Two-step binding mechanism for T-cell receptor recognition of peptide–MHC

T cells probe a diverse milieu of peptides presented by molecules of the major histocompatibility complex (MHC) by using the T-cell receptor (TCR) to scan these ligands with high sensitivity and specificity1. Here we describe a physical basis for this scanning process by studying the residues involved in both the initial association and the stable binding of TCR to peptide–MHC, using the well-characterized TCR and peptide–MHC pair of 2B4 and MCC-IEk (moth cytochrome c, residues 88–103)2. We show that MHC contacts dictate the initial association, guiding TCR docking in a way that is mainly independent of the peptide. Subsequently, MCC-IEk peptide contacts dominate stabilization, imparting specificity and influencing T-cell activation by modulating the duration of binding. This functional subdivision of the peptide–MHC ligand suggests that a two-step process for TCR recognition facilitates the efficient scanning of diverse peptide–MHC complexes on the surface of cells and also makes TCRs inherently crossreactive towards different peptides bound by the same MHC.