CD3E

Summary

CD3E (CD3 epsilon subunit of T-cell receptor complex, HGNC:1674) is a protein-coding gene on chromosome 11q23.3, encoding T-cell surface glycoprotein CD3 epsilon chain (P07766). Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response.

The protein encoded by this gene is the CD3-epsilon polypeptide, which together with CD3-gamma, -delta and -zeta, and the T-cell receptor alpha/beta and gamma/delta heterodimers, forms the T-cell receptor-CD3 complex. This complex plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways. The genes encoding the epsilon, gamma and delta polypeptides are located in the same cluster on chromosome 11. The epsilon polypeptide plays an essential role in T-cell development. Defects in this gene cause immunodeficiency. This gene has also been linked to a susceptibility to type I diabetes in women.

Source: NCBI Gene 916 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 18 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 303 total — 14 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 37
• Druggable target: yes
• MANE Select transcript: NM_000733

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1674
Approved symbol	CD3E
Name	CD3 epsilon subunit of T-cell receptor complex
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	CD3epsilon, CD3-epsilon
Ensembl gene	ENSG00000198851
Ensembl biotype	protein_coding
OMIM	186830
Entrez	916

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 retained_intron, 3 protein_coding

ENST00000361763, ENST00000526146, ENST00000528435, ENST00000528600, ENST00000529713, ENST00000531913, ENST00000853938

RefSeq mRNA: 1 — MANE Select: NM_000733 NM_000733

CCDS: CCDS31685

Canonical transcript exons

ENST00000361763 — 9 exons

Exon	Start	End
ENSE00001434986	118312618	118312866
ENSE00002191012	118304730	118304776
ENSE00003458929	118313707	118313874
ENSE00003463111	118314448	118314494
ENSE00003483202	118315486	118316173
ENSE00003502284	118307288	118307308
ENSE00003556358	118312153	118312170
ENSE00003572243	118308427	118308441
ENSE00003583529	118304894	118305001

Expression profiles

Bgee: expression breadth ubiquitous, 168 present calls, max score 99.17.

FANTOM5 (CAGE): breadth broad, TPM avg 29.2060 / max 1888.5282, expressed in 260 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
116971	29.0772	260
116974	0.1288	58

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.17	gold quality
vermiform appendix	UBERON:0001154	94.27	gold quality
lymph node	UBERON:0000029	93.65	gold quality
spleen	UBERON:0002106	93.22	gold quality
blood	UBERON:0000178	92.60	gold quality
colonic epithelium	UBERON:0000397	91.89	gold quality
thymus	UBERON:0002370	90.58	gold quality
gall bladder	UBERON:0002110	89.44	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.50	gold quality
rectum	UBERON:0001052	87.38	gold quality
ileal mucosa	UBERON:0000331	86.99	gold quality
mucosa of transverse colon	UBERON:0004991	86.99	gold quality
bone marrow cell	CL:0002092	85.62	gold quality
caecum	UBERON:0001153	85.42	gold quality
small intestine	UBERON:0002108	85.20	gold quality
bone marrow	UBERON:0002371	81.41	gold quality
upper lobe of left lung	UBERON:0008952	81.35	gold quality
superficial temporal artery	UBERON:0001614	79.74	silver quality
right lung	UBERON:0002167	79.39	gold quality
right coronary artery	UBERON:0001625	79.12	gold quality
right uterine tube	UBERON:0001302	78.62	gold quality
body of stomach	UBERON:0001161	78.40	gold quality
upper lobe of lung	UBERON:0008948	77.94	gold quality
omental fat pad	UBERON:0010414	77.17	gold quality
transverse colon	UBERON:0001157	77.16	gold quality
peritoneum	UBERON:0002358	77.07	gold quality
jejunal mucosa	UBERON:0000399	75.89	gold quality
adipose tissue of abdominal region	UBERON:0007808	75.69	gold quality
left uterine tube	UBERON:0001303	75.38	gold quality
tonsil	UBERON:0002372	75.09	gold quality

Single-cell (SCXA)

Detected in 29 experiment(s), a significant marker in 25.

Experiment	Marker?	Max mean expression
E-HCAD-15	yes	1339.00
E-CURD-122	yes	1278.26
E-CURD-88	yes	1155.31
E-MTAB-10042	yes	1147.01
E-MTAB-8142	yes	1061.36
E-GEOD-149689	yes	951.42
E-HCAD-4	yes	786.03
E-MTAB-8410	yes	781.05
E-GEOD-139324	yes	688.70
E-HCAD-1	yes	666.17
E-ANND-5	yes	644.63
E-CURD-112	yes	486.73
E-MTAB-9221	yes	426.04
E-MTAB-6701	yes	119.56
E-MTAB-9467	yes	88.73

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, DNMT1, FOS, GATA3, HAND2, HES1, HNF1A, NFATC2, NFIL3, NFKB1, NFKB, PAX3, STAT5A

miRNA regulators (miRDB)

48 targeting CD3E, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-1207-5P	99.49	69.11	2983

Literature-anchored findings (GeneRIF, showing 36)

• Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. (PMID:12110186)
• CD3 epsilon undergoes a conformational change after dimerization with CD3 gamma or CD3 delta (PMID:12410792)
• T cell receptor can be recruited to a subset of plasma membrane rafts, independently of cell signaling and attendantly to raft clustering (PMID:12499387)
• crystal structure at 1.9-A resolution of a complex between a CD3-epsilon/delta ectodomain heterodimer and a single-chain fragment of the UCHT1 antibody (PMID:15534202)
• SCID is caused by a CD3E deficiency. (PMID:15546002)
• CD3 expression was strong in normal proximal and distal tubular epithelium and in renal oncocytomas, weak in chromophobe carcinoma, and negative in clear cell carcinomas, in papillary renal cell carcinoma, and in a transitional cell carcinoma. (PMID:16308105)
• A human CD3 transgene that encodes full length CD3delta and a truncated but functional form of CD3epsilon restored the defective preTCR function in not only CD3epsilon- but CD3gamma- and CD3gammadelta-deficient mice as well. (PMID:16412509)
• analysis of TCRalpha-CD3deltaepsilon and TCRbeta-CD3gammaepsilon dimers and the role of the membrane-proximal tetracysteine motif (PMID:17023417)
• The CD3 epsilon immune recognition receptor cytoplasmic domain binds to acidic and mixed phospholipid vesicles with a binding strength that correlates with the protein net charge and the presence of clustered basic amino acid residues. (PMID:17176095)
• CD3epsilon-mediated signal transduction pathway is essential for this transformation process (PMID:17507663)
• Notch-dependent cytoplasmic CD3 expression can only be achieved during the early phase of NK-cell differentiation. (PMID:17630354)
• In lung adenocarcinoma patients, significant decreases of MFI values for CD3epsilon, but not CD3zeta, were found in CD4+T and CD8+T cells from pleural effusion compared to peripheral blood and in peripheral blood of patients compared to healthy donors. (PMID:17668204)
• Data show that Nck forms a complex with an atypical PxxDY motif of the CD3epsilon tail, which encompasses Tyr166 within the activation motif and a T-cell receptor endocytosis signal. (PMID:18555270)
• Data show that anti-CD3 monoclonal antibody (MAb)-mediated chimpanzee T-cell activation is a function of the anti-CD3 MAb isotype and is not governed by Siglec expression. (PMID:18667496)
• Results suggest that generation of CD3varepsilon chain isoforms with different N-terminal sequence and pI is a general phenomenon. (PMID:19616027)
• Results revealed that the human CD3 epsilon subunit forms a homodimer structure, which provide insight into our understanding of the molecular assembly of the CD3 molecular complex. (PMID:19724882)
• analysis of the transgenic integration site in immunodeficient tgepsilon26 human CD3epsilon transgenic mice (PMID:21203507)
• Data show that the expression pattern of the four CD3 chains was epsilon>zeta>delta>gamma in peripheral blood mononuclear cells from MM, while a gamma>epsilon>zeta>delta expression pattern was found in healthy controls. (PMID:21669053)
• Study characterized the expression pattern of CD3-gamma, -delta, -epsilon and -zeta chain genes from placenta, which contributes to further understanding of the features of T-cell immune status in placenta. (PMID:21669059)
• Results show that levels of CD3epsilon, CD25, CD68, and ICAM-1 mRNA in BCC biopsies may predict risk for new basal cell carcinomas. (PMID:21980389)
• Altered expression of the TCR signaling related genes CD3 and FcepsilonRIgamma in patients with aplastic anemia. (PMID:22401598)
• Local changes in the lipid composition of TCR microclusters render the CD3epsilon cytoplasmic domain accessible during early stages of T cell activation. (PMID:23166358)
• ABCB1 homozygous 3435 TT carrier subjects showed the lowest Pgp activity compared with 3435 CT and CC carriers of renal transplant patients. (PMID:23216707)
• that Nck recruitment to the TCR is fundamental to mount an efficient T cell response in vivo, and that the Nck-CD3epsilon interaction may represent a target for pharmacological modulation of the immune response. (PMID:24470497)
• analysis of the molecular organization of the TCR-CD3 complex (PMID:25422432)
• The docking site for CD3 subunits on the T Cell receptor beta chain has been identified by solution NMR. (PMID:26109064)
• The inducible recruitment of WASp to the TCR-CD3 complex is partially dependent of tyrosine phosphorylation of Cd3e. (PMID:26342115)
• Data suggest that HIV-1 gp41 transmembrane domain (TMD) directly interacts with TMDs of the T-cell receptor and it’s CD3-antigen co-receptors (delta, gamma, and epsilon); these interactions appear to be involved in immune evasion mechanism of HIV-1. (PMID:26828096)
• increase. Our results indicate that the change in CD3zeta-chain expression from the baseline is an independent predictor of residual and recurrent head and neck squamous cell carcinoma. (PMID:26888626)
• the stalk domains of NKp30 and NKp46, another NCR employing CD3zeta for signaling, were not exchangeable without drastic deficiencies in folding, plasma membrane targeting, and/or ligand-induced receptor signaling. (PMID:27754869)
• A novel pathogenic frameshift variant of CD3E gene has been found in two unrelated T-B+ NK+ severe combined immunodeficiency infants from Turkey. (PMID:28597365)
• The ionic CD3-epsilon -Lck interaction controls the phosphorylation level of the T-cell receptor. (PMID:28659468)
• Actin polymerization promotes the recruitment of Nck to the TCR, enhancing downstream signaling, such as phosphorylation of CD3epsilon and lymphocyte activation. (PMID:31674657)
• Biallelic Form of a Known CD3E Mutation in a Patient with Severe Combined Immunodeficiency. (PMID:32016651)
• Multiple Signaling Roles of CD3epsilon and Its Application in CAR-T Cell Therapy. (PMID:32730808)
• Low transcriptomic of PTPRCv1 and CD3E is an independent predictor of mortality in HIV and tuberculosis co-infected patient. (PMID:35710869)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cd3e	ENSMUSG00000032093
rattus_norvegicus	Cd3e	ENSRNOG00000016069

Paralogs (2): CD3G (ENSG00000160654), CD3D (ENSG00000167286)

Protein

Protein identifiers

T-cell surface glycoprotein CD3 epsilon chain — P07766 (reviewed: P07766)

Alternative names: T-cell surface antigen T3/Leu-4 epsilon chain

All UniProt accessions (2): P07766, E9PSH8

UniProt curated annotations — full annotation on UniProt →

Function. Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response. When antigen presenting cells (APCs) activate T-cell receptor (TCR), TCR-mediated signals are transmitted across the cell membrane by the CD3 chains CD3D, CD3E, CD3G and CD247/CD3Z. All CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain. Upon TCR engagement, these motifs become phosphorylated by Src family protein tyrosine kinases LCK and FYN, resulting in the activation of downstream signaling pathways. CD3E ITAM phosphorylation creates docking sites for the protein kinase ZAP70 leading to ZAP70 phosphorylation and its conversion into a catalytically active enzyme. In addition of this role of signal transduction in T-cell activation, CD3E plays an essential role in correct T-cell development. Also participates in internalization and cell surface down-regulation of TCR-CD3 complexes via endocytosis sequences present in CD3E cytosolic region. In addition to its role as a TCR coreceptor, it serves as a receptor for ITPRIPL1. Ligand recognition inhibits T-cell activation by promoting interaction with NCK1, which prevents CD3E-ZAP70 interaction and blocks the ERK-NFkB signaling cascade and calcium influx.

Subunit / interactions. The TCR-CD3 complex is composed of a CD3D-CD3E and a CD3G-CD3E heterodimers that preferentially associate with TCRalpha and TCRbeta, respectively, to form TCRalpha-CD3E-CD3G and TCRbeta/CD3G-CD3E trimers. In turn, the hexamer interacts with CD247/CD3Z homodimer to form the TCR-CD3 complex. Alternatively, TCRalpha and TCRbeta can be replaced by TCRgamma and TCRdelta. Interacts with CD6. Interacts (via Proline-rich sequence) with NCK1; the interaction is ligand dependent but independent of tyrosine kinase activation. Interacts with NUMB; this interaction is important for TCR-CD3 internalization and subsequent degradation. Interacts (when tyrosine phosphorylated) with LAG3; disrupting the association between CD3E and LCK and preventing TCR activation.

Subcellular location. Cell membrane.

Post-translational modifications. Phosphorylated on Tyr residues after T-cell receptor triggering by LCK in association with CD4/CD8.

Disease relevance. Immunodeficiency 18 (IMD18) [MIM:615615] An autosomal recessive primary immunodeficiency characterized by onset in infancy or early childhood of recurrent infections. The severity is variable, encompassing both a mild immunodeficiency and severe combined immunodeficiency (SCID), resulting in early death without bone marrow transplantation in some patients. Immunologic work-up of the IMD18 SCID patients shows a T cell-negative, B cell-positive, natural killer (NK) cell-positive phenotype, whereas T-cell development is not impaired in the mild form of IMD18. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_000724* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003110	Phos_immunorcpt_sig_ITAM	Repeat
IPR003598	Ig_sub2	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015484	CD3_esu/gsu/dsu	Family
IPR036179	Ig-like_dom_sf	Homologous_superfamily

Pfam: PF02189, PF16681

UniProt features (29 total): strand 11, helix 5, region of interest 3, modified residue 2, topological domain 2, domain 2, signal peptide 1, chain 1, disulfide bond 1, transmembrane region 1

Structure

Experimental structures (PDB)

