582

    Open questions at the time
    • Molecular basis of differential coupling of ζη vs. ζζ to phosphoinositide hydrolysis not identified
    • No structural model for the two dimer types
  2. 1989 High

    Demonstrating that CD3ζ co-associates with CD16 on NK cells and permits CD16 surface expression in heterologous cells established ζ as a shared signaling adapter across immune cell types, not exclusive to the TCR.

    Evidence Co-immunoprecipitation from NK cell lysates; co-transfection reconstitution in COS-7 cells

    PMID:2532305

    Open questions at the time
    • Structural basis of ζ–CD16 TM interaction not defined
    • Whether ζ signals identically when paired with CD16 vs. TCR not tested
  3. 1990 High

    Cloning revealed that ζ and η arise from alternative splicing of a single gene, with η lacking one ITAM tyrosine, providing a molecular explanation for their functional divergence.

    Evidence cDNA cloning, protein microsequencing, and genomic analysis

    PMID:2139725 PMID:2150596

    Open questions at the time
    • Physiological regulation of alternative splicing not characterized
  4. 1993 High

    Knockout mice demonstrated that CD3ζ is indispensable for thymocyte development and TCR surface expression in vivo, while η proved dispensable, establishing ζ as the functionally dominant signaling chain.

    Evidence Gene targeting in ES cells; flow cytometry and functional assays in ζ−/−, ζ/η−/−, and η−/− mice crossed with TCR transgenics

    PMID:8112294 PMID:8223444 PMID:8223445

    Open questions at the time
    • How gut IELs compensate via FcεRIγ substitution mechanistically unclear
    • Whether residual signaling in ζ KO is CD3γδε-ITAM dependent not resolved
  5. 1992 High

    A chimeric receptor containing only the ζ cytoplasmic domain proved necessary and sufficient for calcium flux, tyrosine kinase activation, and IL-2 secretion, directly proving ζ ITAMs as autonomous signaling modules.

    Evidence CD8α–ζ chimera transfected into CD3-negative Jurkat cells; calcium flux, kinase assays, ELISA

    PMID:1351920

    Open questions at the time
    • Relative contribution of individual ITAMs not dissected in this system
  6. 1994 High

    Identifying CD45 as a specific phosphatase for ζ ITAMs and mapping the functional asymmetry of N- vs. C-terminal YxxL motifs within each ITAM defined the biochemical logic of ζ signal initiation and termination.

    Evidence Substrate-trap CD45 mutant pulldown; systematic ITAM tyrosine/leucine mutagenesis with multiple downstream readouts

    PMID:7526385 PMID:9295038

    Open questions at the time
    • In vivo relevance of CD45–ζ interaction not tested in knockouts
    • Structural basis of ITAM asymmetry unknown
  7. 1997 High

    Showing that ζ ITAMs quantitatively amplify agonist signals but are dispensable for antagonist responses demonstrated that ζ functions as a signal amplifier whose contribution scales with ligand quality, not just an on/off switch.

    Evidence ITAM-mutant ζ in TCR transgenic mice; IL-2 dose–response and APL antagonism assays; thymic selection analysis in ζ-deficient HY-TCR transgenics

    PMID:10229184 PMID:10395646 PMID:9029099

    Open questions at the time
    • Mechanism by which ζ ITAMs set the positive/negative selection threshold not molecularly defined
  8. 2000 High

    Live imaging revealed that ζ dynamically relocates to the center of the immunological synapse in a cytoskeleton- and costimulation-dependent manner, linking ζ signaling to spatial organization at the T cell–APC interface.

    Evidence GFP-tagged ζ chimera; 3D live video microscopy with calcium imaging

    PMID:10958781 PMID:11970882

    Open questions at the time
    • Molecular machinery driving cSMAC accumulation not identified
    • Peripheral ζ pattern during negative selection not mechanistically explained
  9. 2002 High

    Discovery that L-arginine depletion destabilizes ζ mRNA and that activated macrophage arginase I mediates this effect established a metabolic checkpoint controlling ζ expression in the tumor microenvironment.

