Viral escape at the molecular level explained by quantitative T-cell receptor/peptide/MHC interactions and the crystal structure of a peptide/MHC complex

Viral escape, first characterized for the lymphocytic choriomeningitis viru s (LCMV) in a mouse transgenic for the P14 T cell-receptor (TCR), can be du e to mutations in T-cell epitopes. We have measured the affinity between th e H-2D(b) containing the wild-type and two of its "viral escape" epitopes, as well as other altered peptide ligands (APL), by using BIACORE analysis, and solved the crystal structure of H-2D(b) in complex with the wild-type p eptide at 2.75 Angstrom resolution. We show that viral escape is due to a 5 0 to 100-fold reduction in the level of affinity between the P14 TCR and th e binary complexes of the MHC molecule with the different peptides. Structu rally, one of the mutations alters a TCR contact residue, while the effect of the other on the binding of the TCR must be indirect through structural rearrangements. The former is a null ligand, while the latter still leads t o some central tolerance. This work defines the structural and energetic th reshold for viral escape. (C) 2000 Academic Press.