FINE SPECIFICITY OF THE MYELIN-REACTIVE T-CELL REPERTOIRE - IMPLICATIONS FOR TCR ANTAGONISM IN AUTOIMMUNITY

The use of altered peptide ligands (APL) to modulate T cell responses has been suggested as a means of treating T cell-mediated autoimmune d isorders. We have assessed the therapeutic potential of TCR antagonist peptides in autoimmunity using murine experimental autoimmune encepha lomyelitis (EAE) as a model, The Tg4 transgenic mouse expresses an MHC class II-restricted TCR specific for the immunodominant encephalitoge nic epitope of myelin basic protein, Acl-9 (acetylated N-terminal nona mer), We have used T cell lines derived from Tg4 mice to define the TC R contact residues within;Acl-9. APL with appropriate substitutions at the primary TCR contact residue were effective antagonists of Tg4 T c ells. These antagonist APL, however, were found to induce EAE in susce ptible, nontransgenic strains of mice. Underlying this, the Acl-9-spec ific T cell repertoire of normal mice, rather than reflecting the Tg4 phenotype, showed considerable diversity in fine specificity and was a ble to respond to the Tg4 antagonist APL, Defining antagonist APL in v itro using T cell clones, therefore, was not a reliable approach for t he identification of APL with EAE-suppressing potential in vivo. Our f indings highlight the complexities of the autoreactive T cell repertoi re and have major implications for the use of APL in autoimmune diseas es.