A sequential model for T-cell activation

Following TCR engagement, CD4-associated Lck is brought into proximity of the CD3 complex and phosphorylates the ITAMs (phoshorylation depicted as red dots). Doubly phosphorylated ITAMs then interact with the tandem SH2 domains of ZAP-70. After ITAM binding, ZAP-70 can be phosphorylated by Lck, which results in activation of ZAP-70 catalytic activity and its autophosphorylation. Active ZAP-70 subsequently phosphorylates LAT and SLP-76, which function as scaffolds to recruit many other signaling molecules and lead to T-cell activation, proliferation, and differentiation (not shown).