    Evidence mRNA stability assays; cycloheximide chase; macrophage–T cell co-culture with arginase inhibitors

    PMID:11950832 PMID:12874210

    Open questions at the time
    • RNA-binding protein or cis-element mediating arginine-sensitive mRNA decay not identified
    • In vivo relevance in tumors shown only correlatively at this stage
  10. 2006 High

    Identification of a homozygous CD247 loss-of-function mutation causing human T⁻B⁺NK⁺ SCID confirmed the essential non-redundant role of ζ in human T cell development.

    Evidence Patient genetics; retroviral complementation in ζ-deficient MA5.8 cells; metabolic labeling

    PMID:17170122

    Open questions at the time
    • Whether NK cell function is partially preserved via alternative adapters not fully explored
  11. 2008 High

    Multiple degradation pathways converging on ζ were delineated: LAPTM5 targets intracellular (Golgi) ζ to lysosomes, SLAP/c-Cbl targets internalized surface ζ, and TNF induces SLAP-dependent proteasomal degradation, revealing layered quality-control and inflammation-responsive ζ turnover.

    Evidence LAPTM5 KO mice with motif mutagenesis; TNF treatment with proteasome/lysosome inhibitors and SLAP siRNA; subcellular localization of Golgi-targeting ζ mutants

    PMID:18619870 PMID:22798681 PMID:24638062

    Open questions at the time
    • Ubiquitin ligase acting on ζ in the proteasomal pathway not identified
    • Relative contribution of each pathway in primary T cells in vivo not quantified
  12. 2008 High

    Discovery that ζ is expressed in neurons and negatively regulates dendritic arborization via its ITAMs expanded ζ function beyond the immune system into neural circuit development.

    Evidence siRNA knockdown and ITAM-mutant overexpression in hippocampal neurons; KO mouse RGC dendritic motility and electrophysiology

    PMID:18367546 PMID:20188655

    Open questions at the time
    • Upstream ligand or receptor complex engaging ζ in neurons unknown
    • Signaling intermediates downstream of ζ ITAMs in neurons not defined
  13. 2011 High

    Identifying a basic-rich stretch in the ζ cytoplasmic domain that binds phosphoinositides and is required for stable synapse accumulation provided a phospholipid-dependent mechanism for ζ spatial regulation independent of ITAM phosphorylation.

    Evidence In vitro phosphoinositide-binding assay; BRS mutagenesis; live imaging of synapse formation

    PMID:21543646

    Open questions at the time
    • Which phosphoinositide species is physiologically relevant at the synapse not determined
    • How BRS and ITAM functions are coordinated not resolved
  14. 2023 High

    Demonstrating that ζ ITAMs exert an inhibitory function—suppressing signaling to low-affinity ligands and enabling antagonism—overturned the view of ζ as a purely activating module and established it as a molecular discriminator enforcing ligand quality.

    Evidence Conditional 6F-ITAM ζ switch mouse; cytokine assays; APL antagonism; kinetic proofreading computational model

    PMID:37945821

    Open questions at the time
    • Molecular mechanism by which unphosphorylated ITAMs suppress signaling not structurally resolved
    • Whether this inhibitory function operates equivalently in NK receptors unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the inhibitory ITAM function of ζ is structurally implemented, which phosphoinositide species and binding partners govern ζ synapse retention in vivo, and the identity of the upstream receptor engaging ζ ITAMs in neurons remain unresolved.
  • Structural basis of inhibitory ITAM conformation not determined
  • Neuronal receptor complex for ζ not identified
  • In vivo quantification of relative contributions of LAPTM5 vs. SLAP/c-Cbl vs. proteasomal ζ degradation lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 4 GO:0005768 endosome 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-168256 Immune System 7 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 2
Partners
BTLACD45LAPTM5LCKSAPSLAPTREM2ZAP70
Complex memberships
CD16/FcγRIII complexTCR/CD3 complex

