Modulation of T cell function by TCR/pMHC binding kinetics

The interaction between the T cell receptor (TCR) and the peptide-MHC complex (pMHC) at the interface between the T cell and the antigen presenting cell (APC) is the main event controlling the specificity of antigen recognition by T cells. It is thought that TCR/pMHC binding kinetics are critical for the selection of the T cell repertoire in the thymus, as well as the activation of mature T cells in the periphery. One of the binding parameters that conditions T cell activation by pMHC ligands is the half-life of the TCR/pMHC interaction. This kinetic parameter is highly significant for the regulation of T cell activation and therefore determines the capacity of T cells to respond against pathogen- and tumor-derived antigens, avoiding self-reactivity. Several studies support the notion that T cells are activated only by TCR/pMHC interactions that are above a threshold of half-life. pMHC complexes that bind TCRs with half-lives below that threshold behave as null or antagonistic ligands. However, since prolonged half-lives can also impair T cell activation, there seems to be a ceiling for the TCR/pMHC half life that leads to efficient activation of T cells. According to these observations, efficient T cell activation would require an optimal half-life of TCR/pMHC interaction. These kinetic restrictions for T cell activation are important to generate a protective adaptive immune response minimizing cross-reactivity against self-constituents. The nature of the TCR/pMHC interaction defines in the thymus whether a thymocyte develops into a mature T cell or is eliminated by apoptosis. In addition, the kinetics of TCR/pMHC binding can determine the type of response shown by mature T cells in the periphery. Although several studies have focused on the modulation of T cell function by the affinity of the TCR/pMHC interaction, the binding kinetics rules governing T cell activation remain poorly understood. Here we review recent data and propose a new model for the regulation of T cell function by TCR/pMHC binding kinetics.