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CD3E
CD3 epsilon subunit of T-cell receptor complex
CD3E is located on the long (q) arm of chromosome 11, at band 11q23.3. Arm ratio per GRCh38 - banding schematic.
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Overview
CD3E is located on chromosome 11 and encodes the CD3 epsilon subunit, one of several invariant chains that associate with the T-cell receptor (TCR) on the surface of T lymphocytes. The CD3 complex serves as the signalling apparatus for the TCR, converting the recognition of foreign antigens into intracellular biochemical cascades that activate T cells. Without functional CD3 epsilon, T cells cannot mature properly or mount effective immune responses.
Pathogenic variants in CD3E are inherited in an autosomal recessive pattern, meaning that two copies of an altered gene are required to cause disease. Affected individuals typically present with severe combined immunodeficiency (SCID), characterised by recurrent infections, failure to thrive, and absence of functional T cells. The gene is included on UK clinical panels for primary immunodeficiency, reflecting its established role in immune system disorders.
What the gene does
The CD3 epsilon protein functions as a transmembrane signalling subunit within the T-cell receptor complex. When the TCR recognises a peptide antigen presented by major histocompatibility complex molecules, CD3 epsilon and its partner chains transduce this recognition event into the cell interior. The protein achieves this through specialised signalling motifs embedded in its cytoplasmic tail.
CD3 epsilon pairs with CD3 delta or CD3 gamma chains to form heterodimers that associate with the TCR alpha-beta heterodimer and the CD3 zeta-zeta homodimer. This assembly creates a complete receptor complex capable of initiating T-cell activation. The intracellular portion of CD3 epsilon interacts with kinases and adapter proteins that propagate downstream signalling pathways, ultimately leading to gene transcription, cytokine production, and T-cell proliferation. The protein also participates in quality control during TCR assembly in the endoplasmic reticulum, ensuring that only properly formed receptor complexes reach the cell surface.
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Chromosome location
CD3E is located on the long arm of chromosome 11 at position 23.3 (11q23.3). The gene spans a relatively compact genomic region and contains multiple exons that encode the 207-amino-acid CD3 epsilon protein. This chromosomal region also harbours other genes involved in immune function, though CD3E operates independently within its defined locus. The genomic organisation of CD3E is conserved across mammalian species, reflecting the protein's fundamental role in adaptive immunity.
Protein structure
The CD3 epsilon protein consists of 207 amino acids organised into several functional regions. The N-terminal portion contains an Ig-like domain (amino acids 32-112), which adopts an immunoglobulin fold typical of proteins involved in cell surface recognition and adhesion. This extracellular region participates in stabilising the overall TCR-CD3 complex architecture.
The cytoplasmic tail includes a critical ITAM domain (immunoreceptor tyrosine-based activation motif, amino acids 178-205) that serves as the primary signalling element. When T cells encounter antigen, tyrosine residues within the ITAM are phosphorylated by Src-family kinases, creating docking sites for downstream signalling molecules. A NUMB-binding region (amino acids 175-192) and a proline-rich sequence (amino acids 179-186) provide additional interaction surfaces for regulatory proteins. The C-terminal portion contains a disordered region (amino acids 161-207), which affords conformational flexibility necessary for dynamic protein-protein interactions during signal transduction.
Key variants
Pathogenic variants in CD3E disrupt the production or function of the CD3 epsilon protein, impairing T-cell development and signalling. Most disease-causing variants are loss-of-function changes, including nonsense mutations, frameshift insertions or deletions, and splice-site alterations that prevent normal protein expression. Missense variants affecting critical residues within the ITAM or Ig-like domain can also abolish protein function even when the protein is produced. The distribution of pathogenic variants reflects the gene's autosomal recessive inheritance pattern, with affected individuals carrying biallelic mutations.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.131_132del | p.Thr44fs | Pathogenic/Likely pathogenic | ★★☆☆ | Immunodeficiency 18 |
c.173del | p.Leu58fs | Pathogenic | ★★☆☆ | not provided |
c.288T>A | p.Tyr96Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Severe combined immunodeficiency disease |
c.49+1G>C | - | Pathogenic | ★★☆☆ | Immunodeficiency 18 |
g.(118175492_118175608)_(118186889_?)del | - | Pathogenic | ★☆☆☆ | Immunodeficiency 18 |
g.(?_118175668)_(118178043_?)del | - | Pathogenic | ★☆☆☆ | Immunodeficiency 18 |
c.310A>T | p.Lys104Ter | Pathogenic | ★☆☆☆ | Immunodeficiency 18 |
c.416dup | p.Cys139fs | Pathogenic | ★☆☆☆ | Immunodeficiency 18 |
c.428del | p.Gly143fs | Pathogenic | ★☆☆☆ | Immunodeficiency 18 |
c.472A>T | p.Lys158Ter | Pathogenic | ★☆☆☆ | Immunodeficiency 18 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in CD3E cause a form of severe combined immunodeficiency characterised by profoundly reduced or absent T lymphocytes. Affected infants typically present within the first few months of life with recurrent bacterial, viral, and fungal infections, chronic diarrhoea, and failure to gain weight appropriately. The condition is life-threatening without immune reconstitution, usually achieved through haematopoietic stem cell transplantation. While CD3E-related SCID shares clinical features with other forms of SCID, the specific immunological profile-absence of mature T cells but presence of B cells and natural killer cells-can help distinguish it from defects in other immune genes.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic CD3E variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
CD3E is included on the NHS Genomic Medicine Service panel for primary immunodeficiency or monogenic inflammatory bowel disease, where it holds green (high evidence) classification. The gene has also been included on the COVID-19 research panel, reflecting interest in immune response variability during the pandemic. These panel memberships indicate that CD3E variants are routinely assessed in NHS laboratories when evaluating patients with suspected inherited immune disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the CD3E gene do?
CD3E encodes the epsilon subunit of the CD3 complex, which works alongside the T-cell receptor to transmit activation signals into T lymphocytes. This signalling is essential for T cells to recognise threats and coordinate immune responses.
How is CD3E inherited?
CD3E-related conditions follow an autosomal recessive inheritance pattern. An individual must inherit two pathogenic variants (one from each parent) to develop severe combined immunodeficiency. Carriers with one variant typically have normal immune function.
What happens if CD3E is not working properly?
Loss of functional CD3 epsilon prevents normal T-cell development and activation, resulting in severe combined immunodeficiency. Affected individuals have profoundly reduced T-cell numbers and experience recurrent, life-threatening infections from infancy.