T-CELLS RECOGNIZE A GLYCOPEPTIDE DERIVED FROM TYPE-II COLLAGEN IN A MODEL FOR RHEUMATOID-ARTHRITIS

Even though most eucaryotic proteins are glycosylated, very Little is known on if, or how, the glycans influence essential immunological eve nts such as antigen processing, major histocompatibility complex (MHC) restricted presentation, and recognition by T cells. We have used syn thetic glycopeptides to elucidate the specificity of T cell hybridomas , obtained by immunization with the glycoprotein type II collagen in a mouse model for rheumatoid arthritis. To enable these studies, glycos ylated and suitably protected derivatives of (5R)-5-hydroxy-L-lysine, and the similar 5-hydroxy-L-norvaline, were prepared and then used in Fmoc solid-phase synthesis of glycopeptides related to the immunodomin ant fragment from type II collagen, CII(256-270). Evaluation of the sy nthetic glycopeptides provided evidence that antigen-presenting cells can indeed process glycoproteins to glycopeptides, which elicit a T ce ll response when presented by class II MHC molecules. A glycopeptide c arrying a single B-D-galactosyl residue attached to hydroxylysine at p osition 264 in the center of the CII(256-270) peptide was recognized b y most of the hybridomas in a way involving specific contacts between the carbohydrate and the T cell receptor. The results suggest an expla nation for the recent observation that glycosylated type II collagen i nduces more severe forms of arthritis in the mouse than deglycosylated type II collagen and provide additional knowledge on how rheumatoid a rthritis may occur also in humans.