MODIFICATIONS OF PEPTIDE LIGANDS ENHANCING T-CELL RESPONSIVENESS IMPLY LARGE NUMBERS OF STIMULATORY LIGANDS FOR AUTOREACTIVE T-CELLS

In this report, we demonstrate for autoreactive T cell clones that sin gle amino acid modifications of the antigenic ligand can result in not only abrogated, decreased, or unmodified, but also increased, T cell responsiveness (superagonist ligands). We further studied the effects of combinations of multiple substitutions with different effects in si ngle peptides. Experiments with peptides carrying multiple amino acid exchanges revealed that the final outcome of TCR ligation by a given l igand is the integration of negative, neutral, and positive effects of each single residue, In addition, the introduction of superagonist su bstitutions together with nonconservative modifications of primary and secondary TCR contacts resulted in stimulatory ligands, These finding s indicate that: 1) the specificity of a single TCR is highly degenera te; 2) ligands exist for autoreactive T cells that have higher agonist activity than the autoantigen itself; 3) the rules to search for cros s-reactive epitopes in autoimmunity should take into account that amin o acids at certain positions within an antigenic peptide may exert sup eragonist activity and compensate for the negative effects of residues at other positions that would otherwise not be tolerated.