T-cell surface glycoprotein CD3 zeta chain (CD3Z) (CD3Z)

The T-cell surface glycoprotein CD3 zeta chain (CD247) is a vital structural and functional component of the T-cell receptor (TCR) complex, primarily responsible for signal transduction following antigen recognition (UniProt P20963). Unlike other CD3 subunits, the zeta chain possesses a short extracellular domain and a long cytoplasmic tail containing three immunoreceptor tyrosine-based activation motifs (ITAMs) (NCBI Gene 919). Upon engagement of the TCR with an antigen-MHC complex, these ITAMs are phosphorylated by Src-family kinases, which recruits ZAP-70 to initiate downstream signaling pathways for T-cell proliferation and cytokine production (PubMed: 25607730). In the context of modern oncology, the intracellular signaling domain of CD3 zeta is the standard "Signal 1" component used in the construction of Chimeric Antigen Receptors (CARs) for CAR-T cell therapy (PubMed: 30552151). Drugs like Tisagenlecleucel and Axicabtagene ciloleucel utilize this domain to trigger potent anti-tumor responses in patients with hematologic malignancies. However, the potent activation mediated by this chain can lead to significant safety concerns, such as cytokine release syndrome (CRS) and neurotoxicity. Beyond cancer, defects in CD3 zeta expression are associated with various immunodeficiencies and the T-cell dysfunction often observed in the tumor microenvironment.

Other names

CD247CD3-ZETAT3ZTCRZCD3zT-cell receptor T3 zeta chainCD3H

Signal transduction via phosphorylation of Immunoreceptor Tyrosine-based Activation Motifs (ITAMs) by Src-family kinases, leading to recruitment of ZAP-70 and subsequent T-cell activation.