CD8+ T Cell Activation Is Governed by TCR-Peptide/MHC Affinity, Not Dissociation Rate

Abstract

Binding of peptide/MHC (pMHC) complexes by TCR initiates T cell activation. Despite long interest, the exact relationship between the biochemistry of TCR/pMHC interaction (particularly TCR affinity or ligand off-rate) and T cell responses remains unresolved, because the number of complexes examined in each independent system has been too small to draw a definitive conclusion. To test the current models of T cell activation, we have analyzed the interactions between the mouse P14 TCR and a set of altered peptides based on the lymphocytic choriomeningitis virus epitope gp33–41 sequence bound to mouse class I MHC Db. pMHC binding, TCR-binding characteristics, CD8+ T cell cytotoxicity, and IFN-γ production were measured for the peptides. We found affinity correlated well with both cytotoxicity and IFN-γ production. In contrast, no correlation was observed between any kinetic parameter of TCR-pMHC interaction and cytotoxicity or IFN-γ production. This study strongly argues for an affinity threshold model of T cell activation.