title: The BH3-only proteins Bim and Puma cooperate to impose deletional tolerance of organ-specific antigens.
abstract: Although the proapoptotic BH3-only protein, Bim, is required for deletion of autoreactive thymocytes, Bim-deficient mice do not succumb to extensive organ-specific autoimmune disease. To determine whether other BH3-only proteins safeguard tolerance in the absence of Bim, we screened mice lacking Bim as well as other BH3-only proteins. Most strains showed no additional defects; however, mice deficient for both Puma and Bim spontaneously developed autoimmunity in multiple organs, and their T cells could transfer organ-specific autoimmunity. Puma- and Bim-double-deficient mice had a striking accumulation of mature, single-positive thymocytes, suggesting an additional defect in thymic deletion was the basis for disease. Transgenic mouse models of thymocyte deletion by peripheral neoantigens confirmed that the loss of Bim and Puma allowed increased numbers of autoreactive thymocytes to escape deletion. Our data show that Puma cooperates with Bim to impose a thymic-deletion checkpoint to peripheral self-antigens and cement the notion that defects in apoptosis alone are sufficient to cause autoimmune disease.
authors.affiliation: Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia. dgray@wehi.edu.au
authors.forename: Daniel H D
authors.initials: DH
authors.lastname: Gray
authors.forename: Fiona
authors.initials: F
authors.lastname: Kupresanin
authors.forename: Stuart P
authors.initials: SP
authors.lastname: Berzins
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Herold
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: O'Reilly
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D000072224:Bcl-2-Like Protein 11; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060168:Thymocytes / Q000276:immunology* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D001324:Autoantigens; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; C488588:PUMA protein, mouse; C408009:Pmaip1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins