Abstract
BH3-only proteins, such as Bim and Bad, contribute to tissue homeostasis by initiating apoptosis in a cell type- and stimulus-specific manner. Loss of Bim provokes lymphocyte accumulation in vivo and renders lymphocytes more resistant to diverse apoptotic stimuli and Bad has been implicated in the apoptosis of haematopoietic cells upon cytokine deprivation. To investigate whether their biological roles in apoptosis overlap, we generated mice lacking both Bim and Bad and compared their haematopoietic phenotype with that of the single-knockout and wild-type (wt) animals. Unexpectedly, bad(-/-) mice had excess platelets due to prolonged platelet life-span. The bim(-/-)bad(-/-) mice were anatomically normal and fertile. Their haematopoietic phenotype resembled that of bim(-/-) mice but lymphocytes were slightly more elevated in their lymph nodes. Although resting B and T lymphocytes from bim(-/-)bad(-/-) and bim(-/-) animals displayed similar resistance to diverse apoptotic stimuli, mitogen activated bim(-/-)bad(-/-) B cells were more refractory to cytokine deprivation. Moreover, combined loss of Bim and Bad-enhanced survival of thymocytes after DNA damage and accelerated development of γ-irradiation-induced thymic lymphoma. Unexpectedly, their cooperation in the thymus depended upon thymocyte-stromal interaction. Collectively, these results show that Bim and Bad can cooperate in the apoptosis of thymocytes and activated B lymphocytes and in the suppression of thymic lymphoma development.