44 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5QU2	X-RAY DIFFRACTION	1.04
9T46	X-RAY DIFFRACTION	1.65
8VY4	X-RAY DIFFRACTION	1.7
8F0L	X-RAY DIFFRACTION	1.81
1XIW	X-RAY DIFFRACTION	1.9
1SY6	X-RAY DIFFRACTION	2.1
8ES8	ELECTRON MICROSCOPY	2.65
1A81	X-RAY DIFFRACTION	3
7FJE	ELECTRON MICROSCOPY	3
9CI8	ELECTRON MICROSCOPY	3.01
8ES7	ELECTRON MICROSCOPY	3.04
7PHR	ELECTRON MICROSCOPY	3.08
9JY1	ELECTRON MICROSCOPY	3.08
7FJF	ELECTRON MICROSCOPY	3.1
8TW6	ELECTRON MICROSCOPY	3.1
9IRU	ELECTRON MICROSCOPY	3.14
9IRS	ELECTRON MICROSCOPY	3.18
7FJD	ELECTRON MICROSCOPY	3.2
9JY2	ELECTRON MICROSCOPY	3.24
8ES9	ELECTRON MICROSCOPY	3.25
9CQ4	ELECTRON MICROSCOPY	3.27
9IPD	ELECTRON MICROSCOPY	3.29
9JY4	ELECTRON MICROSCOPY	3.29
8TW4	ELECTRON MICROSCOPY	3.3
9BBC	ELECTRON MICROSCOPY	3.3
9IPE	ELECTRON MICROSCOPY	3.31
9JXZ	ELECTRON MICROSCOPY	3.31
9JY3	ELECTRON MICROSCOPY	3.35
9CIA	ELECTRON MICROSCOPY	3.39
8JC0	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07766-F1	73.56	0.30

Antibody-complex structures (SAbDab): 9 — 1SY6, 1XIW, 8F0L, 8VY4, 9CIA, 9CQ4, 9JY0, 9JY1, 9JY2

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 188, 199

Disulfide bonds (1): 49–98

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-202424	Downstream TCR signaling
R-HSA-202427	Phosphorylation of CD3 and TCR zeta chains
R-HSA-202430	Translocation of ZAP-70 to Immunological synapse
R-HSA-202433	Generation of second messenger molecules
R-HSA-389948	Co-inhibition by PD-1
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-202403	TCR signaling
R-HSA-388841	Regulation of T cell activation by CD28 family

MSigDB gene sets: 446 (showing top): FERRANDO_TAL1_NEIGHBORS, GOBP_DENDRITE_DEVELOPMENT, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, MORF_FLT1, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_TOLERANCE_INDUCTION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, BIOCARTA_TCRA_PATHWAY, GOBP_THYMIC_T_CELL_SELECTION, MODULE_45, MODULE_64

GO Biological Process (39): positive regulation of cell-matrix adhesion (GO:0001954), adaptive immune response (GO:0002250), positive regulation of T cell anergy (GO:0002669), T cell anergy (GO:0002870), cell surface receptor signaling pathway (GO:0007166), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), signal complex assembly (GO:0007172), G protein-coupled receptor signaling pathway (GO:0007186), smoothened signaling pathway (GO:0007224), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), dendrite development (GO:0016358), calcium-mediated signaling (GO:0019722), cerebellum development (GO:0021549), T cell costimulation (GO:0031295), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-2 production (GO:0032743), positive regulation of interleukin-4 production (GO:0032753), positive regulation of cell-cell adhesion mediated by integrin (GO:0033634), CD4-positive, alpha-beta T cell proliferation (GO:0035739), positive regulation of T cell proliferation (GO:0042102), T cell activation (GO:0042110), regulation of apoptotic process (GO:0042981), positive thymic T cell selection (GO:0045059), negative thymic T cell selection (GO:0045060), negative regulation of smoothened signaling pathway (GO:0045879), gamma-delta T cell activation (GO:0046629), alpha-beta T cell activation (GO:0046631), positive regulation of calcium-mediated signaling (GO:0050850), T cell receptor signaling pathway (GO:0050852), protein-containing complex assembly (GO:0065003), apoptotic signaling pathway (GO:0097190), positive regulation of CD4-positive, alpha-beta T cell proliferation (GO:2000563), immune system process (GO:0002376), regulation of signal transduction (GO:0009966), T cell proliferation (GO:0042098), positive regulation of MAPK cascade (GO:0043410), lymphocyte activation (GO:0046649), positive regulation of T cell activation (GO:0050870)

GO Molecular Function (8): transmembrane signaling receptor activity (GO:0004888), SH3 domain binding (GO:0017124), protein kinase binding (GO:0019901), signaling receptor complex adaptor activity (GO:0030159), protein-macromolecule adaptor activity (GO:0030674), T cell receptor binding (GO:0042608), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (12): immunological synapse (GO:0001772), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), external side of plasma membrane (GO:0009897), T cell receptor complex (GO:0042101), alpha-beta T cell receptor complex (GO:0042105), gamma-delta T cell receptor complex (GO:0042106), dendritic spine (GO:0043197), cell body (GO:0044297), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
TCR signaling	4
Adaptive Immune System	3
Regulation of T cell activation by CD28 family	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of cytokine production	3
cellular anatomical structure	3
signal transduction	2
gene expression	2
regulation of gene expression	2
anatomical structure development	2
signaling receptor binding	2
protein binding	2
plasma membrane	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
T cell receptor complex	2
regulation of cell-matrix adhesion	1
cell-matrix adhesion	1
positive regulation of cell-substrate adhesion	1
immune response	1
positive regulation of T cell tolerance induction	1
regulation of T cell anergy	1
T cell anergy	1
positive regulation of lymphocyte anergy	1
lymphocyte anergy	1
T cell tolerance induction	1
enzyme-linked receptor protein signaling pathway	1
regulation of signal transduction	1
protein-containing complex assembly	1
G protein-coupled receptor activity	1
cell surface receptor signaling pathway	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
neuron projection development	1
intracellular signaling cassette	1
metencephalon development	1
lymphocyte costimulation	1
positive regulation of T cell activation	1
type II interferon production	1
regulation of type II interferon production	1
interleukin-2 production	1
regulation of interleukin-2 production	1
interleukin-4 production	1

