Bad is a distant relative of Bcl-2 and acts to promote cell death. Here, we show that Bad expression levels are greatly increased in thymocytes during apoptosis. We generated bad transgenic mice to study the action of upregulated Bad expression on T cell apoptosis. The T cells from these mice are highly sensitive to apoptotic stimuli, including anti-CD95. The numbers of T cells are greatly depleted and the processes of T cell development and selection are perturbed. We show that the proapoptotic function of Bad in primary T cells is regulated by Akt kinase and that Bad overexpression enhances both cell cycle progression and interleukin 2 production after T cell activation. These data suggest that Bad can act as a key regulator of T cell apoptosis and that this is a consequence of its upregulation after exposure to death stimuli.
T cell development is characterized by the induction of apoptosis in most immature thymocytes and the rescue from apoptosis of a small proportion of cells by the process of positive selection.Up‐regulation of the anti‐apoptotic molecule Bcl‐2 is associated with thymocytes undergoing positive selection and a bcl‐2 transgene promotes the generation of mature T cells. In contrast,mice transgenic for the pro‐apoptotic molecule Bax show impaired T cell maturation. We have used fetal thymic organ culture to determine the action of Bcl‐2 and Bax on positive selection of thymocytes. Our data show that Bcl‐2 and Bax do not alter the number of thymocytes positively selected by a defined peptide ligand. This implies that Bcl‐2 and Bax alter the production of mature T cells in vivo by influencing thymocyte viability rather than by direct action on positive selection. It also presents a solution to the `chicken‐and‐egg' scenario relating to Bcl‐2 up‐regulation and positive selection. The data suggest that the up‐regulation of Bcl‐2 associated with T cell maturation is a consequence of positive selection rather than a cause of it.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.