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 CD3ζ homodimer specifically co-associates with CD16 (FcγRIII) on human NK cells, and co-transfection of CD3ζ cDNA permits surface expression of a transmembrane-linked CD16 complex on COS-7 cells, establishing CD3ζ as a common signal-transducing adapter for receptors of diverse cell types. Co-immunoprecipitation from NK cell lysates; co-transfection in COS-7 cells Nature High 2532305
1988 CD3ζη heterodimers differentially couple the TCR to phosphoinositide hydrolysis; T cell variants with reduced CD3ζη but normal CD3ζ2 show impaired phosphatidylinositol hydrolysis and serine kinase activation upon stimulation, while tyrosine kinase activation is unaffected, indicating functionally distinct roles for the two zeta-family dimers. Biochemical fractionation; functional stimulation assays comparing parental and variant cell lines Science High 2845582
1990 CD3η and CD3ζ are produced by alternative splicing from a single common gene; the CD3η chain has an identical N-terminal sequence through amino acid 122 but diverges at the C-terminus, lacking one tyrosine phosphorylation site and a putative nucleotide-binding site present in CD3ζ. cDNA cloning; protein microsequencing; genomic analysis Proceedings of the National Academy of Sciences High 2139725 2150596
1993 CD3ζ/η gene products are required for efficient surface TCR expression and the generation/survival of CD4+CD8+ thymocytes; CD3ζ/η-deficient mice show near-absence of mature single-positive thymocytes, establishing an essential role in intrathymic T cell differentiation. Gut intraepithelial lymphocytes can express TCR with FcεRIγ homodimers replacing CD3ζ. Gene targeting in embryonic stem cells; flow cytometry; thymus/lymph node analysis of knockout mice The EMBO Journal High 8223444 8223445
1993 CD3ζ-specific knockout mice (retaining CD3η) show greatly reduced thymocyte and peripheral T cell numbers and 5-fold lower TCR surface expression, with impaired proliferative responses, demonstrating that CD3ζ specifically is critical for T cell development and signal transduction in vivo. Gene targeting; flow cytometry; T cell proliferation assay The EMBO Journal High 8223445
1992 The CD3ζ cytoplasmic domain alone (fused to CD8α extracellular/transmembrane domains) is necessary and sufficient to couple CD2 stimulation to intracellular calcium rise, protein tyrosine kinase activation, and IL-2 secretion in Jurkat cells lacking other TCR subunits. Chimeric receptor transfection in CD3-negative Jurkat cells; calcium flux; kinase assay; ELISA The Journal of Experimental Medicine High 1351920
1994 CD45 protein-tyrosine phosphatase specifically binds to and preferentially dephosphorylates tyrosine-phosphorylated CD3ζ chain; the catalytically inactive CD45 C828S mutant trapped phosphorylated CD3ζ, and neither LAR nor CD45-LAR hybrid PTPases bound CD3ζ, establishing CD3ζ as a specific high-affinity substrate of CD45. GST fusion protein pulldown with enzymatically inactive CD45 mutant; in vitro dephosphorylation assay; substrate specificity comparison Proceedings of the National Academy of Sciences High 7526385
1994 The CD3η subunit is not required for thymic selection or T cell function; CD3η-deficient mice show no difference in thymocyte cellularity, subset composition, alloproliferative responses, or CTL generation compared to wild type, in contrast to the essential role of CD3ζ. Gene targeting; crossing with anti-HY TCR transgenic mice; CTL assay; proliferation assay The EMBO Journal High 8112294
1994 CD3ζ/η deficiency leads to absence of the HSA+CD44−CD25− double-negative thymocyte subset and prevents normal proliferative expansion of DN thymocytes, indicating a specific role of CD3ζ in controlling DN thymocyte proliferation during T cell development. Flow cytometry of DN thymocyte subsets; cell cycle analysis in CD3ζ−/− mice European Journal of Immunology Medium 7520000
