Analysis of peptide/MHC-induced TCR downregulation: deciphering the triggering kinetics

The interaction of T-lymphocytes with antigen-presenting cells displaying a small number of specific peptide/major histocompatibility complexes results in the downregulation of a large number of T-cell receptors (TCR), suggesting serial TCR triggering. However, the details of TCR downregulation are controversial. In particular, the level of comodulation of nonengaged TCR reported by different authors ranges from essentially none to considerable levels. Here, we address this controversy using complementary experimental and mathematical techniques. We find that TCR downregulation is very rapid during the first 2-4 min after T-cell antigen-presenting cells contact formation. After this phase, TCR downregulation proceeds at a relatively slow rate. Statistical and computational analyses show that this pronounced change in downregulation kinetics is compatible with the notion of initial serial triggering of clustered TCR followed by serial triggering of individual TCR. We further propose a compatible mechanism for concurrent triggering of multiple TCR by a single peptide/major histocompatibility complex. We provide a unified picture of productive TCR engagement and downregulation in which TCR triggering characteristics evolve from an initial cooperative phase to a sustained phase of signal accumulation.