title: Negative selection of semimature CD4(+)8(-)HSA+ thymocytes requires the BH3-only protein Bim but is independent of death receptor signaling.
abstract: T cell receptor/CD3 ligation induces apoptosis in semimature CD4(+)8(-)HSA+ thymocytes, and this helps establish immunological tolerance and constitutes one of the safeguards against autoimmune disease. We analyzed several knockout and transgenic mouse lines and found that T cell receptor/CD3-ligation-induced killing of semimature thymocytes occurred independently of Fas and "death receptor" signaling in general but required the proapoptotic BH3-only protein Bim and could be inhibited by Bcl-2. Loss of Apaf-1 or caspase-9, which act downstream of the Bcl-2 family protein family, provided only minor protection, indicating that the "apoptosome" functions as an amplifier rather than as an essential initiator of this death program. These results reveal the mechanisms of apoptosis in negative selection of semimature thymocytes and have implications for immunological tolerance and autoimmunity.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia. andreas.villunger@uibk.ac.at
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.forename: Vanessa S
authors.initials: VS
authors.lastname: Marsden
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhan
authors.forename: Miriam
authors.initials: M
authors.lastname: Erlacher
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lew
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
authors.forename: Stuart
authors.initials: S
authors.lastname: Berzins
authors.forename: Dale I
authors.initials: DI
authors.lastname: Godfrey
authors.forename: William R
authors.initials: WR
authors.lastname: Heath
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D000072224:Bcl-2-Like Protein 11; D015704:CD4 Antigens / Q000276:immunology*; D002352:Carrier Proteins / Q000378:metabolism*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D017637:Clonal Deletion / Q000276:immunology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013950:Thymus Gland / Q000276:immunology*
chemical_list: C506593:Apaf1 protein, mouse; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D015704:CD4 Antigens; D002352:Carrier Proteins; D008565:Membrane Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases