DIFFERENTIAL ACTIVATION OF HUMAN AUTOREACTIVE T-CELL CLONES BY ALTERED PEPTIDE LIGANDS DERIVED FROM MYELIN BASIC-PROTEIN PEPTIDE-(87-99)

We have examined the functional consequences induced by interaction of DR2a-restricted myelin basic protein (MBP) (87-99)-specific T cell cl ones (TCC) with altered peptide ligands (APL) derived from MBP peptide (87-99). The immunodominant MBP peptide (87-99) has been implicated a s a candidate antigen in multiple sclerosis (MS) by several lines of e vidence. In the present study, we have defined the T cell receptor (TC R) contact residues for DR2a-restricted, (87-99)-specific T helper typ e 1 T cells to design APL suitable to modify the functions of such T c ells potentially relevant for the pathogenesis of MS. We show that neu tral (L-alanine substitutions) or conservative exchanges of the primar y and secondary TCR contact residues lead to various alterations of T cell function, ranging from differences in interleukin-2 receptor up-r egulation to anergy induction and TCR antagonism. The potential useful ness of APL as an immunomodulating therapy for DR2(+) MS patients is d iscussed.