The BH3-Only Proteins Bim and Puma Cooperate to Impose Deletional Tolerance of Organ-Specific Antigens
- Author(s)
- Gray, DHD; Kupresanin, F; Berzins, SP; Herold, MJ; O'Reilly, LA; Bouillet, P; Strasser, A;
- Details
- Publication Year 2012-09-21,Volume 37,Issue #3,Page 451-462
- Journal Title
- IMMUNITY
- Publication Type
- Journal Article
- 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.
- Publisher
- CELL PRESS
- Keywords
- PROGRAMMED CELL-DEATH; FAMILY-MEMBER BIM; AUTOIMMUNE-DISEASE; DEFICIENT MICE; T-CELLS; LYMPHOCYTE DEVELOPMENT; APOPTOTIC RESPONSES; AIRE DEFICIENCY; BAX; EXPRESSION
- Research Division(s)
- Molecular Genetics Of Cancer
- Link To PubMed Central Version
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3500635/
- Publisher's Version
- https://doi.org/10.1016/j.immuni.2012.05.030
- Terms of Use/Rights Notice
- Copyright © 2012 Elsevier Inc. All rights reserved.
Creation Date: 2012-09-21 12:00:00