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

The structure of the A6 alpha beta TCR/HTLV-1 Tax-peptide/MHC I complex wit h 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 associat ed with low affinity of the A6 alpha beta TCR for Tax-P6A/HLA-A2. We show t hat stepwise repair of a packing defect in the TCR/MHC interface using N-al kylated amino acids results in stepwise increases in TCR affinity and activ ity. Kinetic and thermodynamic measurements suggest that for some ligands t he 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.