1994 Differences in the cytoplasmic domain of CD3ζ and CD3η modulate two distinct types of TCR signals: common ITAM-dependent signals (shared with CD3γδε) and CD3ζ-specific ITAM-dependent signals; the unique C-terminal region of CD3η exerts an inhibitory function on phosphorylation, Ca2+ responses, and IL-2 production. Transfection of ITAM mutant and η-chain constructs; Ca2+ flux; IL-2 ELISA; tyrosine phosphorylation assays International Immunology Medium 7865460
1995 CD3ζ undergoes rapid turnover independently of the rest of the TCR-CD3 complex in normal T cells; newly synthesized ζ exchanges with ζ already in the surface TCR complex, suggesting a dynamic ζ metabolism where the TCR complex may be transported to the surface along the ζ turnover pathway. Metabolic pulse-chase labeling; surface immunoprecipitation Immunity Medium 7796297
1996 A mutation (Y→stop) in the TCRβ transmembrane ITAM-like motif causes loose association of CD3ζ and defective TCR assembly, but high-expressing mutant cells still activate normally (CD25/CD69, IL-2); however, mutant cells are resistant to activation-induced apoptosis and fail to express CD95L, implicating CD3ζ association via TCRβ TM domain specifically in the apoptotic signaling pathway. Site-directed mutagenesis; transfection; flow cytometry; AICD assay The Journal of Biological Chemistry Medium 8940006
1997 Antigenic stimulation causes antigen dose-dependent degradation of internalized TCR-CD3ζ complexes in the lysosomal compartment; inhibitors of lysosomal function (bafilomycin A1, folimycin) block ζ degradation and cause accumulation of ζ in large Lamp1+ vesicles. FACS on fixed/permeabilized T-APC conjugates; Western blot; lysosomal inhibitor treatment The Journal of Experimental Medicine High 9151711
1997 Functional analysis of CD3ζ ITAM YxxL segments shows that the N-terminal YxxL segment is required for all downstream signals (Ca2+, PLCγ1, lck association, ZAP-70 binding), while the C-terminal YxxL segment is specifically required for IL-2 production and stable ZAP-70 binding but not for upstream tyrosine phosphorylation or Ca2+ flux, demonstrating that the two YxxL segments within a single ITAM are functionally distinct. ITAM tyrosine/leucine mutagenesis in chimeric receptors; IL-2 ELISA; ZAP-70 co-IP; Ca2+ flux; lck association assay European Journal of Immunology High 9295038
1997 Reduction of TCR signaling by CD3ζ deficiency shifts thymic selection from negative to positive selection of autoreactive HY-specific T cells; positively selected CD3ζ-deficient autoreactive T cells are anergic, demonstrating that the quantity of CD3ζ-mediated TCR signal directly regulates the threshold for positive versus negative thymic selection. CD3ζ KO crossed with HY TCR transgenic mice; flow cytometry; antigen stimulation assays Journal of Immunology High 9029099
1999 CD3ζ ITAMs are required for full agonist but not antagonist TCR responses; T cells expressing CD3ζ mutants lacking all phosphorylatable tyrosines show 5-fold reduced IL-2 and 30-fold reduced sensitivity to agonist, but are still strongly antagonized by altered peptide ligands, demonstrating that differential CD3ζ phosphorylation is not a prerequisite for T cell antagonism. ITAM tyrosine mutagenesis; IL-2 ELISA; antagonism assay with APL Journal of Immunology High 10395646
1999 Eliminating all CD3ζ ITAMs does not abolish the spectrum of activation events and effector functions in mature CD8+ T cells bearing a P14 TCR; CD3γδε ITAMs are sufficient for qualitatively normal TCR signaling, with CD3ζ ITAMs contributing only quantitative enhancement at suboptimal peptide concentrations. Genetic substitution of ITAM-mutant CD3ζ in P14 TCR transgenic mice; functional assays Immunity High 10229184
2000 CD4 and CD3ζ initially co-cluster at the T cell-APC interface upon TCR engagement (coincident with Ca2+ rise); subsequently, CD3ζ stabilizes at the center of the immunological synapse (cSMAC) through signaling-, costimulation-, and cytoskeleton-dependent processes, while CD4 moves to the periphery. GFP-tagged chimera live 3D video microscopy; calcium imaging Science High 10958781
2000 SOCS-1 inhibits CD3ζ/Syk-mediated NF-AT activation by directly interacting with Syk and the ITAMs in CD8/ζ chimeric receptors in 293T cells reconstituted for TCR signaling. Co-expression in 293T cells; NF-AT reporter assay; co-immunoprecipitation FEBS Letters Medium 10788618
