Early T cell development in the thymus depends on signals from the IL-7 receptor. To determine the nature of these signals, we examined the effects of IL-7 on very early thymocytes obtained from mouse embryos. We observed that pro-T cells at stages I, II and III underwent rapid apoptotic death in culture and that IL-7 protected them from death, whereas beyond these stages IL-7 did not have trophic activities. Cells deprived of IL-7 underwent death by mechanisms independent of p53 and fas pathways; caspase inhibitors blocked DNA fragmentation but did not maintain cell viability. The trophic activity of IL-7 was attributable in part to sustaining a favorable bcl-2/bax ratio, whereas bcl-x1, bcl-w and bad were not detectable in these cells. Emigration of cells from the thymus was examined using a new method for culturing the mouse embryonic thymus and collecting cells that emigrated from it. Tap1-/- thymuses were used to synchronize positive selection. Within 24 hr following positive selection, T cells expressing a mature phenotype emigrated from the thymus. These emigrants unexpectedly expressed CTLA-4, which normally represses T cell function. Although thymic emigrants tested in vitro recognized alloantigens presented on dendritic cells and proliferated, in vivo they did not induc acute graft-versus-host disease, suggesting that CTLA-4 or some other mechanism suppresses self reactivity of emigrants.
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