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Differential Sensitivity to Mutations in a Single Peptide by Two TCRs Having Identical -Chains and Closely Related -Chains¹

Section of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06510

The TCR on CD4 T cells binds to and recognizes MHC class II:antigenic peptide complexes through molecular contacts with the peptide amino acid residues that face up and out of the peptide-binding groove. This interaction primarily involves the complementarity-determining regions (CDR) of the TCR - and -chains contacting up to five residues of the peptide. We have used two TCRs that recognize the same antigenic peptide and have identical V8.2 chains, but differ in all three CDR of their related V2 chains, to examine the fine specificity of the TCR:peptide contacts that lead to activation. By generating a peptide library containing all 20 aa residues in the five potential TCR contact sites, we were able to demonstrate that the two similar TCRs responded differentially when agonist, nonagonist, and antagonist peptide functions were examined. Dual substituted peptides containing an agonist residue at the N terminus, which interacts with CDR2, and an antagonist residue at the C terminus, which interacts with the CDR3, were used to show that the nature of the overall signal through the TCR is determined by a combination of the type of signal received through both the TCR - and -chains.

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