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CD3 (cluster of differentiation 3) is aprotein complex andT cellco-receptor that is involved in activating both thecytotoxic T cell (CD8+ naive T cells) andT helper cells (CD4+ naive T cells).^[1] It is composed of four distinct chains. In mammals, the complex contains aCD3γ chain, aCD3δ chain, and twoCD3ε chains. These chains associate with theT-cell receptor (TCR) and theCD3-zeta (ζ-chain) to generate an activation signal inT lymphocytes. The TCR, CD3-zeta, and the other CD3 molecules together constitute the TCR complex.

The CD3γ, CD3δ, and CD3ε chains are highly related cell-surface proteins of theimmunoglobulin superfamily containing a singleextracellular immunoglobulin domain.

A structure of the extracellular and transmembrane regions of the CD3γε/CD3δε/CD3ζζ/TCRαβ complex was solved withCryoEM, showing for the first time how the CD3 transmembrane regions enclose the TCR transmembrane regions in an open barrel.^[2]

Containingaspartate residues, the transmembrane region of the CD3 chains is negatively charged, a characteristic that allows these chains to associate with the positively charged TCR chains.^[3]

The intracellular tails of the CD3γ, CD3ε, and CD3δ molecules each contain a single conserved motif known as animmunoreceptor tyrosine-based activation motif, or ITAM for short, which is essential for the signaling capacity of the TCR. The intracellular tail of CD3ζ contains 3 ITAM motifs.

Phosphorylation of theITAM on CD3 renders the CD3 chain capable of binding anenzyme calledZAP70 (zeta associated protein), akinase that is important in the signaling cascade of the T cell.

Because CD3 is required forT-cell activation, drugs (oftenmonoclonal antibodies) that target it are being investigated asimmunosuppressant therapies (e.g.,otelixizumab,teplizumab) fortype 1 diabetes and otherautoimmune diseases.^[4]

New anticancer drug treatments are being developed based upon the CD3 T cell co-receptor, with molecules being designed for altering the co-stimulatory signal to help get the T-cell to recognize the cancer cell and become fully activated. Cancers that possess the B7-H3 immunoregulatory checkpoint receptor on the tumor cell have been one such target in clinical trials. This B7-H3 protein is expressed on cancer cell for several types of cancer. Often, the drug will contain two domains, one binding the T-cell's CD3 and the other targeting and binding cancer cells.

CD3 is initially expressed in the cytoplasm of pro-thymocytes, thestem cells from which T-cells arise in thethymus. The pro-thymocytes differentiate into commonthymocytes, and then into medullary thymocytes, and it is at this latter stage that CD3 antigen begins to migrate to the cell membrane. The antigen is found bound to the membranes of all mature T-cells, and in virtually no other cell type, although it does appear to be present in small amounts inPurkinje cells.

This high specificity, combined with the presence of CD3 at all stages of T-cell development, makes it a usefulimmunohistochemical marker for T cells in tissue sections. The antigen remains present in almost all T-celllymphomas andleukaemias, and can therefore be used to distinguish them from superficially similarB-cell andmyeloidneoplasms.^[5]

• Media related toCD3 (immunology) at Wikimedia Commons
• CD3+Antigens at the U.S. National Library of MedicineMedical Subject Headings (MeSH)
• Mouse CD Antigen Chart
• Human CD Antigen Chart

• Genes on human chromosome 11
• Clusters of differentiation
• T cells
• Immunology

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