Breaking the kinetic window of T-cell activation

Abstract

T cells recognize peptide antigens associated with MHC molecules on the surface of target cells. The antigen specificity of T cells is conferred by the T-cell receptor (TCR). During the development of T cells, those expressing a TCR that recognizes a self-peptide–MHC weakly are selected for and those that bind to such a complex with high avidity are selected against. These positive and negative selection processes produce a peripheral T-cell repertoire that is MHC-restricted but not self-reactive. The ability of a peptide–MHC complex (pMHC) to trigger T-cell activation does not relate necessarily to the equilibrium binding affinity of the TCR–pMHC complex, but correlates better with the off-rate of the interaction. Small changes in the sequence of an antigenic peptide can lead to slightly faster off-rates; relatively small changes in the off-rate, and hence the half-life of the TCR–pMHC interaction, can affect greatly the ability of a ligand to trigger T cells. A single agonist pMHC has been shown to engage and down-regulate >100 TCR molecules from the T-cell surface. This process of ‘serial triggering’ is believed to be necessary for optimal T-cell signaling and activation. Further extrapolation has predicted that agonist TCR–pMHC interactions fall within a ‘kinetic window’, representing a compromise between sufficient time to allow all of the molecular steps required to trigger the TCR and a rapid enough dissociation from the triggered TCR to make it available for further cycles of binding and triggering. An ‘affinity ceiling’, beyond which there is no advantage to T-cell activation, is implicit in such models.