What do TCR–pMHC crystal structures teach us about MHC restriction and alloreactivity?

MHC-encoded molecules govern immune responses by presenting antigenic peptides to T-cell receptors (TCRs). Several crystal structures of TCR–pMHC (peptide–MHC) complexes have unveiled the atomic details of this interaction, which is crucial to T-cell activation. By combining these data with biological and thermodynamical results, we revisit the structural basis of TCR crossreactivity and alloreactivity and the dynamics of the TCR binding process. Some emerging principles are at variance with recently proposed models of TCR recognition that would bring one back to ‘dual recognition’ models, in which TCR discriminates which part of its ligand is MHC and which part is peptide