Protein interactions and networks

STRING

2124 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD3E	CD3D	P04234	999
CD3E	CD3G	P09693	999
CD3E	CD247	P20963	991
CD3E	CD4	P01730	864
CD3E	LCK	P06239	858
CD3E	CD8A	P01732	848
CD3E	AOC3	Q16853	844
CD3E	E9PD41	E9PD41	824
CD3E	PTPRC	P08575	817
CD3E	THY1	P04216	792
CD3E	CD19	P15391	786
CD3E	IL7R	P16871	784
CD3E	ITGAM	P11215	774
CD3E	ZAP70	P43403	762
CD3E	CD28	P10747	754

IntAct

56 interactions, top by confidence:

A	B	Type	Score
PTPN22	LCK	psi-mi:“MI:0914”(association)	0.780
EPS8L1	CD3E	psi-mi:“MI:0915”(physical association)	0.750
CD3E	EPS8L1	psi-mi:“MI:0915”(physical association)	0.750
CD3E	EPS8L1	psi-mi:“MI:0407”(direct interaction)	0.750
EPS8L1	CD3E	psi-mi:“MI:0407”(direct interaction)	0.750
CD3E	NCK1	psi-mi:“MI:0915”(physical association)	0.740
NCK1	CD3E	psi-mi:“MI:0407”(direct interaction)	0.740
NCK2	CD3E	psi-mi:“MI:0915”(physical association)	0.680
CD3E	NCK2	psi-mi:“MI:0915”(physical association)	0.680
SYK	CD3E	psi-mi:“MI:0914”(association)	0.600
CD3E	BNIP3	psi-mi:“MI:0915”(physical association)	0.560
CD3E	ADAM33	psi-mi:“MI:0915”(physical association)	0.560
CD3E	MUC15	psi-mi:“MI:0915”(physical association)	0.560
ZFPL1	CD3E	psi-mi:“MI:0915”(physical association)	0.560
CD3E	PKMYT1	psi-mi:“MI:0915”(physical association)	0.560
ZAP70	CD3E	psi-mi:“MI:0914”(association)	0.530

BioGRID (87): ITPRIPL1 (Affinity Capture-MS), GHDC (Affinity Capture-MS), HLA-A (Affinity Capture-MS), LNPEP (Affinity Capture-MS), GP1BB (Affinity Capture-MS), TM2D3 (Affinity Capture-MS), C10orf35 (Affinity Capture-MS), CD3E (Co-localization), LNPEP (Affinity Capture-MS), GHDC (Affinity Capture-MS), TM2D3 (Affinity Capture-MS), C10orf35 (Affinity Capture-MS), GP1BB (Affinity Capture-MS), CD3E (Affinity Capture-Western), CD3E (Affinity Capture-Western)

ESM2 similar proteins: A4F4L0, O00453, O14669, O43914, O54885, P04234, P04235, P07766, P0CAN6, P18438, P19377, P20963, P24161, P29328, P29329, P59646, Q13113, Q28072, Q28073, Q2KIP5, Q3TYX2, Q5R1Q1, Q5RA41, Q63113, Q64159, Q6AYD4, Q6ITQ4, Q6X9T7, Q764N2, Q8K1T1, Q8MII8, Q8N386, Q8NET5, Q8R182, Q8WNQ8, Q923S2, Q925F2, Q95J79, Q95LI5, Q95LI8

Diamond homologs: P07766, P22646, P27597, P29328, Q28073, Q5R1Q1, Q7YRN2, Q95LI5, Q98910, Q9TUF9, P04234, Q95LI8

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
CD3E	“form complex”	CD3	binding
CD3E	“up-regulates activity”	NCK1	relocalization
STOML2	“up-regulates activity”	CD3E	binding
LCK	“up-regulates activity”	CD3E	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 24 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Translocation of ZAP-70 to Immunological synapse	6	200.3×	3e-11
Phosphorylation of CD3 and TCR zeta chains	5	143.1×	1e-08
Generation of second messenger molecules	6	109.3×	1e-09
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	5	22.9×	5e-05
Adaptive Immune System	6	9.4×	3e-04
Innate Immune System	5	6.7×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
T cell activation	5	58.9×	1e-06
T cell receptor signaling pathway	7	48.3×	2e-08
adaptive immune response	5	19.1×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

