MOLECULAR-BASIS FOR DEGENERATE T-CELL RECOGNITION OF ONE PEPTIDE IN THE CONTEXT OF SEVERAL DR MOLECULES

We report the study of one CD4(+) T-cell clone that recognizes peptide HA306-320 in the concert of autologous DR1101 molecules as well as of allogeneic DR1301, DR0402, DR1501, and DR1601 molecules. This degener ate T-cell recognition is mediated by a single T-cell receptor (TCR) a s judged by both TCR-V beta sequencing and cold-target competition ass ays. Restriction analysis shows that substitutions of DR residues with in the third hypervariable region result in a loss of T-cell reactivit y, which is restored by additional substitutions in che first and/or s econd hypervariable regions. Thus, there is no correlation between ant igen presentation abilities of the different allelic DR products and t he degree of sequence homology between these products. DR residues who se substitution is compatible with T-cell recognition potentially inte ract with peptides rather than with TCRs by virtue of their location i n the floor of the groove or as previously documented for residues of the a-helix. Furthermore, antigen presentation by allogeneic DR molecu les occurs independently of their affinity for the peptide, as determi ned in cell surface-binding assays using biotinylated HA306-320. Altog ether these data suggest that degenerate T-cell recognition mainly dep ends on an influence of polymorphic DR residues on the configuration a dopted by the peptide in the DR groove so that the epitope is left int act.