Thymocyte activation and death: a mechanism for molding the T cell repertoire.

The programmed death of thymocytes and T cells was studied. Injection of anti-TCR antibodies into adult mice caused the specific deletion of CD4+ CD8+ thymocytes, an effect that was largely reversed by cyclosporin A. Surprisingly, using either anti-TCR antibodies or superantigens, it was found that the susceptibility of these thymocytes to clonal deletion changed during ontogeny. Double positive thymocytes from newborn and young (3 week old) mice were readily depleted, whereas thymocytes from 1 week old mice were relatively refractory. The differences between these groups could not be accounted for by cell surface TCR expression, TCR-mediated early signal transduction pathways such as phosphoinositide hydrolysis or Ca2+ mobilization, or differences in susceptibility to Dex- or ionomycin-induced programmed cell death. These results suggest that there is a relatively synchronous wave of maturing thymocytes that are susceptible to deletional signals during fetal life and shortly after birth, but not 7 days after birth. By 3 weeks of age, the next wave (or waves) of susceptible cells have populated the thymus. These observations closely follow the experimental model known as "neonatal tolerance," and we suggest that the failure to tolerize 1 week old mice in that system reflects an alteration in the cells' susceptibility to clonal deletion. In a separate set of experiments exploring the mechanisms of PCD, it was found that although the activation- and glucocorticoid-induced PCD pathways were distinct (being distinguishable by their sensitivity to CsA and the glucocorticoid antagonist RU-486), they were mutually antagonistic. Attempts to identify the level of the antagonism failed to demonstrate any direct interference between the two stimuli, up to and including the transcription and translation of a GRE-controlled reporter gene. Based upon these observations, we propose the following model of thymocyte development: glucocorticoids eliminate thymocytes with little or no avidity for self; antagonism between glucocorticoids and cellular activation allows thymocytes that recognize self with low or moderate avidity to survive (positive selection); activation of thymocytes that recognize self with high avidity dominates the antagonistic effect of glucocorticoids, leading to PCD (negative selection).