2002 TCR activation induces human T cells to release exosomes (50–100 nm) bearing the TCR/CD3/ζ complex including phosphorylated ζ chain, originating from endocytic compartments (CD63+); CD28 and CD45 are excluded from exosomes despite high plasma membrane expression, indicating selective sorting of activated TCR complexes. Ultracentrifugation; electron microscopy; Western blot; FACS of microvesicles Journal of Immunology High 11907077
2002 During negative selection, CD3ζ-GFP is recruited to the thymocyte:stromal cell immunological synapse but fails to accumulate at the center (as in mature T cells), instead concentrating at the periphery across a wide range of ligand densities, implicating differences in synapse geometry in initiation of apoptotic signals. Reaggregate thymus organ culture; GFP live imaging Immunity High 11970882
2002 The CD3ζ transmembrane domain forms an alpha-helical bundle with an average tilt of ~12° in lipid bilayers; the N-terminal side is more tilted and structural results are consistent with a tetrameric (left-handed) oligomeric organization rather than a simple dimer. Multiple site-specific infrared dichroism with 13C=18O isotope labeling; molecular dynamics simulations Journal of Molecular Biology Medium 11851344 11851345
2002 L-arginine availability regulates CD3ζ expression post-transcriptionally: L-arginine depletion decreases CD3ζ mRNA half-life (not transcription rate) through a cycloheximide-sensitive mechanism, leading to decreased CD3ζ protein and impaired T cell proliferation. mRNA stability assay; cycloheximide chase; Western blot; flow cytometry The Journal of Biological Chemistry High 11950832
2003 Macrophages stimulated with IL-4+IL-13 upregulate arginase I (not iNOS or arginase II), depleting extracellular L-arginine and causing decreased CD3ζ expression and diminished T cell proliferation; competitive arginase inhibitors or excess L-arginine restore CD3ζ expression. Co-culture assay; arginase inhibition; flow cytometry; proliferation assay Journal of Immunology High 12874210
2005 Increased caspase-3 expression and activity in SLE T cells cleaves CD3ζ, reducing its expression and association with lipid rafts; caspase-3 inhibition restores CD3ζ protein levels, lipid raft association, and normalizes TCR-induced calcium responses and FcRγ expression in SLE T cells. Caspase-3 inhibitor treatment; Western blot; lipid raft fractionation; calcium flux; flow cytometry Journal of Immunology High 16116236
2006 Complete homozygous CD3ζ deficiency in a human patient causes T−B+NK+ SCID by preventing TCR assembly and surface expression; mutant CD3ζ protein was unstable and rapidly degraded, and retroviral transduction of mutant cDNA failed to rescue TCR assembly in CD3ζ-deficient mouse hybridoma cells. Patient genetics; Western blot; flow cytometry; retroviral complementation in CD3ζ-deficient MA5.8 cells; metabolic labeling Blood High 17170122
2007 B and T lymphocyte attenuator (BTLA) co-clusters with CD3ζ at the immunological synapse and interacts with phosphorylated TCRζ within lipid rafts; BTLA co-ligation significantly decreases accumulation of phosphorylated TCRζ in lipid rafts, inhibiting T cell signaling. Two-photon microscopy; co-immunoprecipitation; lipid raft fractionation Immunology and Cell Biology Medium 17607320
2008 PP2A dephosphorylates Elf-1 at Thr-231 in SLE T cells, preventing the 98 kDa active form from binding the CD3ζ promoter, thereby decreasing CD3ζ transcription; PP2A knockdown restores CD3ζ expression and corrects aberrant early signaling. siRNA knockdown; Western blot; chromatin immunoprecipitation; phospho-specific antibodies; reporter assay Journal of Immunology High 18714041
2008 The LAPTM5 lysosomal protein specifically interacts with CD3ζ (not CD3ε, δ, or γ) and promotes its lysosomal degradation via its polyproline-tyrosine motifs and ubiquitin-interacting motif; LAPTM5 deficiency elevates TCR surface expression and enhances T cell responses. Co-immunoprecipitation; LAPTM5 knockout mice; flow cytometry; Western blot; mutagenesis of LAPTM5 motifs Immunity High 18619870
