Structural Basis for T Cell Recognit ion o f Altered Peptide Ligands : A Single T Cell Receptor Can Productively Recognize a Large

T cells recognize short linear peptides bound to major histocompatibility complex ( M H C ) encoded molecules. Subtle molecular changes in peptide antigens produce altered peptide ligands (APLs), which induce different T cell responses from those induced by the antigenic ligand. A molecular basis for how these slight molecular variations lead to such different consequences for the T cell has not been described. To address this issue, we have made amino acid substitutions at the primary T cell receptor (TCR) contact residue of the murine hemoglobin determinant, Hb(64-76)/I-E k and produced 12 peptides that interact with the T C R of the T cell clone 3.L2. The 3.L2 T cell responds to these peptides, which vary 1 million-fold in their activity, and enables them to be ranked according to their relative ability to signal through the 3.L2 TCR. Such a ranking reveals that the ability of the 3.L2 T cell to respond to these peptides depends on how well the structure of the side chain at the primary T C R contact site mimics that of the Asn residue present in the antigenic ligand. The reactivity of the 3.L2 T cell also depends on an M H C contact residue that is next to the primary T C R contact residue, suggesting that conformation of the Asn side chain is also important. By using nonnatural amino acids at a T C R contact residue, we have demonstrated that APLs can be rationally designed based on structure. These data are consistent with a model in which the affinity of a peptideM H C complex for the T C R determines how the T cell will respond.