Details for: CD3E

Gene ID: 916

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: CD3E

Ensembl ID: ENSG00000198851

Description: CD3 epsilon subunit of T-cell receptor complex

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • CD4-positive helper T cell CL0000492
    CSI 96.51
    rCSI 73%
    PRS 99.42
  • naive thymus-derived CD8-positive, alpha-beta T cell CL0000900
    CSI 93.1
    rCSI 65.39%
    PRS 98.73
  • central memory CD8-positive, alpha-beta T cell CL0000907
    CSI 91.54
    rCSI 61.67%
    PRS 99.36
  • mucosal invariant T cell CL0000940
    CSI 81.95
    rCSI 66.21%
    PRS 98.26
  • double-positive, alpha-beta thymocyte CL0000809
    CSI 76.82
    rCSI 78.3%
    PRS 98.29
  • central memory CD4-positive, alpha-beta T cell CL0000904
    CSI 75.52
    rCSI 44.6%
    PRS 99.65
  • CD8-positive, alpha-beta memory T cell CL0000909
    CSI 70.76
    rCSI 73.9%
    PRS 98.45
  • CD4-positive, alpha-beta memory T cell CL0000897
    CSI 68.21
    rCSI 48.97%
    PRS 99.19
  • T follicular helper cell CL0002038
    CSI 60.14
    rCSI 45.01%
    PRS 98.94
  • T-helper 17 cell CL0000899
    CSI 58.08
    rCSI 46.12%
    PRS 99.41
  • gamma-delta T cell CL0000798
    CSI 54.45
    rCSI 63.96%
    PRS 97.47
  • CD16-positive, CD56-dim natural killer cell, human CL0000939
    CSI 53.6
    rCSI 35.72%
    PRS 98.07
  • effector CD8-positive, alpha-beta T cell CL0001050
    CSI 52.57
    rCSI 39.98%
    PRS 99.25
  • naive T cell CL0000898
    CSI 52.02
    rCSI 36.2%
    PRS 99.42
  • naive thymus-derived CD4-positive, alpha-beta T cell CL0000895
    CSI 50.72
    rCSI 63.74%
    PRS 98.63
  • activated type II NK T cell CL0000931
    CSI 48.1
    rCSI 54.14%
    PRS 98.77
  • effector memory CD8-positive, alpha-beta T cell CL0000913
    CSI 47.73
    rCSI 43.47%
    PRS 99.15
  • activated CD8-positive, alpha-beta T cell CL0000906
    CSI 45.18
    rCSI 44.41%
    PRS 98.21
  • effector memory CD4-positive, alpha-beta T cell CL0000905
    CSI 45.13
    rCSI 61.47%
    PRS 99.33
  • CD16-negative, CD56-bright natural killer cell, human CL0000938
    CSI 44.52
    rCSI 33.38%
    PRS 98.85
  • CD4-positive, CD25-positive, alpha-beta regulatory T cell CL0000792
    CSI 44.32
    rCSI 43.53%
    PRS 99.23
  • double negative thymocyte CL0002489
    CSI 43.56
    rCSI 30.28%
    PRS 99.15
  • activated CD8-positive, alpha-beta T cell, human CL0001049
    CSI 43.51
    rCSI 74.43%
    PRS 98.36
  • mature T cell CL0002419
    CSI 43.4
    rCSI 33.76%
    PRS 98.99
  • CD4-positive, alpha-beta cytotoxic T cell CL0000934
    CSI 40.03
    rCSI 55%
    PRS 99.22
  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 40.01
    rCSI 48.49%
    PRS 80.82
  • activated CD4-positive, alpha-beta T cell CL0000896
    CSI 39.89
    rCSI 36.87%
    PRS 99.15
  • CD8-positive, CD28-negative, alpha-beta regulatory T cell CL0000920
    CSI 36.64
    rCSI 73.05%
    PRS 98.55
  • CD4-positive, alpha-beta thymocyte CL0000810
    CSI 35.96
    rCSI 28.8%
    PRS 96.02
  • alpha-beta T cell CL0000789
    CSI 35.44
    rCSI 41.52%
    PRS 99.01
  • T-helper 1 cell CL0000545
    CSI 35.25
    rCSI 63.64%
    PRS 99.04
  • group 3 innate lymphoid cell CL0001071
    CSI 34.05
    rCSI 25.58%
    PRS 97.48
  • mature NK T cell CL0000814
    CSI 32.73
    rCSI 41.86%
