Critical relationship between TCR signaling potential and TCR affinity during thymocyte selection

Whether a developing thymocyte becomes positively or negatively selected is thought to be determined by the affinity/avidity of its TCR for MHC/peptid e ligands expressed in the thymus, Presumably, differences in affinity tran slate into differences in the potency of the ensuing TCR-mediated signals, and these differences in signal strength determine the outcome of thymocyte selection. However, there is little direct evidence establishing a relatio nship between TCR-ligand affinity and signal strength during positive and n egative selection. The TCR complex contains multiple signaling motifs, know n as immunoreceptor tyrosine-based activation motifs (ITAMs) that are requi red for T cell activation. To examine the effects of TCR signal strength on selection, the signaling potential of the TCR was modified by substituting transgenic TCR 5-chains containing either three, one, or zero ITAMs for en dogenous (3-ITAM) zeta -chain. These zeta -chain variants were then bred in to different alpha beta TCR transgenic backgrounds. We report that reductio ns in TCR signaling potential have distinct effects on the selection of thy mocytes expressing different TCRs, and that the requirement for zeta -chain ITAMs critically depends upon the specificity and apparently, affinity, of the TCR for its selecting ligand(s).