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

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 Aq 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 Ala261 and Gly262 in the glycopeptide was selected for replacement with ψ[COCH2], ψ[CH2NH2+], and ψ[(E)-CHCH] isosteres. Ala-Gly isostere building blocks were then synthesized and introduced in CII260-267 and CII259−273 glycopeptides. The modified glycopeptides were evaluated for binding to the Aq molecule, and the results were interpreted in view of the Aq/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 Aq/glycopeptide/T-cell receptor complexes that activate T cells in autoimmune arthritis and suggest possibilities for new vaccination approaches.