ON DEFINING THE RULES FOR INTERACTIONS BETWEEN THE T-CELL RECEPTOR AND ITS LIGAND - A CRITICAL ROLE FOR A SPECIFIC AMINO-ACID RESIDUE OF THE T-CELL RECEPTOR-BETA CHAIN

The specificity of T cell-mediated immune responses is primarily deter mined by the interaction between the T cell receptor (TCR) and the ant igenic peptide presented by the major histocompatibility complex (MHC) molecules, To refine our understanding of interactions between the TC R and the antigenic peptide of vesicular stomatitis virus (VSV) presen ted by the class I MHC molecule H-2K(b), rye constructed a TCR alpha c hain transgenic mouse in a TCR alpha-deficient background to define sp ecific structural features in the TCR beta chain that are important fo r the recognition of the VSV/H-2K(b) complex. We found that for a give n peptide, a peptide-specific, highly conserved amino acid could alway s be identified at position 98 of the complementarity-determining regi on 3 (CDR3) loop of TCR beta chains, Further, we demonstrated that sub stitutions at position 6, but not position 1, of the VSV peptide induc ed compensatory changes in the TCR in both the amino acid residue at p osition 98 and the length of the CDR3 beta loop. We conclude that the amino acid residue at position 98 of the CDR3 beta loop is a key resid ue that plays a critical role in determining the specificity of TCR-VS V/H-2K(b) interactions and that a specific length of the CDR3 beta loo p is required to facilitate such interactions. Further, these findings suggest that the alpha and beta chains of TCRs interact with amino ac id residue(s) toward the N and C termini of the VSV peptide, respectiv ely, providing functional evidence for the orientation of a TCR with i ts peptide/MHC ligand as observed in the crystal structures of TCR/pep tide/MHC complexes.