Duration and strength of extracellular signal-regulated kinase signals arealtered during positive versus negative thymocyte selection

During thymocyte development, high-affinity/avidity TCR engagement leads to the induction of negative selection and apoptosis, while lower TCR affinit y-avidity interactions lead to positive selection and survival. To elucidat e how these extracellular interactions are translated into intracellular si gnals that distinguish between positive and negative selection, we develope d a culture system in which naive double-positive thymocytes were either in duced to differentiate along the CD8(+) lineage pathway or were triggered f or clonal deletion. Using this system, we show that sustained low level act ivation of extracellular signal-regulated kinases (ERKs) promotes positive selection, whereas strong but transient ERK activation is coupled with nega tively selecting stimuli. Importantly, similar ERK activation profiles were demonstrated during positive selection for strong agonist ligands presente d at low concentrations or weak agonist ligands. This is consistent with th e affinity/avidity model and a role for strong or weak agonists during posi tive selection. Surprisingly, the addition of a pharmacological inhibitor w hich blocks ERK activation prevented the induction of negative selection. T hese data suggest that the duration and strength of the TCR signal is invol ved in discriminating between positive and negative selection.