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

Abstract

The vesicular stomatitis virus (VSV) octapeptide RGYVYQGL binds to H-2Kb and triggers a cytotoxic T cell response in mice. A variant peptide, RGYVYEGL (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 different 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 Vβ elements and the sequences of the complementarity-determining region 3 loops of their TCRs. Further experiments found that the E6 peptide can act as an antagonist for VSV-specific T cell hybridomas. To determine whether these differences in Vβ usage, complementarity-determining 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-2Kb. This structure shows that the only significant structural difference between H-2Kb/E6 and the previously determined H-2Kb/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 biological outcome of the TCR-peptide/MHC interaction.