A mathematical analysis of TCR serial triggering and down-regulation.

Despite the increasing knowledge on the pathways involved in TCR signal transduction and T cell activation, the molecular mechanism of TCR triggering by ligand, MHC-peptide complexes, is still elusive and controversial. The present paper addresses the controversy on the early events of TCR engagement and triggering. Mathematical modelling techniques are applied to experimental data to infer plausible molecular mechanisms of TCR triggering and down-regulation. A similar approach has been followed by Bachmann et al. (Eur. J. Immunol. 1998, 28: 2571 - 2579), who concluded that the TCR triggering requires the formation of MHC-TCR dimers or trimers. We report here the failure to generalize this conclusion to the data reported by Valitutti et al. (Nature 1995, 375: 148 - 151). We show that there are several kinetic features in these experimental curves of TCR down-regulation that cannot be explained by the simple model proposed by Bachmann et al. unless some phenomenological extensions are considered. These extensions are: (1) a ligand independent 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.