    PRS 97.38
  • CD4-positive, alpha-beta T cell CL0000624
    CSI 32.3
    rCSI 41.33%
    PRS 95.57
  • mononuclear phagocyte CL0000113
    CSI 28.47
    rCSI 62.67%
    PRS 97.53
  • CD8-positive, alpha-beta cytotoxic T cell CL0000794
    CSI 28.09
    rCSI 33.53%
    PRS 98.88
  • regulatory T cell CL0000815
    CSI 27.98
    rCSI 32.43%
    PRS 90.16
  • erythrocyte CL0000232
    CSI 27.21
    rCSI 61.74%
    PRS 94.5
  • plasmacytoid dendritic cell, human CL0001058
    CSI 26.06
    rCSI 18.2%
    PRS 97.63
  • T cell CL0000084
    CSI 24.75
    rCSI 48.39%
    PRS 97.79
  • early lymphoid progenitor CL0000936
    CSI 22.63
    rCSI 19.88%
    PRS 97.76
  • CD8-positive, alpha-beta thymocyte CL0000811
    CSI 21.79
    rCSI 33.97%
    PRS 97.66
  • intraepithelial lymphocyte CL0002496
    CSI 20.9
    rCSI 56.89%
    PRS 98.75
  • natural T-regulatory cell CL0000903
    CSI 20.41
    rCSI 38.65%
    PRS 99.19
  • memory T cell CL0000813
    CSI 20.17
    rCSI 38.86%
    PRS 98.97
  • platelet CL0000233
    CSI 19.44
    rCSI 80.66%
    PRS 92.69
  • plasmablast CL0000980
    CSI 16.85
    rCSI 13.26%
    PRS 96.68
  • innate lymphoid cell CL0001065
    CSI 15.55
    rCSI 32.1%
    PRS 90.68
  • helper T cell CL0000912
    CSI 15.29
    rCSI 21.62%
    PRS 91.47
  • effector memory CD8-positive, alpha-beta T cell, terminally differentiated CL0001062
    CSI 14.49
    rCSI 72.7%
    PRS 98.87
  • effector CD4-positive, alpha-beta T cell CL0001044
    CSI 14.13
    rCSI 40.51%
    PRS 99.45
  • common dendritic progenitor CL0001029
    CSI 12.87
    rCSI 16.15%
    PRS 98.17
  • activated CD4-positive, alpha-beta T cell, human CL0001043
    CSI 11.54
    rCSI 27.75%
    PRS 98.87
  • group 2 innate lymphoid cell CL0001069
    CSI 11.47
    rCSI 62.03%
    PRS 98.94
  • lung resident memory CD8-positive, alpha-beta T cell CL4033039
    CSI 10.44
    rCSI 27.01%
    PRS 98.77
  • CD8-alpha-alpha-positive, alpha-beta intraepithelial T cell CL0000915
    CSI 10.19
    rCSI 46.32%
    PRS 99.11
  • granulocyte CL0000094
    CSI 9.95
    rCSI 15.2%
    PRS 98.03
  • monocyte CL0000576
    CSI 9.12
    rCSI 16.48%
    PRS 96.77
  • mature alpha-beta T cell CL0000791
    CSI 8.9
    rCSI 32.22%
    PRS 99.54
  • thymocyte CL0000893
    CSI 8.6
    rCSI 30.56%
    PRS 99.18
  • CD34-positive, CD56-positive, CD117-positive common innate lymphoid precursor, human CL0001074
    CSI 5.87
    rCSI 68.14%
    PRS 98.56
  • dendritic cell, human CL0001056
    CSI 5.83
    rCSI 8.96%
    PRS 98.64
  • hepatic pit cell CL2000054
    CSI 4.59
    rCSI 62.96%
    PRS 97.11
  • megakaryocyte CL0000556
    CSI 4.26
    rCSI 18.5%
    PRS 95.72
  • double negative T regulatory cell CL0011024
    CSI 3.79
    rCSI 72.21%
    PRS 98.52
  • decidual natural killer cell, human CL0002343
    CSI 3.54
    rCSI 36.03%
    PRS 97.59
  • cytotoxic T cell CL0000910
    CSI 3.49
    rCSI 20.01%
    PRS 93.34
  • NKp44-negative group 3 innate lymphoid cell, human CL0001080
    CSI 1.94
    rCSI 60.36%
    PRS 98.76
  • lung resident memory CD4-positive, alpha-beta T cell CL4033038
    CSI 1.72
    rCSI 16.89%
    PRS 97.9
  • pro-T cell CL0000827
    CSI 1.14
    rCSI 26.61%
    PRS 99.43
  • immature alpha-beta T cell CL0000790
    CSI 0.45
    rCSI 6.51%
    PRS 98.85

