AUTOANTIGEN RECOGNITION BY HUMAN CD8 T-CELL CLONES - ENHANCED AGONISTRESPONSE INDUCED BY ALTERED PEPTIDE LIGANDS

Determination of immunodominant epitopes of MHC class I-restricted sel f-Ags and elucidation of TCR contact residues is of potential importan ce in providing a means of manipulating the immune response to self-Ag s in human autoimmune diseases. A computer algorithm was used to exami ne the sequences of the two major encephalitogenic proteins of myelin, MBP and PLP, for HLA-A2 binding motifs. Thirty-eight peptides with HL A-A2.1 binding motifs were synthesized and their binding to HLA-A2.1 w as measured. A panel of HLA-A2-restricted T cell clones directed again st the PLPp80-88 epitope, which exceeded the binding affinity of the o ther myelin-peptides tested by at least one order of magnitude, was ge nerated. Using a set of analogue peptides with single amino acid subst itutions, we detected a distinct pattern of TCR contact residues for e ach clone. Surprisingly, modification of different presumed TCR contac t residues generated superagonist peptides, which are defined as pepti des with equal or lower MHC binding affinity to HLA-A2 that induce hal f-maximal effector responses at 100-fold lower concentrations than the original peptide. These agonist peptides could drive cytotoxic T cell clones to proliferate, secrete cytokines, and clonally expand at conc entrations at which the native peptide induced only cytotoxic response s. The proliferation induced by the superagonist peptides gives additi onal evidence that the clonal expansion of CD8 T cell clones may in pa rt be regulated on the level of Ag recognition by the TCR.