A model depicting TCR-mediated ζ chain phosphorylation. The figure depicts the TCR (α and β) along with the associated CD3 chains and the p21 form of the ζ homodimer. In the resting state, some TCRs are associated with p21ζ, which bears phosphorylated tyrosines in ITAM B (3, 4) and C (5, 6) that can potentially be bound by up to four inactive ZAP-70 molecules (depicted in upper TCR complex). The Src family PTK Lck is shown myristoylated and associated with CD4 or CD8. The Src family PTK Fyn is not shown but is known to associate with the CD3ε subunit. Upon agonist binding there is receptor clustering (not shown), and CD4/8-associated Lck (and CD3ε-associated Fyn, not shown) can then phosphorylate the four tyrosines within the membrane-proximal ITAM (ITAM-A, tyrosines 1 and 2) to produce p23ζ. In addition, active Lck phosphorylates and activates bound ZAP-70, and tyrosines within the ITAMs of other CD3 subunits, resulting in the recruitment and activation of more ZAP-70 molecules (depicted in lower left). In contrast, upon binding to a partial agonist or an antagonist there is potentially less activation of Lck, which results in neither the full phosphorylation of the p21ζ into the p23ζ form (bottom right) nor the activation and recruitment of ZAP-70 (bottom right). Because of the blunted response through the TCR, signals that would normally result in T cell activation do not occur. Whether or not monophosphorylated ITAMs are formed and whether they serve to recruit negative regulators following partial agonist- or antagonist-TCR interaction will require further experimentation.