Calculations show substantial serial engagement of T cell receptors.

The serial engagement model provides an attractive and plausible explanation for how a typical antigen presenting cell, exhibiting a low density of peptides recognized by a T cell, can initiate T cell responses. If a single peptide displayed by a major histocompatibility complex (MHC) can bind, sequentially, to different T cell receptors (TCR), then a few peptides can activate many receptors. To date, arguments supporting and questioning the prevalence of serial engagement have centered on the down-regulation of TCR after contact of T cells with antigen presenting cells. Recently, the existence of serial engagement has been challenged by the demonstration that engagement of TCR can down-regulate nonengaged bystander TCR. Here we show that for binding and dissociation rates that characterize interactions between T cell receptors and peptide-MHC, substantial serial engagement occurs. The result is independent of mechanisms and measurements of receptor down-regulation. The conclusion that single peptide-MHC engage many TCR, before diffusing out of the contact region between the antigen-presenting cell and the T cell, is based on a general first passage time calculation for a particle alternating between states in which different diffusion coefficients govern its transport.