CARRIER-REACTIVE HAPTEN-SPECIFIC CYTOTOXIC T-LYMPHOCYTE CLONES ORIGINATE FROM A HIGHLY PRESELECTED T-CELL REPERTOIRE - IMPLICATIONS FOR CHEMICAL-INDUCED SELF-REACTIVITY

We have recently described trinitrophenyl (TNP)-specific cytotoxic T l ymphocyte (CTL) clones from C57BL/6 mice specific for hapten-modified peptides bearing a TNP-lysine in a peripheral position, i.e. in positi on 7 of H-2K(b)-bound octapeptides. CTL recognition of such determinan ts is always sequence-dependent due to co-recognition of TNP as well a s amino acid side chains of the carrier peptide. By the use of glycine -based designer peptides for primary induction of CTL in vitro, we hav e identified two sub-epitopes on individual position 7-haptenated pept ides that form two TcR contact points and which can be independently r ecognized by cloned CTL. One of these sub-epitopes is represented by t he hapten itself, the other by the amino acids tyrosine and lysine in positions 3 and 4 of the carrier peptide, respectively. Immunization w ith such TNP-modified peptides frequently results in the specific indu ction of CTL also reacting with the unmodified carrier peptides. DNA s equence analyses of the TcR revealed an extraordinary similarity of se veral independent TcR of CTL from individual mice and induced with dif ferent TNP-peptides. These receptor similarities clearly correlate wit h structural elements common to the immunizing peptides and suggest th eir origin from positive thymic selection of TcR on K-b-associated sel f-peptides bearing Tyr in position 3. Our data provide additional info rmation concerning the topology of TcR binding to peptide/MHC complexe s with, but also without, TNP. They also indicate a mechanism which mi ght explain the potential of chemicals or drugs to induce autoimmune p henomena.