T cell receptor V alpha bias can be determined by TCR-contact residues within an MHC-bound peptide.

Many antigen-specific T cell responses show profound V-region biases in one or both chains of the TCR alpha beta heterodimer. We have examined how changes in residues within an MHC-bound peptide can influence V-region selection. Single-chain TCR transgenic mice were derived using a beta-chain specific for the Kb-restricted peptide from ovalbumin, OVA257-264. Transgenic T cells were stimulated in vitro using OVA257-264 or a single residue variant having a lysine to aspartic acid substitution at determinant position 7 (7D). Recent crystallographic analyses have shown that this variant residue is involved in direct contact with the TCR. Sequence analysis of the T cell populations showed that the majority OVA257-264-specific T cells used V alpha 10-positive TCR while the majority of the 7D-specific TCR expressed the V alpha 4 element. In both peptide responses we found that some cell lines appeared to be made up of more than one clone expressing the same V alpha sequence but having limited variation at the V-J junction. These results show that the TCR contact residues within the target peptide can influence V-region bias and suggest that the first and second hypervariable regions of the TCR are directly or indirectly involved in determining peptide specificity.