T-CELL RECOGNITION MOTIFS OF AN IMMUNODOMINANT PEPTIDE OF MYELIN BASIC-PROTEIN IN PATIENTS WITH MULTIPLE-SCLEROSIS - STRUCTURAL REQUIREMENTS AND CLINICAL IMPLICATIONS

Myelin basic protein (MBP)-reactive T cells may play an important role in the pathogenesis of multiple sclerosis (MS). The T cell response t o the 83-99 region of MBP represents a dominant autoreactive response to MBP in MS patients of DR2 haplotype, in this study, a large panel o f DR2- and DR4-restricted T cell clones specific for the! MBP83-99 pep tide were examined for the recognition motifs and structural requireme nts for antigen recognition using alanine-substituted peptides. Our st udy revealed that although the recognition motifs of the T cell clones were diverse, the TCR contact residues within the 83-99 region of MBP were highly conserved. Two central residues (Phe90 and Lys91) sewed a s the critical TCR contact points for both DR2- and DR4-restricted T c ell clones. Single alanine substitution at residue 90 or residue 91 ab olished the responses of 81-95 % of the T cell clones while a double a lanine substitution rendered all T cell clones unresponsive. It was al so demonstrated in this study that the substituted peptides altered th e cytokine profile of some, but not all, T cell clones. Some MBP83-99- specific T cell clones were able to sustain alanine substitutions and were susceptible to activation by microbial antigens. The study has an important implication in designing a peptide-based therapy far MS.