FIG 1.

Models for early steps of TCR signaling. (A) In the conventional model, coreceptor CD4/CD8 binds to MHC when agonist peptide is bound. In the absence of agonist pMHC, ITAM is unphosphorylated, and only in the presence of agonist peptide does ITAM become phosphorylated, leading to Zap70 binding and subsequent activation. (B) In contrast to the conventional model outlined above, it has been shown that even in the absence of agonist pMHC, Zap70 is bound to doubly phosphorylated ITAM but not activated. We suggest a mechanism by which Zap70 can bind to phosphorylated ITAM even in the absence of agonist pMHC, but due to slow subsequent phosphorylation of Tyr319 on Zap70 by Lck and binding of Lck to this residue, full activation is prevented until binding of agonist pMHC.