The specificity and orientation of a TCR to its peptide-MHC class II ligands

A T cell-mediated immune response is mainly determined by the 3-5 aa residues that protrude upwards from a peptide bound to an MHC molecule. Alterations of these peptide residues can diminish, eliminate or radically alter the signal that the T cell receives through its T cell receptor (TCR). We have used peptide immunizations of normal mice and mice carrying alpha or beta chain TCR transgenes to identify three distinct peptide contact points. One, near the carboxyl terminus of the peptide, involves the beta chain CDR3 region; the second was centrally located and interacted with both the alpha and beta chain CDR3 loops; the third was near the amino terminus of the peptide, and affected V alpha gene usage, but not the structure of CDR3 of either TCR chain. Based on these results, we propose an orientation for the TCR of this cloned line and argue for its generality.