CD3 epsilon (CD3ε) is a protein component of the adaptive immune system. It is integral to the function of T-cells, a type of white blood cell that orchestrates immune responses and kills infected cells. CD3ε is one subunit of a larger protein assembly on the surface of every T-cell that allows it to recognize foreign invaders. The protein is encoded by the CD3E gene. Without this protein, the T-cell’s recognition and signaling apparatus fails, impairing the ability to fight infections.
The T-Cell Receptor Complex
T-cells use a multi-protein assembly called the T-cell receptor (TCR) complex to detect threats. This complex has two principal parts. The first consists of the antigen-binding chains, TCR-α and TCR-β, which are variable and allow the T-cell to recognize a unique molecular signature from a pathogen or abnormal cell. These chains extend outside the T-cell, acting as antennae searching for their specific target.
The second part is the CD3 complex, a collection of invariant signaling chains associated with the antigen-binding chains. This part is responsible for transmitting the signal from the outside of the cell to the inside. The CD3 complex is composed of several protein subunits: CD3 gamma (γ), CD3 delta (δ), CD3 epsilon (ε), and the zeta (ζ) chains. This arrangement includes two copies of the CD3ε subunit, highlighting its importance.
Structure of the CD3ε Subunit
The CD3ε protein’s molecular architecture enables its function and has three main sections. The first is an extracellular domain on the outside of the T-cell membrane. This domain is part of the immunoglobulin superfamily and helps stabilize the association with other components of the TCR complex. A single transmembrane domain, a helical segment passing through the cell membrane, anchors the protein.
The final part is the cytoplasmic tail, which extends into the T-cell’s interior. This tail contains a sequence of amino acids known as an Immunoreceptor Tyrosine-based Activation Motif (ITAM), which acts as a switch. In its resting state, the ITAM is inactive, but upon T-cell receptor activation, it becomes chemically modified, initiating a signal cascade. Its key tyrosine residues—the ones modified during signaling—are tucked into the cell membrane in a resting T-cell. This sequestration is thought to be a mechanism to prevent accidental activation.
Role in T-Cell Signal Transduction
CD3ε is central to T-cell signal transduction, the process that converts antigen recognition into a cellular response. When the TCR-α/β chains bind to their specific antigen, it triggers a shape change in the TCR complex. This conformational shift causes the cytoplasmic tails of the CD3 subunits, including CD3ε, to become exposed, making the ITAM sequence on the CD3ε tail accessible to enzymes.
The enzyme Lck is brought close to the complex and phosphorylates the tyrosine amino acids within the ITAM. Phosphorylation, the addition of a phosphate group, changes the ITAM’s properties, turning it into a docking site for other proteins. The phosphorylated CD3ε ITAM then recruits a signaling protein called ZAP-70 from the cytoplasm.
ZAP-70 binds to the phosphorylated ITAMs, which localizes it to the receptor complex and activates its own function. Activated ZAP-70 then phosphorylates downstream targets, setting off a signaling cascade that leads to T-cell activation. This involves gene expression changes, rapid cell division, and developing functions like killing infected cells or helping other immune cells.
Clinical Significance and Therapeutic Targeting
The absence of functional CD3ε has severe medical consequences. Mutations in the CD3E gene that prevent the production of a functional CD3ε protein can lead to a type of Severe Combined Immunodeficiency (SCID). This condition is characterized by a complete lack of functional T-cells. The absence of T-cells cripples the adaptive immune response, leaving infants vulnerable to life-threatening infections from otherwise minor pathogens.
Conversely, the presence of CD3ε on T-cells makes it an effective target for therapeutic intervention, especially in cancer treatment. Scientists have developed a class of drugs known as Bispecific T-cell Engagers (BiTEs). These molecules act as a bridge, with one end binding to the CD3ε subunit on a T-cell and the other to a protein on the surface of cancer cells.
This dual binding physically links a T-cell to a tumor cell, forcing an interaction that might not otherwise occur. The engagement of CD3ε by the BiTE triggers the T-cell’s activation machinery, tricking it into recognizing the cancer cell as a threat. This causes the T-cell to release cytotoxic granules that kill the cancer cell. Blinatumomab, a BiTE that targets CD19 on B-cell leukemias and lymphomas and CD3ε on T-cells, exemplifies this approach and is approved for clinical use.