Magnitude of protein tyrosine phosphorylation-linked signals determines growth versus death of thymic T lymphocytes.

Using concanavalin A (Con A) as a multireceptor-reactive agonist, we studied the relationship between the growth or death of thymic T lymphocytes and the agonist concentration-dependent magnitude of the intracellularly delivered signal. Both immature and mature thymic T lymphocytes were subjected to a high concentration of Con A-mediated signal for apoptotic cell death. In this model, a number of cellular proteins including mitogen activated protein kinases were phosphorylated at tyrosine depending on the concentration of Con A. This effect was followed by corresponding increase in serine 73 phosphorylation of c-jun and transcription of c-fos. DNA fragmentation and cell membrane disruption developed concomitantly after stimulation with high concentrations of Con A. The addition of inhibitors of protein kinases which completely inhibited the growth of cells stimulated with low concentrations of Con A only partially prevented death, and even promoted DNA fragmentation of cells stimulated with high concentrations of Con A. The dissociated sensitivities of Con A-mediated cell growth and cell death to the inhibitors were, however, shown to be due to the different efficiency of inhibition of high and low levels of intracellularly delivered signals. The results indicate that the magnitude of signaling could be the principal element that determines the growth versus death of thymic T lymphocytes.