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [CD3E](/details-gene/916), or the CD3 epsilon subunit, is a protein-coding gene located on chromosome 11q23.3. It encodes a critical component of the T-cell receptor (TCR) complex, which is fundamental for the activation and function of T lymphocytes. Functionally, [CD3E](/details-gene/916) acts as a signaling adaptor, participating in the assembly of the TCR complex and the transduction of signals following antigen recognition. Its expression is highly specific to the T-cell lineage, with high significance observed across nearly all T-cell subtypes, including helper, cytotoxic, memory, and developmental stages like thymocytes. Mutations in this gene are associated with severe combined immunodeficiency ([186830](https://omim.org/entry/186830)), highlighting its indispensable role in the adaptive immune system ([Link](https://doi.org/10.1038/ng0193-77)). ## Cellular Roles and Expression Landscape The expression profile of [CD3E](/details-gene/916) firmly establishes it as a pan-T-cell marker, essential throughout the lifecycle of T lymphocytes. **Overall**, the gene shows the highest significance in mature T-cell populations, including [CD4-positive helper T cell](/details-cell/CL0000492) (CSI: 96.51), various subsets of [CD8-positive, alpha-beta T cell](/details-cell/CL0000900) (CSI up to 93.10), and both [CD4-positive, alpha-beta memory T cell](/details-cell/CL0000897) and [CD8-positive, alpha-beta memory T cell](/details-cell/CL0000909). This indicates its sustained importance in both initiating and recalling adaptive immune responses. High significance is also observed in less conventional T-cell populations such as [mucosal invariant T cell](/details-cell/CL0000940) (CSI: 81.95) and [gamma-delta T cell](/details-cell/CL0000798) (CSI: 54.45), underscoring its conserved function across different TCR types. Furthermore, its expression in [double-positive, alpha-beta thymocyte](/details-cell/CL0000809) (CSI: 76.82) is consistent with its crucial role during T-cell development and selection processes in the thymus. A notable, albeit lower, significance in [CD16-positive, CD56-dim natural killer cell, human](/details-cell/CL0000939) (CSI: 53.60) suggests a potential role in a subset of NK cells, a finding that has been explored in the literature ([Link](https://pubmed.ncbi.nlm.nih.gov/1387664/)). The data collectively portrays [CD3E](/details-gene/916) not merely as a marker, but as a central functional component defining the identity and operational capacity of virtually all T cells. ## Pathways and Molecular Function The molecular function of [CD3E](/details-gene/916) is intrinsically linked to its role within the TCR complex. It is a key player in the [T cell receptor signaling pathway](/details-go/GO:0050852), a process initiated upon antigen presentation. According to Reactome pathway analysis, this involvement begins with the [Phosphorylation of cd3 and tcr zeta chains](/details-reactome/R-HSA-202427) and is critical for the [Translocation of zap-70 to immunological synapse](/details-reactome/R-HSA-202430), leading to [Downstream tcr signaling](/details-reactome/R-HSA-202424). This cascade ultimately results in [T cell activation](/details-go/GO:0042110) and the execution of effector functions. Gene Ontology annotations corroborate this, highlighting its role in processes such as [Alpha-beta t cell activation](/details-go/GO:0046631), [Positive thymic t cell selection](/details-go/GO:0045059), and [T cell costimulation](/details-go/GO:0031295). As a molecule with [Signaling receptor complex adaptor activity](/details-go/GO:0030159), [CD3E](/details-gene/916) facilitates