Structural requirements for the interaction between class II MHC molecules and peptide antigens

Abstract

Previous work from our and other laboratories indicates that T cells recognize a complex between the MHC restriction element and peptide antigen fragments. This paper reviews the structural characteristics of the formation of such a complex. By analyzing in detail the interactions between purified IA^d and IE^d molecules and their peptide ligands, we found that some structural characteristics apply to both antigen-MHC interactions. In particular, we found: (1) each MHC molecule is capable of binding many unrelated peptides through the same peptide-binding site; (2) despite this permissiveness of binding, it is possible to define certain structural features of peptides that are associated with the capacity to bind to a particular MHC specificity (IA^d or IE^d); (3) IA^d and IE^d molecules recognize different and independent structures on the antigen molecule; (4) only ≈10% of the single amino acid substitutions tested on two IA^d-and IE^d-binding peptides had significant effect on their MHC-binding capacities, while over 80% of these substitutions significantly impaired T cell recognition of the Ia-peptide complex; (5) based on the segregation between residues that are crucial for T cell activation and Ia binding, the easiest model for the antigen-Ia-T-cell-receptor complex pictures the antigen molecule sandwiched in a planar conformation between the MHC and the T cell.