303 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	7
Uncertain significance	85
Likely benign	149
Benign	26

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
12745	NM_000733.4(CD3E):c.176G>A (p.Trp59Ter)	Pathogenic
12746	NM_000733.4(CD3E):c.128_129del (p.Thr43fs)	Pathogenic
2423383	NC_000011.9:g.(?118175668)(118179176_?)del	Pathogenic
2704456	NM_000733.4(CD3E):c.190A>T (p.Lys64Ter)	Pathogenic
2735762	NM_000733.4(CD3E):c.49+1G>C	Pathogenic
2735763	NM_000733.4(CD3E):c.428del (p.Gly143fs)	Pathogenic
2786487	NM_000733.4(CD3E):c.49+1G>A	Pathogenic
2864291	NM_000733.4(CD3E):c.472A>T (p.Lys158Ter)	Pathogenic
3244672	NC_000011.9:g.(?118175668)(118178043_?)del	Pathogenic
3340358	NM_000733.4(CD3E):c.173del (p.Leu58fs)	Pathogenic
3647560	NM_000733.4(CD3E):c.310A>T (p.Lys104Ter)	Pathogenic
4721598	NM_000733.4(CD3E):c.416dup (p.Cys139fs)	Pathogenic
847887	NM_000733.4(CD3E):c.261_262del (p.Ser88fs)	Pathogenic
847888	NM_000733.4(CD3E):c.490C>T (p.Arg164Ter)	Pathogenic
12744	NM_000733.4(CD3E):c.520+2T>C	Likely pathogenic
1475194	NM_000733.4(CD3E):c.71-2A>G	Likely pathogenic
2700001	NM_000733.4(CD3E):c.353-1G>A	Likely pathogenic
2708832	NM_000733.4(CD3E):c.520+1G>A	Likely pathogenic
3635757	NM_000733.4(CD3E):c.86-1G>A	Likely pathogenic
570046	NM_000733.4(CD3E):c.103+1G>T	Likely pathogenic
835442	NM_000733.4(CD3E):c.103+1G>A	Likely pathogenic

SpliceAI

903 predictions. Top by Δscore:

Variant	Effect	Δscore
11:118313705:A:AG	acceptor_gain	1.0000
11:118313706:G:GA	acceptor_gain	1.0000
11:118313706:GT:G	acceptor_gain	1.0000
11:118313706:GTGT:G	acceptor_gain	1.0000
11:118313872:GGG:G	donor_gain	1.0000
11:118313873:GG:G	donor_gain	1.0000
11:118313873:GGG:G	donor_gain	1.0000
11:118313874:GG:G	donor_gain	1.0000
11:118304773:AATGG:A	donor_loss	0.9900
11:118304774:ATGG:A	donor_loss	0.9900
11:118304775:TGG:T	donor_loss	0.9900
11:118304776:GGTG:G	donor_loss	0.9900
11:118304777:GTGA:G	donor_loss	0.9900
11:118304778:T:G	donor_loss	0.9900
11:118304892:A:AG	acceptor_gain	0.9900
11:118304893:G:GG	acceptor_gain	0.9900
11:118304893:GAA:G	acceptor_gain	0.9900
11:118307489:G:T	donor_gain	0.9900
11:118308514:G:GG	donor_gain	0.9900
11:118308547:G:T	donor_gain	0.9900
11:118313696:A:AG	acceptor_gain	0.9900
11:118313697:C:G	acceptor_gain	0.9900
11:118313705:AGT:A	acceptor_gain	0.9900
11:118313705:AGTGT:A	acceptor_gain	0.9900
11:118313706:G:T	acceptor_loss	0.9900
11:118313706:GTG:G	acceptor_gain	0.9900
11:118313706:GTGTG:G	acceptor_gain	0.9900
11:118313871:AGGGG:A	donor_loss	0.9900
11:118313872:GGGGT:G	donor_loss	0.9900
11:118313873:GGGT:G	donor_loss	0.9900

AlphaMissense

1342 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:118312691:G:C	W59C	0.994
11:118312691:G:T	W59C	0.994
11:118313769:T:C	C139R	0.992
11:118312773:T:C	F87L	0.991
11:118312775:T:A	F87L	0.991
11:118312775:T:G	F87L	0.991
11:118312855:T:C	L114P	0.987
11:118314489:T:C	Y188H	0.987
11:118312654:T:C	L47S	0.986
11:118312629:T:C	S39P	0.985
11:118312806:T:C	C98R	0.985
11:118312808:C:G	C98W	0.985
11:118312659:T:C	C49R	0.984
11:118312806:T:A	C98S	0.984
11:118312807:G:A	C98Y	0.984
11:118312807:G:C	C98S	0.984
11:118312774:T:G	F87C	0.983
11:118313781:G:C	G143R	0.983
11:118312659:T:A	C49S	0.982
11:118312660:G:C	C49S	0.982
11:118312635:T:C	S41P	0.980
11:118312689:T:A	W59R	0.980
11:118312689:T:C	W59R	0.980
11:118312633:T:C	I40T	0.978
11:118313782:G:A	G143D	0.978
11:118315490:T:C	I191T	0.977
11:118313710:G:A	C119Y	0.976
11:118313720:C:G	C122W	0.976
11:118312648:T:A	V45E	0.974
11:118312660:G:A	C49Y	0.972

