UNIQUE T-CELL ANTAGONIST PROPERTIES OF THE EXACT SELF-CORRELATE OF A PEPTIDE ANTIGEN REVEALED BY SELF-SUBSTITUTION OF NON-SELF-POSITIONS INTHE PEPTIDE SEQUENCE

The role of self peptides in shaping the T cell receptor (TCR) reperto ire remains to be established. While TCR reactive to certain self-pept ides are thought to be deleted in the thymus, the selection of TCR spe cificity for foreign peptide reactivity appears to require recognition of self-peptide(s) bound to the groove of thymic major histocompatibi lity complex (MHC) molecules, This dichotomy suggests that different T CR affinities, accessory signals, and/or different sets of self-peptid es dictate the eventual fate of any given TCR-bearing clone, Recently, it has been established for several T cell epitopes that derivatives with substitutions in TCR-contact residues can antagonize the prolifer ation of T cell clones against the wild-type peptide antigen, Moreover , these altered peptide ligands have demonstrated activity in the posi tive selection of thymocytes with TCR reactive to the wild-type peptid e antigen, We have investigated the specificity of T cell antagonism w ith step-wise substitution of self-amino acids into each nonconserved position of a la-amino-acid foreign peptide antigen, Our data demonstr ate that the ability to antagonize proliferation without competition f or MHC binding is unique to the exact self derivative, where all five of the self-substitutions are inserted, These properties may specifica lly allow certain self-peptides to downregulate T cell activation to t he foreign ligand and/or provide a source of stimulation for immunolog ic memory. (C) 1996 Academic Press, Inc.