A structural difference limited to one residue of the antigenic peptide can profoundly alter the biological outcome of the TCR-peptide/MHC class I interaction

The vesicular stomatitis virus (VSV) octapeptide RGYVYQGL binds to H-2K(b) and triggers a cytotoxic T cell response In mice. A variant peptide, RGYVYE GL (E6) with a glutamic acid for glutamine replacement at position 6 of the VSV peptide, elicits a T cell response with features that are quite differ ent from those elicited by the wild-type VSV peptide, The differences found in the nature of the T cells responding to the E6 peptide include changes in both the V beta elements and the sequences of the complementarity-determ ining region 3 loops of their TCRs, Further experiments found that the E6 p eptide can act as an antagonist for VSV-specific T cell hybridomas. To dete rmine whether these differences in V beta usage, complementarity-determinin g region 3 sequences, and the switch from agonism to antagonism are caused by a conformational change on the MHC, the peptide, or both, we determined the crystal structure of the variant E6 peptide bound to H-2K(b). This stru cture shows that the only significant structural difference between H-2K(b) /E6 and the previously determined n-2K(b)/VSV is limited to the side chain of position 6 of the peptide, with no differences in the MHC molecule. Thus , a minor conformational change In the peptide can profoundly alter the bio logical outcome of the TCR-peptide/MHC interaction.