2008 TCR engagement induces a conformational change transmitted to CD3ζ cytoplasmic tail, causing it to adopt a compact, protease-resistant structure; both CD3ε and CD3ζ cytoplasmic tails become fully protected from protease digestion upon TCR triggering. Protease-sensitivity assay on intact cells before and after TCR triggering PloS One Medium 18320063
2008 CD3ζ is expressed in neurons and functions as a negative regulator of dendrite development; siRNA knockdown of CD3ζ or overexpression of an ITAM tyrosine-mutant loss-of-function CD3ζ increases dendritic arborization, while antibody-mediated activation of endogenous CD3ζ reduces dendritic arbor size through ITAM-based mechanisms. siRNA knockdown; overexpression of mutant CD3ζ; immunofluorescence; live imaging in hippocampal neurons Molecular Biology of the Cell High 18367546
2010 CD3ζ is expressed in retinal ganglion cells (RGCs) and is required for normal RGC dendritic motility, dendritic density regulation, glutamate-receptor-mediated synaptic activity, and eye-specific segregation of RGC axon projections to the CNS. CD3ζ-deficient mice; in vivo imaging of dendritic motility; electrophysiology; anatomical tracing Neuron High 20188655
2010 Tyrosine-phosphorylated CD3ζ accumulates on endosomal vesicles distinct from lysosomes following TCR activation, demonstrated by genetically encoded live-cell reporters; this intracellular phospho-ζ pool may sustain TCR signaling after receptor internalization. Genetically encoded phosphorylation reporters; live-cell imaging; fluorescence co-localization Proceedings of the National Academy of Sciences High 21135224
2010 CARs containing the CD3ζ transmembrane domain incorporate into the endogenous TCR/CD3 complex through receptor dimerization; abrogating dimerization or the interaction with the endogenous TCR via TM domain mutations reduces CAR functional capacity, indicating that endogenous complex incorporation is required for optimal antigen responsiveness. TM domain mutagenesis; co-immunoprecipitation; functional cytokine assay in Jurkat cells Journal of Immunology High 20483753
2010 NKG2D signaling in human T and NK cells activates Fas ligand/Fas-mediated caspase-3/-7 activation, resulting in CD3ζ degradation and impairment of multiple CD3ζ-dependent receptors (TCR, FcγRIII, NKp30, NKp46); this mechanism links chronic NKG2D stimulation to CD3ζ deficiency in cancer and autoimmune disease. NKG2D stimulation; caspase activation assays; Western blot for CD3ζ degradation; functional receptor assays; tumor-infiltrating lymphocyte analysis Journal of Immunology High 20926796
2011 The CD3ζ cytoplasmic domain contains a basic-rich stretch (BRS) that binds phosphoinositides (PtdIns(3)P, PtdIns(4)P, PtdIns(5)P, PtdIns(3,5)P2, PtdIns(3,4,5)P3) with high affinity; loss of this phosphoinositide-binding function impairs stable accumulation of CD3ζ at the immunological synapse during T cell-APC interactions without affecting early TCR signaling. Phosphoinositide-binding assay; mutagenesis of BRS residues; live-cell imaging of immunological synapse formation; T cell functional assays Journal of Immunology High 21543646
2012 TNF selectively downregulates CD3ζ expression in human T lymphocytes through a Src-like adaptor protein (SLAP)-dependent proteasomal degradation pathway (not lysosomal); TNF enhances SLAP expression and SLAP-CD3ζ colocalization, and SLAP siRNA knockdown prevents TNF-induced CD3ζ downregulation. TNF treatment; proteasome/lysosome inhibitors; siRNA; co-localization by confocal; Western blot; IL-2 ELISA Journal of Immunology High 22798681
2012 SAP (SLAM-associated protein) directly associates with the first membrane-proximal ITAM of CD3ζ; SAP knockdown decreases ERK, Akt, and PLCγ1 activation and reduces IL-2 and IL-4 mRNA induction downstream of TCR-CD3 signaling. Co-immunoprecipitation; shRNA knockdown; signaling pathway analysis by Western blot; cytokine qPCR PloS One Medium 22912825
