T cells like a firm molecular handshake

Abstract

T cell activation is one of the most extensively studied intercellular recognition processes. Adaptive immune responses are initiated when a T cell interacts with major histocompatibility complex molecules bearing mixtures of different peptides (MHC peptide) on the surface of an antigen-presenting cell through formation of an immunological synapse (1). The presence of just a few functionally defined agonist MHC peptide complexes in the synapse initiates the T cell response (2). Although CD4 or CD8 coreceptors also interact with the MHC molecules, the binding sites are some distance away from the antigen peptide. The only known direct physical con-tact the peptide has with the T cell is through the T cell antigen receptor (TCR). This interaction is analogous to a handshake where the interacting binding sites are tethered to large bodies. How could TCR tell different peptides from such a handshake? The kinetic-proofreading model suggests that signaling events downstream of the TCR–MHC peptide interaction require time for assembly and reaction such that the half-lives of the TCR–MHC peptide complexes can be used to rank the biological efficacy of different agonist MHC peptide complexes (3). However, numerous exceptions have been observed in which the potencies of MHC peptides to trigger T cell activation do not correlate with the half-lives of their interactions with TCR. A recent study (4) has shown that multiplying the half-life with the heat capacity change between the bound and free states could bring several outliers into line, but the physical basis of this correlation was not clear.