the assembly of the functional TCR complex ([GO:0042101](/details-go/GO:0042101)) on the external side of the plasma membrane ([GO:0009897](/details-go/GO:0009897)) and binds other signaling proteins, including kinases ([GO:0019901](/details-go/GO:0019901)). This web of interactions positions [CD3E](/details-gene/916) as an essential transducer that converts an extracellular antigen recognition event into an intracellular biochemical response, forming the foundation of the [Adaptive immune system](/details-reactome/R-HSA-1280218). ## Research Directions Given the foundational role of [CD3E](/details-gene/916) in T-cell function, future research can explore its more nuanced roles in immune regulation and pathology. Its universal expression on T-cells makes it a prime candidate for therapeutic manipulation, but a deeper understanding of its regulatory mechanisms is needed. **Proposed Hypotheses:** 1. *Hypothesis on Signal Modulation:* The phosphorylation status of specific tyrosine or serine residues on the cytoplasmic tail of [CD3E](/details-gene/916) may act as a rheostat for TCR signaling, where different patterns of phosphorylation finely tune the threshold for T-cell activation versus anergy. This could explain how T-cells integrate signals from various co-stimulatory and co-inhibitory receptors, such as those involved in the [Pd-1 signaling](/details-reactome/R-HSA-389948) pathway. 2. *Hypothesis on Autoimmunity:* Allelic variants of [CD3E](/details-gene/916) that result in subtle changes in protein conformation or expression level, while not causing overt immunodeficiency, may contribute to the genetic risk for autoimmune diseases by altering the signaling dynamics during thymic selection or peripheral T-cell activation. **Experimental Approach:** To test the hypothesis on signal modulation, a powerful approach would be to use advanced phosphoproteomics. Specifically, one could isolate primary human [CD4-positive helper T cell](/details-cell/CL0000492) and stimulate them under different conditions: (i) TCR stimulation alone (anti-CD3/CD28 beads), (ii) TCR stimulation with co-inhibitory signals (e.g., adding PD-L1), and (iii) TCR stimulation with strong co-stimulation. The cytoplasmic domain of [CD3E](/details-gene/916) could then be immunoprecipitated and analyzed by mass spectrometry to create a quantitative map of its phosphorylation sites under each condition. Functional validation could be achieved by generating cell lines expressing [CD3E](/details-gene/916) variants with mutated phosphorylation sites (e.g., phosphomimetic or non-phosphorylatable mutations) and assessing downstream outcomes like ZAP-70 recruitment, calcium flux, and cytokine production ([Link](https://doi.org/10.1126/scisignal.2000007)). **Therapeutic Potential:** [CD3E](/details-gene/916) is already a well-established therapeutic target. Its constant and high-level expression on T-cells makes it an ideal anchor for therapies designed to redirect T-cell cytotoxicity. Bispecific T-cell engagers (BiTEs), such as blinatumomab, utilize an anti-CD3 arm to engage T-cells and direct them to kill tumor cells expressing a second target antigen (e.g., CD19). Therefore, the therapeutic strategy is not inhibition or activation of [CD3E](/details-gene/916) itself, but rather its *engagement* to leverage the T-cell's powerful cytotoxic machinery. Future applications could involve developing novel formats of T-cell engagers with improved safety profiles or targeting different tumor antigens, all while continuing to rely on [CD3E](/details-gene/916) as the universal handle for T-cell activation.