dbSNP variants (sampled 300 via entrez): RS1000001538 (11:118306805 G>A,T), RS1000174656 (11:118310410 A>G), RS1000231091 (11:118307049 C>T), RS1000374938 (11:118316185 C>T), RS1000430333 (11:118315909 T>C), RS1001290668 (11:118314367 A>C,G,T), RS1001678129 (11:118303657 A>C,G), RS1001730915 (11:118310455 T>A,C), RS1001783180 (11:118310095 A>C), RS1002179786 (11:118307462 C>T), RS1002304455 (11:118313011 T>C,G), RS1003243068 (11:118302820 G>A,C), RS1003891577 (11:118309250 T>C), RS1004322289 (11:118315624 G>A), RS1004369493 (11:118316422 A>C,T)

Disease associations

OMIM: gene MIM:186830 | disease phenotypes: MIM:615615

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 18	Definitive	Autosomal recessive
T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
immunodeficiency 18	Definitive	AR

Mondo (3): immunodeficiency 18 (MONDO:0014278), severe combined immunodeficiency (MONDO:0015974), T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta (MONDO:0015703)

Orphanet (1): Severe combined immunodeficiency (Orphanet:183660)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000388	Otitis media
HP:0000403	Recurrent otitis media
HP:0001019	Erythroderma
HP:0001433	Hepatosplenomegaly
HP:0001880	Increased total eosinophil count
HP:0001888	Decreased total lymphocyte count
HP:0001945	Fever
HP:0002014	Diarrhea
HP:0002039	Anorexia
HP:0002090	Pneumonia
HP:0002205	Recurrent respiratory infections
HP:0002719	Recurrent infections
HP:0002721	Immunodeficiency
HP:0002722	Recurrent abscess formation
HP:0002850	Decreased circulating total IgM
HP:0003460	Decreased circulating total IgA
HP:0003593	Infantile onset
HP:0004315	Decreased circulating IgG concentration
HP:0004385	Protracted diarrhea
HP:0005353	Recurrent herpes
HP:0005401	Recurrent candida infections
HP:0005403	Decreased total T cell count
HP:0006532	Recurrent pneumonia
HP:0008866	Failure to thrive secondary to recurrent infections
HP:0009098	Chronic oral candidiasis
HP:0010702	Increased circulating immunoglobulin concentration
HP:0010975	Abnormal B cell count
HP:0011463	Childhood onset
HP:0012115	Hepatitis

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004749_30	Lung cancer in ever smokers	4.000000e-07
GCST007096_210	Pulse pressure	3.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016511	Severe Combined Immunodeficiency	C16.320.798.750; C16.614.815; C18.452.284.800; C20.673.795.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1975 (SINGLE PROTEIN), CHEMBL2364168 (PROTEIN COMPLEX)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — CD molecules

Most potent curated ligand interactions (8 total), top 8:

Ligand	Action	Affinity	Parameter
AX-024	Binding	9.0	pIC50
xaluritamig	Binding	8.56	pKd
tarlatamab	Binding	8.36	pKd
ZWB67	Binding	8.0	pKd
PF-07062119	Binding	7.62	pKd
blinatumomab	Binding	7.0	pKd
linvoseltamab	Binding	6.92	pEC50
tepoditamab	Binding	6.75	pKd

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
perfluorooctanoic acid	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
Fingolimod Hydrochloride	decreases expression	1
Antineoplastic Agents, Immunological	affects binding, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Allergens	increases expression, affects cotreatment	1
Amphotericin B	increases expression	1
Arsenic	affects methylation	1
Vehicle Emissions	affects cotreatment, increases expression	1
Benzene	decreases expression, increases expression	1
Benzo(a)pyrene	increases methylation	1
Calcifediol	affects binding, affects cotreatment, increases expression, increases reaction, decreases reaction	1
Calcitriol	decreases reaction, affects binding, affects cotreatment, increases expression, increases reaction (+1 more)	1
Cycloheximide	decreases expression, decreases reaction	1
Ketoconazole	affects binding, affects cotreatment, decreases reaction, increases expression, increases reaction (+1 more)	1
Nickel	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tetrachlorodibenzodioxin	decreases expression, decreases reaction	1

