What is CD3 ?
CD3 (cluster of differentiation 3) is a protein complex and is involved in the activation of cytotoxic T cells (CD8+ naive T cells) and T helper cells (CD4+ naive T cells). In mammals, this complex contains one CD3γ chain, one CD3δ chain, and two CD3ε chains. These chains bind to the T cell receptor (TCR) and CD3ζ chain to generate an activation signal in T lymphocytes. The transmembrane region of the CD3 chains contains aspartic acid residues and is negatively charged, a property that allows these chains to bind to the positively charged TCR chains. The intracellular tails of the CD3γ, CD3ε, and CD3δ molecules each contain a conserved motif called the immunoreceptor tyrosine-based activation motif, or ITAM for short, that is critical for TCR signaling capabilities.
The CD3-T cell receptor (TCR) complex plays a central role in T cell-mediated immune responses as it is involved in antigen recognition and subsequent signal transduction and activation of immunocompetent T lymphocytes. For this reason, the CD3 and TCR molecules are among the surface structures of lymphocytes that have been the most extensively studied. There are two types of TCRs, distinguished by their heterodimers, αβ- and γδ-TCRs. Recent studies have shown that cells carrying the γδ-TCR (γδ-T cells) differ from cells carrying the αβ-TCR (αβ-T cells) early in ontogeny, encompassing limited V gene utilization coupled with substantial diversity in connectivity.
Fig.1 TCRα/TCRβ and TCRγ/TCRδ heterodimers form complexes with the CD3 molecules (Shah K., et al. 2021).
Expression of CD3
Initial expression of CD3 occurs in the cytoplasm at perinuclear positions in prothymocytes. As T cell maturation progresses, cytoplasmic CD3 expression disappears and the CD3 antigen appears on the cell surface. Prothymocytes differentiate into ordinary thymocytes and then into medullary thymocytes, at which stage the CD3 antigen begins to migrate to the cell membrane. The specificity of the CD3 antigen for T cells and its representation at various stages of T cell development make it an ideal T cell marker for the detection of normal T cells and T cell neoplasms (lymphomas and leukemias) and make it a useful immune tissue chemical reagents markers of T cells in tissue sections. CD3 is also weakly expressed by some macrophages, Purkinje cells in the brain, and Hodgkin and Reed-Sternberg cells, both of which are found in Hodgkin lymphoma and are usually derived from cells of the B cell lineage.
CD3 as A Drug Target in Cancer Research
CD3 antigen was found bound to the membranes of all mature T cells and was hardly present in other cell types, although it did appear to be present in small amounts in Purkinje cells. This high specificity, coupled with the presence of CD3 at all stages of T cell development, makes it a useful immunohistochemical marker of T cells in tissue sections. This antigen is present in virtually all T-cell lymphomas and leukemias and thus can be used to distinguish them from superficially similar B-cell and myeloid neoplasms.
New anticancer therapeutics are being developed based on the CD3 (cluster of differentiation 3) T cell co-receptor, a molecule designed to alter co-stimulatory signals to help T cells recognize cancer cells and become fully activated. An illustrative target in clinical trials involves the B7-H3 immunomodulatory checkpoint receptor associated with cancer. This B7-H3 protein is manifest in various cancer types. Typically, the drug candidates feature two distinct domains—one binding to T cell CD3 and the other targeting and binding to cancer cells.
References
- Shah K.; et al. T cell receptor (TCR) signaling in health and disease. Signal Transduction and Targeted Therapy. 2021, 6(1): 412.
- Campagne O.; et al. Integrated pharmacokinetic/pharmacodynamic model of a bispecific CD3xCD123 DART molecule in nonhuman primates: evaluation of activity and impact of immunogenicity. Clinical Cancer Research. 2018, 24(11): 2631-2641.
.
