Apoptosis regulators Fas and Bim cooperate in shutdown of chronic immune responses and prevention of autoimmunity.
Apoptotic death of T lymphocytes is critical for shutdown of immune responses and hemopoietic cell homeostasis. Both death receptor (Fas) activation and mitochondrial apoptosis triggered by the BH3-only protein Bim have been implicated in the killing of antigen-stimulated T cells. We examined mice lacking the gene encoding Bim (Bcl2l11) and with the inactivating lpr mutation in the gene encoding Fas (Fas), designated Bcl2l11(-/-)Fas(lpr/lpr) mice. Shutdown of an acute T cell response to herpes simplex virus involved only Bim with no contribution by Fas, whereas both pathways synergized in killing antigen-stimulated T cells in chronic infection with murine gamma-herpesvirus. Bcl2l11(-/-)Fas(lpr/lpr) mice developed remarkably enhanced and accelerated fatal lymphadenopathy and autoimmunity compared to mice lacking only one of these apoptosis inducers. These results identify critical overlapping roles for Fas and Bim in T cell death in immune response shutdown and prevention of immunopathology and thereby resolve a long-standing controversy.
Hughes
Peter D
PD
Molecular Genetics of Cancer, The Walter and Eliza Hall Institute of Medical Research, Melbourne 3050, Australia.
Belz
Gabrielle T
GT
Fortner
Karen A
KA
Budd
Ralph C
RC
Strasser
Andreas
A
Bouillet
Philippe
P
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D015551:Autoimmunity; D000072224:Bcl-2-Like Protein 11; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D002908:Chronic Disease; D018142:Gammaherpesvirinae / Q000276:immunology; D006561:Herpes Simplex / Q000276:immunology / Q000821:virology; D006566:Herpesviridae Infections / Q000276:immunology; D018259:Herpesvirus 1, Human / Q000276:immunology; D008206:Lymphatic Diseases / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010047:Ovalbumin / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019014:fas Receptor; D010047:Ovalbumin