Cellosaurus cell lines

11 cell lines: 9 cancer cell line, 1 transformed cell line, 1 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8D1	Abcam HCT 116 CD3E KO	Cancer cell line	Male
CVCL_B8TN	Abcam MCF-7 CD3E KO	Cancer cell line	Female
CVCL_B9UM	Abcam A-549 CD3E KO	Cancer cell line	Male
CVCL_E1G4	Abcam Jurkat CD3E KO	Cancer cell line	Male
CVCL_E4AD	Genomeditech HEK-293 H_CD3	Transformed cell line	Female
CVCL_E4IL	Genomeditech CHO-K1 H_CD3	Spontaneously immortalized cell line	Female
CVCL_E8IP	Jurkat-NFAT-Luc2-CD3D-CD3E-KO-1C4	Cancer cell line	Male
CVCL_E8IQ	Jurkat-NFAT-Luc2-CD3D-CD3E-KO-2A3	Cancer cell line	Male
CVCL_E8IR	Jurkat-NFAT-Luc2-CD3E-KO-1A1	Cancer cell line	Male
CVCL_E8IS	Jurkat-NFAT-Luc2-CD3E-KO-1B3	Cancer cell line	Male

Clinical trials (associated diseases)

44 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT01420627	PHASE3	COMPLETED	EZN-2279 in Patients With ADA-SCID
NCT06940570	PHASE3	SUSPENDED	Methadone as an Alternative Treatment for Children Underdoing HSCT
NCT00000603	PHASE2	COMPLETED	Cord Blood Stem Cell Transplantation Study (COBLT)
NCT00794508	PHASE2	COMPLETED	MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID
NCT01182675	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HSCT) for Children With SCID Utilizing Alemtuzumab, Plerixafor & Filgrastim
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT02177760	PHASE2	WITHDRAWN	Sirolimus Prophylaxis for aGVHD in TME SCID
NCT03619551	PHASE2	ACTIVE_NOT_RECRUITING	Conditioning SCID Infants Diagnosed Early
NCT00008450	PHASE1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT00028236	PHASE1	COMPLETED	Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID)
NCT00152100	PHASE1	COMPLETED	Transplantation of Hematopoietic Cells in Children With Severe Combined Immunodeficiency Syndrome
NCT02860559	PHASE1	UNKNOWN	Safety and Early Efficacy Study of TBX-1400 in Patients With Severe Combined Immunodeficiency
NCT01019876	PHASE2/PHASE3	COMPLETED	Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases
NCT00228852	PHASE1/PHASE2	COMPLETED	IMM 0212: Busulfan With Fludarabine and Antithymocyte Globulin as Preparative Therapy for Hematopoietic Stem Cell Transplant for the Treatment of Severe Congenital T-Cell Immunodeficiency
NCT00579137	PHASE1/PHASE2	TERMINATED	Allogeneic SCT Of Pts With SCID And Other Primary Immunodeficiency Disorders
NCT01129544	PHASE1/PHASE2	COMPLETED	Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector
NCT01852370	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT02127892	PHASE1/PHASE2	TERMINATED	SCID Bu/Flu/ATG Study With T Cell Depletion
NCT02963064	PHASE1/PHASE2	TERMINATED	JSP191 Antibody Targeting Conditioning in SCID Patients
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT03538899	PHASE1/PHASE2	RECRUITING	Autologous Gene Therapy for Artemis-Deficient SCID
NCT03597594	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Haplocompatible Transplant Using TCRα/β Depletion Followed by CD45RA-Depleted Donor Lymphocyte Infusions for Severe Combined Immunodeficiency (SCID)
NCT00001255	Not specified	COMPLETED	Gene Transfer Therapy for Severe Combined Immunodeficieny Disease (SCID) Due to Adenosine Deaminase (ADA) Deficiency: A Natural History Study
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies
NCT00006335	Not specified	COMPLETED	Influences on Female Adolescents’ Decisions Regarding Testing for Carrier Status of XSCID
NCT00055172	Not specified	RECRUITING	Genetic Basis of Immunodeficiency
NCT00695279	Not specified	COMPLETED	Long Term Follow Up Of Patients Who Have Received Gene Therapy Or Gene Marked Products
NCT00845416	Not specified	COMPLETED	Newborn Screening for Severe Combined Immunodeficiency (SCID) in a High-Risk Population
NCT01186913	Not specified	ENROLLING_BY_INVITATION	Natural History Study of SCID Disorders
NCT01346150	Not specified	UNKNOWN	Patients Treated for SCID (1968-Present)
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT01953016	Not specified	COMPLETED	Participation in a Research Registry for Immune Disorders
NCT02231983	Not specified	UNKNOWN	Clinical Characteristics and Genetic Profiles of Severe Combined Immunodeficiency in China
NCT02590328	Not specified	COMPLETED	Neonatal Screening of Severe Combined Immunodeficiencies
NCT04049084	Not specified	ENROLLING_BY_INVITATION	An Observational LTFU Study for Patients Previously Treated With Autologous ex Vivo Gene Therapy for ADA-SCID
NCT04172181	Not specified	UNKNOWN	Multi-center Clinical Study of Cord Blood Stem Cell Transplantation for SCID
NCT04246840	Not specified	COMPLETED	Study Through Imaging of Visceral Lymphoid Organs in Patients With SCID Who Have Recieved Bone Marrow Allograft
NCT04331483	Not specified	WITHDRAWN	A Study to Assess a Physical Activity Program in Children, Adolescents and Young Adults Requiring Hematopoietic Stem Cell Allografts