Figure 1.

TCR/pMHCI/CD8 interactions represented in the model. (A) Kinetics of TCR/pMHCI/CD8 complex formation. TCRs and CD8s are located on the T-cell side and pMHCIs on the APC side. Four possible states are shown: in (I) and (II), pMHCI is not bound to CD8 whereas in (III) and (IV), pMHCI is bound to CD8; in (I) and (III), pMHCI is not bound to TCR/CD3 whereas in (II) and (IV), pMHCI is bound to TCR/CD3. Transition rates between these four states are indicated with forward rates labeled as λ_i and backward rates labeled as λ_−i (where i = 1, 2, 3, 4). The white circles in the tails of the TCR/CD3 complex represent the ITAMs, which are present on the cytoplasmic tails of the γ, δ, the two ϵ, and the two ζ polypeptide chains of the CD3 complex; only one such tail is indicated here, for clarity. There are n such ITAMs, with only three shown here for the sake of clarity. This part of the kinetic scheme is assumed to be in equilibrium. (B) The TCR/pMHCI bound states (II) and (IV) are further subdivided into n states each depending on the number of phosphorylated ITAMs, resulting in a Markov chain. The triggered states are the right-most ones where all n ITAMs have been phosphorylated (indicated as filled-in circles). At each state a reversal (at rate λ₋₁ or λ₋₄) to the unbound states (I) or (III), respectively, can occur. Transitions between the sequences occur at rates λ₂ and λ₋₂. Left-to-right transitions within the sequences correspond to ITAM phosphorylation by kinases such as p56^lck and ZAP-70, at rate nλ = n/T_R in the sequence with CD8 unbound and at rate $n{\mathrm{\lambda }}^{\ast }=n∕T_R^{\ast }$ in the chain with CD8 bound. The Markov chain serves to calculate the TCR triggering probability and is not assumed to be in equilibrium.