T-cell receptor (TCR) signal transduction: Biochemical mechanisms and possible clinical implications

The T-cell receptor (TCR) is a multiprotein complex composed of the Ti subunit responsible for antigen binding, the CD3 complex and the ζ family dimers involved in the TCR signal transduction. This function is mainly due to the presence of a 17 aminoacid motif, known as the ARAM (Antigen Recognition Activation Motifs) sequence, present in the cytoplasmic domains of the γ, δ, and ε chains of the CD3 complex and the ζ dimers. One of the earliest biochemical events after TCR cross-linking is the enhanced phosphorylation of several cellular substrates on tyrosine residues. Since the TCR/CD3 complex lacks intrinsic tyrosine kinase activity, five cytoplasmic protein tyrosine kinases (PTKs) belonging to three different families have been shown to be sequentially activated after TCR engagement: p56(lck) and p59(fyn) of the Src family, p70(zap) and p72(syk) of the Syk family and p50(csk) of the Csk family. p56(lck) interacts noncovalently with the cytoplasmic domains of the co-receptors CD4 and CD8, in helper and suppressor T cells, respectively; p59(fyn) has been shown to weakly associate directly with the TCR complex. The catalytic activity of the Src family kinases is regulated by the CD45 transmembrane phosphatase and the Csk cytosolic tyrosine-kinase. Both these enzymes act on the same C-terminal regulatory tyrosine residue of the Src-like PTKs. TCR stimulation rapidly induces tyrosine phosphorylation of p56(lck) and p59(fyn), whose most important cellular substrates are the ARAM sequences of the CD3 complex and the ζ chains. The phosphorylated ARAMs create the binding sites for the two SH2 domains of p70(zap), leading to p70(zap) activation. Even though p72(syk) is known to be activated after TCR stimulation, its exact temporal localization in the signaling cascade is not completely understood. Recruitment of downstream signal transducers, such as phospholipase C γ1 (PLCγ1) and Ras, follows p70(zap) activation. All these events lead to changes in gene expression, production of lymphokines and cell proliferation. This review focuses on the biochemical pathways activated by TCR engagement and on the posible clinic-therapeutic implications of the altered activity of the involved tyrosine-kinases.