Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis.

Bak and Bax are required and redundant regulators of an intrinsic mitochondrial cell death pathway. To analyze this pathway in T cell development and homeostasis, we reconstituted mice with Bak(-/-)Bax<(-/-) hematopoietic cells. We found that the development and selection of Bak(-/-)Bax(-/-) thymocytes was disrupted, with altered representation of thymic subsets and resistance to both death-by-neglect and antigen receptor-induced apoptosis. Elimination of Bak(-/-)Bax(-/-) T cells that responded to endogenous superantigen was also reduced. Despite more efficient early reconstitution and apoptotic resistance of Bak(-/-)Bax(-/-) thymocytes, thymic cellularity declined over time. Reduced thymic cellularity resulted from a progressive cessation of thymopoiesis. However, animals developed splenomegaly as a result of accumulated memory T cells that were not deleted after antigen-driven expansion. These data indicate that Bak and Bax are required for thymic selection and peripheral lymphoid homeostasis and suggest that thymopoiesis can be negatively regulated by the accumulation of cells that would normally be eliminated by pro-apoptotic Bcl-2-related genes.