Genular Protein ID: 4230133941

Symbol: CD3E_HUMAN

Name: T-cell surface glycoprotein CD3 epsilon chain

UniProtKB Accession Codes:

P07766 A8K997

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 BMRB 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEMBL 1 ChiTaRS 1 ComplexPortal 4 DMDM 1 DNASU 1 DisGeNET 1 DisProt 1 DrugBank 10 DrugCentral 1 ELM 1 EMBL 12 EMDB 14 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 51 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 20 PDBsum 20 PIR 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 6 RefSeq 1 SIGNOR 1 SMART 2 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 3012357

Title: Isolation of cDNA clones encoding the 20K non-glycosylated polypeptide chain of the human T-cell receptor/T3 complex.

PubMed ID: 3012357

DOI: 10.1038/321431a0

PubMed ID: 3267235

Title: Human CD3-epsilon gene contains three miniexons and is transcribed from a non-TATA promoter.

PubMed ID: 3267235

DOI: 10.1073/pnas.85.21.8156

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 2470098

Title: The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex.

PubMed ID: 2470098

DOI: 10.1073/pnas.86.9.3277

PubMed ID: 1387664

Title: 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.

PubMed ID: 1387664

PubMed ID: 8490660

Title: Independent mutations of the human CD3-epsilon gene resulting in a T cell receptor/CD3 complex immunodeficiency.

PubMed ID: 8490660

DOI: 10.1038/ng0193-77

PubMed ID: 10384095

Title: The CD3 epsilon subunit of the TCR contains endocytosis signals.

PubMed ID: 10384095

PubMed ID: 12522270

Title: Profiling of tyrosine phosphorylation pathways in human cells using mass spectrometry.

PubMed ID: 12522270

DOI: 10.1073/pnas.2436191100

PubMed ID: 15144186

Title: Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry.

PubMed ID: 15144186

DOI: 10.1021/ac035352d

PubMed ID: 15546002

Title: Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3.

PubMed ID: 15546002

DOI: 10.1172/jci22588

PubMed ID: 15294938

Title: Relevance of CD6-mediated interactions in T cell activation and proliferation.

PubMed ID: 15294938

DOI: 10.4049/jimmunol.173.4.2262

PubMed ID: 15972658

Title: The CD3epsilon proline-rich sequence, and its interaction with Nck, is not required for T cell development and function.

PubMed ID: 15972658

DOI: 10.4049/jimmunol.175.1.270

PubMed ID: 15592455

Title: Immunoaffinity profiling of tyrosine phosphorylation in cancer cells.

PubMed ID: 15592455

DOI: 10.1038/nbt1046

PubMed ID: 19690332

Title: Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions.

PubMed ID: 19690332

DOI: 10.1126/scisignal.2000007

PubMed ID: 26507128

Title: CD3epsilon recruits Numb to promote TCR degradation.

PubMed ID: 26507128

DOI: 10.1093/intimm/dxv060

PubMed ID: 9698567

Title: Structural basis for Syk tyrosine kinase ubiquity in signal transduction pathways revealed by the crystal structure of its regulatory SH2 domains bound to a dually phosphorylated ITAM peptide.

PubMed ID: 9698567

DOI: 10.1006/jmbi.1998.1964

PubMed ID: 15136729

Title: Crystal structure of the human T cell receptor CD3 epsilon gamma heterodimer complexed to the therapeutic mAb OKT3.

PubMed ID: 15136729

DOI: 10.1073/pnas.0402295101

PubMed ID: 15534202

Title: Crystal structure of a human CD3-epsilon/delta dimer in complex with a UCHT1 single-chain antibody fragment.

PubMed ID: 15534202

DOI: 10.1073/pnas.0407359101

Sequence Information:

  • Length: 207
  • Mass: 23147
  • Checksum: A1603D01CE9957D7
  • Sequence:
    • MQSGTHWRVL GLCLLSVGVW GQDGNEEMGG ITQTPYKVSI SGTTVILTCP QYPGSEILWQ 
HNDKNIGGDE DDKNIGSDED HLSLKEFSEL EQSGYYVCYP RGSKPEDANF YLYLRARVCE 
NCMEMDVMSV ATIVIVDICI TGGLLLLVYY WSKNRKAKAK PVTRGAGAGG RQRGQNKERP 
PPVPNPDYEP IRKGQRDLYS GLNQRRI