T cell antigen recognition at the cell membrane

T cell antigen receptors (TCRs) on the surface of T cells bind specifically to particular peptide bound major histocompatibility complexes (pMHCs) presented on the surface of antigen presenting cells (APCs). This interaction is a key event in T cell antigen recognition and activation. Most studies have used surface plasmon resonance (SPR) to measure the in vitro binding kinetics of TCR–pMHC interactions in solution using purified proteins. However, these measurements are not physiologically precise, as both TCRs and pMHCs are membrane-associated molecules which are regulated by their cellular environments. Recently, single-molecule förster resonance energy transfer (FRET) and single-molecule mechanical assays were used to measure the in situ binding kinetics of TCR–pMHC interactions on the surface of live T cells. These studies have provided exciting insights into the biochemical basis of T cell antigen recognition and suggest that TCRs serially engage with a small number of antigens with very fast kinetics in order to maximize TCR signaling and sensitivity.

► The TCR–pMHC interaction determines T cell fate and responsiveness.
► Single molecule assays measure the in situ binding kinetics of TCR–pMHC interactions.
► We propose a fast kinetics based TCR serial triggering model for T cell activation.