2013 CD3ζ deficiency in mice enables spontaneous multi-organ tissue inflammation; CD3ζ-deficient T cells display increased CD44, CCR2 adhesion molecules and produce elevated IFN-γ, and infiltrate tissues, demonstrating that CD3ζ deficiency per se confers a pro-inflammatory, tissue-infiltrating T cell phenotype. CD3ζ KO mice; polyI:C and GvH challenge; flow cytometry; IFN-γ blockade rescue Journal of Immunology Medium 23980209
2013 CD247 (CD3ζ) deficiency in Dahl salt-sensitive rats blunts CD3+ T cell infiltration into the kidney after high-salt diet, reduces mean arterial blood pressure, and attenuates proteinuria and kidney damage, demonstrating that functional T cells expressing CD3ζ are required for full development of salt-sensitive hypertension. Zinc-finger nuclease knockout rat; Western blot; flow cytometry; blood pressure telemetry; urinary albumin measurement Hypertension High 24343121
2013 Quantitative phosphoproteomics reveals that LAT (linker for activation of T cells) provides negative feedback to upstream signaling: absence of LAT results in augmented and persistent CD3ζ and ZAP70 tyrosine phosphorylation despite repressed ERK and PLCγ1 phosphorylation, positioning LAT as a modulator of CD3ζ phosphorylation dynamics. MS-based quantitative phosphoproteomics in LAT-sufficient vs LAT-deficient Jurkat cells PloS One Medium 24204825
2014 LAPTM5 promotes lysosomal degradation of intracellular CD3ζ (likely at the Golgi) independently of TCR signaling; a Golgi-localizing CD3ζ mutant is degraded by LAPTM5, while cell surface CD3ζ in mature TCR complexes is not targeted; LAPTM5 and SLAP/c-Cbl operate in distinct degradation pathways. Subcellular localization analysis; Golgi-targeting mutants; ITAM tyrosine-phenylalanine mutants; co-expression studies; Western blot Immunology and Cell Biology High 24638062
2014 Ly108 (SLAM family receptor) dampens CD3ζ phosphorylation through two modes of Ly108-CD3ζ interaction: constitutive colocalization-dependent inhibition (within ~100-200 nm on quiescent cells) and ligation-dependent interaction requiring the Ly108 transmembrane domain; replacement of the Ly108 TM domain abrogates ligation-dependent CD3ζ dephosphorylation and suppression of T cell-APC adhesion. Phospho-flow cytometry; super-resolution imaging; TM domain swap mutagenesis; T cell-APC conjugation assay Journal of Immunology High 25217164
2021 TREM-2 interacts with the CD3ζ-ZAP70 complex (rather than DAP12) in CD4+ T cells following Mycobacterium tuberculosis infection, activating STAT1/STAT4 and T-bet transcription to promote Th1 responses; this was confirmed by co-immunoprecipitation and CD4+ T cell-specific TREM-2 conditional KO mice. Co-immunoprecipitation; T cell-specific conditional KO mice; Rag2−/− reconstitution; STAT1/4 phosphorylation assay The Journal of Clinical Investigation High 34623322
2022 Specific residues in the mouse CD3ζ transmembrane domain prevent efficient complex formation with mouse CD16, dampening ADCC; mutating these mouse TM residues to their human counterparts rescues CD16 receptor function, demonstrating that the CD3ζ TM domain structure determines species-specific differences in CD16 signaling in NK cells. Systematic mutagenesis of TM domain; functional NK cell assays; co-immunoprecipitation The Journal of Experimental Medicine High 35320345
2023 CD3ζ ITAMs exert an unexpected inhibitory function in TCR signaling: T cells with inactivated (6F) CD3ζ ITAMs show enhanced signaling and cytokine responses to low-affinity ligands and are refractory to antagonism by altered peptide ligands, revealing that CD3ζ ITAMs enable ligand discrimination by suppressing responses to low-affinity peptides. Conditional ITAM 6F-CD3ζ 'switch' mouse model; cytokine assays; APL antagonism assay; in silico kinetic proofreading model Nature Immunology High 37945821
2024 CD28 costimulation in CAR-NK cells enhances antitumor efficacy by linking CD3ζ to LCK and ZAP70, creating a signaling platform that initiates a kinase cascade enhancing CAR-NK cell function; CD28 is not normally present in mature NK cells, but its incorporation with CD3ζ recruits LCK/ZAP70. CAR-NK cell engineering; kinase recruitment assays; xenograft tumor models; in vitro cytotoxicity Cancer Discovery Medium 38900051

