Calculations show substantial serial engagement of T cell receptors

The serial engagement model provides an attractive and plausible explanatio n for how a typical antigen presenting cell, exhibiting a low density of pe ptides recognized by a T cell, can initiate T cell responses. If a single p eptide displayed by a major histocompatibility complex (MHC) can bind, sequ entially, to different T cell receptors (TCR), then a few peptides can acti vate many receptors. To date, arguments supporting and questioning the prev alence of serial engagement have centered on the down-regulation of TCR aft er contact of T cells with antigen presenting cells. Recently, the existenc e of serial engagement has been challenged by the demonstration that engage ment of TCR can down-regulate nonengaged bystander TCR, Here we show that f or binding and dissociation rates that characterize interactions between T cell receptors and peptide-MHC, substantial serial engagement occurs. The r esult is independent of mechanisms and measurements of receptor down-regula tion. The conclusion that single peptide-MHC engage many TCR, before diffus ing 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.