Efficient cell activation requires an optimal dwell-time of interaction between the TCR and the pMHC complex

Cytotoxic T cell (CTL) activation by antigen requires the specific detectio n of peptide-major histocompatibility class I (pMHC) molecules on the targe t-cell surface by the T cell receptor (TCR). We examined the effect of muta tions in the antigen-binding site of a K-b-restricted TCR on T cell activat ion, antigen binding and dissociation from antigen. These parameters were a lso examined for variants derived from a K-d-restricted peptide that was re cognized by a CTL clone, Using these two independent systems, we show that T cell activation can be impaired by mutations that either decrease or incr ease the binding half-life of the TCR-pMHC interaction. Our data indicate t hat efficient T cell activation occurs within an optimal dwell-time range o f TCR-pMHC interaction. This restricted dwell-time range is consistent with the exclusion of either extremely low or high affinity T cells from the ex panded population during immune responses.