Probing Molecular Interactions within Class II MHC A~q/Glycopeptide/T-Cell Receptor Complexes Associated with Collagen-Induced Arthritis

摘要

T cells obtained in a mouse model for rheumatoid arthritis are activated by a glycopeptide fragment from rat type II collagen(CII)bound to the class II major histocompatibility complex A~q molecule.We report a comparative model of Aq in complex with the glycopeptide CII260-267.This model was used in a structure-based design approach where the amide bond between Ala~(261)and Gly~(262)in the glycopeptide was selected for replacement with psi[COCH2],psi[CH2NH_2~+],and psi[(E)-CR=CH] isosteres.Ala-Gly isostere building blocks were then synthesized and introduced in CIJ260-267 and CII259-273 glycopeptides.The modified glycopeptides were evaluated for binding to the A~q molecule,and the results were interpreted in view of the A~q/glycopeptide model.Moreover,recognition by a panel of T-cell hybridomas revealed high sensitivity for the backbone modifications.These studies contribute to the understanding of the interactions in the ternary A~q/glycopeptide/T-cell receptor complexes that activate T cells in autoimmune arthritis and suggest possibilities for new vaccination approaches.