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex. Journal of immunology (Baltimore, Md. : 1950) 543 11907077
1989 Co-association of CD3 zeta with a receptor (CD16) for IgG Fc on human natural killer cells. Nature 426 2532305
2003 L-arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 387 12874210
2002 Regulation of T cell receptor CD3zeta chain expression by L-arginine. The Journal of biological chemistry 387 11950832
2010 Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nature genetics 309 20383147
2000 Differential clustering of CD4 and CD3zeta during T cell recognition. Science (New York, N.Y.) 294 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) 250 25520398
1997 Degradation of T cell receptor (TCR)-CD3-zeta complexes after antigenic stimulation. The Journal of experimental medicine 250 9151711
1993 T cell development in mice lacking the CD3-zeta/eta gene. The EMBO journal 226 8223444
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) 208 20483753
2005 L-Arginine modulates CD3zeta expression and T cell function in activated human T lymphocytes. Cellular immunology 179 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
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
2002 Imaging synapse formation during thymocyte selection: inability of CD3zeta to form a stable central accumulation during negative selection. Immunity 109 11970882
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
2004 Site-specific vibrational dynamics of the CD3zeta membrane peptide using heterodyned two-dimensional infrared photon echo spectroscopy. The Journal of chemical physics 97 15268045
1999 Crippling of CD3-zeta ITAMs does not impair T cell receptor signaling. Immunity 85 10229184
2006 Inherited and somatic CD3zeta mutations in a patient with T-cell deficiency. The New England journal of medicine 83 16672702
1992 The CD3 zeta cytoplasmic domain mediates CD2-induced T cell activation. The Journal of experimental medicine 74 1351920
1995 Rapid turnover of the CD3 zeta chain independent of the TCR-CD3 complex in normal T cells. Immunity 70 7796297
2011 The CD3 zeta subunit contains a phosphoinositide-binding motif that is required for the stable accumulation of TCR-CD3 complex at the immunological synapse. Journal of immunology (Baltimore, Md. : 1950) 68 21543646
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
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