Negative selection of seminature CD4(+)8(-)HSA(+) thymocytes requires the BH3-only protein Bim but is independent of death receptor signaling
- Author(s)
- Villunger, A; Marsden, VS; Zhan, YF; Erlacher, M; Lew, AM; Bouillet, P; Berzins, S; Godfrey, DI; Heath, WR; Strasser, A;
- Details
- Publication Year 2004-05-04,Volume 101,Issue #18,Page 7052-7057
- Journal Title
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
- Publication Type
- Journal Article
- 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.
- Publisher
- NATL ACAD SCIENCES
- Keywords
- CASPASE ACTIVATION; CELL-DEATH; AUTOREACTIVE THYMOCYTES; BCL-2 EXPRESSION; T-LYMPHOCYTES; APOPTOSIS; MICE; HOMEOSTASIS; DEFICIENCY; TRANSGENE
- Publisher's Version
- https://doi.org/10.1073/pnas.0305757101
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2004-05-04 12:00:00