Molecular analysis of the interaction between T cell receptors and the VSV peptide presented by murine class I H-2K(b) molecules in TCR (alpha) chain transgenic mice

Abstract

The CDR3 loops of TCR {dollar}\alpha{dollar} and {dollar}\beta{dollar} chains are predominantly involved in contact with the antigenic peptides presented by MHC molecules. To define the specific structural features important for the interaction between the CDR3{dollar}\beta{dollar} loop of TCRs and the VSV peptide ({dollar}\sp1{dollar}RGYVYQG{dollar}\sp8{dollar}L) presented by the H-2K{dollar}\rm\sp{lcub}b{rcub}{dollar} molecule, we constructed TCR {dollar}\alpha{dollar} chain transgenic mice in a TCR {dollar}\alpha{dollar}-deficient background using the TCR {dollar}\alpha{dollar} chain of a VSV peptide-specific T cell clone (N30.7).Using these mice as an analytic system, we analyzed the CDR3{dollar}\beta{dollar} sequences of TCRs that specifically recognize and respond to the VSV peptide or its variants altered at position 1 or 6 of the VSV peptide. We found that substitutions at position 6, but not position 1, of the VSV 8-mer peptide induced compensatory changes in both the amino acid residue at position 98 and the length of the CDR3{dollar}\beta{dollar} loop of TCRs. Such results provide strong in vivo evidence for a specific CDR3{dollar}\beta{dollar}-peptide interaction in the class I MHC system and, more importantly, identify the amino acid residue at position 98 of the CDR3{dollar}\beta{dollar} loop as a key residue that plays a critical role in determining the specificity of TCR-VSV/H-2K{dollar}\rm\sp{lcub}b{rcub}{dollar} interactions. These results also indicate that the length of the CDR3{dollar}\beta{dollar} loop is important for the interaction between a TCR and its ligand and suggest that the TCR {dollar}\alpha{dollar} chain interacts with amino acid residues towards the C-terminus of the VSV peptide whereas the TCR {dollar}\alpha{dollar} chain interacts with amino acid residues towards the N-terminus of the VSV peptide.