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.
Rathmell
Jeffrey C
JC
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Lindsten
Tullia
T
Zong
Wei-Xing
WX
Cinalli
Ryan M
RM
Thompson
Craig B
CB
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D006410:Hematopoiesis; D016130:Immunophenotyping; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein