A mathematical analysis of TCR serial triggering and down-regulation

Despite the increasing knowledge on the pathways involved in TCR signal tra nsduction and T cell activation, the molecular mechanism of TCR triggering by ligand, MHC-peptide complexes, is still elusive and controversial. The p resent paper addresses the controversy on the early events of TCR engagemen t and triggering. Mathematical modelling techniques are applied to experime ntal data to infer plausible molecular mechanisms of TCR triggering and dow n-regulation. A similar approach has been followed by Bachmann et al. (Eur. J, Immunol 1998, 28: 2571-2579), who concluded that the TCR triggering req uires the formation of MHC-TCR dimers or trimers. We report here the failur e to generalize this conclusion to the data reported by Valitutti et at. (N ature 1995, 375: 148-151). We show that there are several kinetic features in these experimental curves of TCR down-regulation that cannot be explaine d by the simple model proposed by Bachmann et al. unless some phenomenologi cal extensions are considered. These extensions are: (1) a ligand independe nt turnover of the TCR; (2) a transient accumulation of triggered TCR; (3) a high order of TCR triggering kinetics; and (4) two pools of membrane TCR in dynamic equilibrium.