CD247/CD3Z: The Gatekeeper of T-cell Activation
Structurally, the TCR-CD3 complex consists of the TCR and the CD3 complex. The TCR is a heterodimer composed of two different protein chains. In 95% of T-cells the TCR consists of an alpha (α) and beta (β) chain, whereas 5% of T-cells have a gamma (γ) and delta (δ) chain instead. Only the α/β heterodimer interacts with the CD3 complex with both the α and β chain have a variable domain that is capable of binding to an MHC molecule1,4. The CD3 complex consists of four CD3 chains (CD3D. CD3G, CD3E and CD247/CD3Z) which form two heterodimers (CD3D-CD3E and CD3G-CD3E) flanking either side of the TCR and one homodimer of CD247/CD3Z sitting below the α/β heterodimer1,2. All four CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain that are capable of being phosphorylated.
The activation of the TCR by an MHC molecule sets off a signaling cascade that allows T-cells to differentiate, proliferate and secrete cytokines. First, depending on the type of T-cell either the TCR co-receptor CD4 or CD8 binds to the MHC molecule activating the tyrosine kinase Lck5,6. Next, Lck phosphorylates the intracellular ITAMs of the CD3 complex creating a docking site for protein kinase ZAP-70. CD247/CD3Z is particularly important because it's the only CD3 component that has multiple ITAM sites which allows ZAP-70 to bind in a position that enables the phosphorylation of the transmembrane protein linker of activated T cells (LAT)7,8. Once phosphorylated, LAT acts as a docking site for SH2 domain-containing proteins recruiting multiple downstream signaling molecules. Ultimately, this culminates in the activation of important signaling pathways including the Ras-MEK-ERK pathway and transcription factors NF-kB, NFAT and AP-11.
Given the role of CD247/CD3Z in T-cell activation it's not surprising that it may also be an important biomarker for evaluating the immune status of patients with diseases characterized by chronic inflammation9,10,11,12,13. During chronic inflammation T-cell activation is suppressed, which is associated with the downregulation of only CD247/CD3Z while the remaining components of the TCR-CD3 complex are unaffected14. Additionally, when inflammation is treated CD247/CD3Z levels normalize suggesting it's a correlate for T-cell activation. Given this, CD247CD3Z is being investigated as a potential biomarker for determining the immune status and disease severity where traditional inflammation biomarkers like hs-CRP and TNF-α are not specific to T-cell activation14.
Taken together, CD247/CD3Z plays an incredibly important role in the activation of T-cells. As part of the TCR-CD3 complex, CD247/CD3Z is an important docking site for ZAP-70 which is critical for downstream signaling of the TCR-CD3 complex. Lastly, CD247/CD3Z is also potentially a valuable biomarker for checking the immune status in patients.