EPITOPE GLYCOSYLATION PLAYS A CRITICAL ROLE FOR T-CELL RECOGNITION OFTYPE-II COLLAGEN IN COLLAGEN-INDUCED ARTHRITIS

Immunization of mice with type II collagen (CII) leads to collagen-ind uced arthritis (CIA), a model for rheumatoid arthritis. T cell recogni tion of CII is believed to be a critical step in CIA development. We h ave analyzed the T cell determinants on CII and the TCR used for their recognition, using twenty-nine T cell hybridomas derived from C3H.Q a nd DBA/1 mice immunized with rat CII. All hybridomas were specific for the CII(256-270) segment. However posttranslational modifications (hy droxylation and variable O-linked glycosylation) of the lysine at posi tion 264 generated five T cell determinants that were specifically rec ognized by different T cell hybridoma subsets. TCR sequencing indicate d that each of the five T cell epitopes selected its own TCR repertoir e, The physiological relevance of this observation was shown by in viv o antibody-driven depletion of TCR V alpha 2-positive T cells, which r esulted in an inhibition of the T cell proliferative response in vitro towards the non-modified CII(256-270), but not towards the glycosylat ed epitope. Most hybridomas (20/29) specifically recognized CII(256-27 0) glycosylated with a monosaccharide (beta-D-galactopyranose). We con clude that this glycopeptide is immunodominant in CIA and that posttra nslational modifications of CII create new T cell determinants that ge nerate a diverse TCR repertoire.