Conversion of a T cell antagonist into an agonist by repairing a defect in the TCR/peptide/MHC interface: Implications for TCR signaling

The structure of the A6 alpha beta TCR/HTLV-1 Tax-peptide/MHC I complex with proline 6 of Tax substituted with alanine (P6A), an antagonist, is nearly identical to the structure with wild-type Tax agonist. Neither the proline in the agonist nor the alanine in the antagonist is contacted by the alpha beta TCR. Here, we demonstrate that antagonist activity of P6A is associated with low affinity of the A6 alpha beta TCR for Tax-P6A/HLA-A2. We show that stepwise repair of a packing defect in the TCR/MHC interface using N-alkylated amino acids results in stepwise increases in TCR affinity and activity. Kinetic and thermodynamic measurements suggest that for some ligands the range of T cell outcomes does not correlate with either their alpha beta TCR affinity or the half-life of the alpha beta TCR/peptide/MHC complex.