Intrahepatic murine CD8 T-Cell activation associates with a distinct phenotype leading to Bim-dependent death
- Author(s)
- Holz, LE; Benseler, V; Bowen, DG; Bouillet, P; Strasser, A; O'Reilly, L; D'Avigdor, WMH; Bishop, AG; McCaughan, GW; Bertolino, P;
- Details
- Publication Year 2008-09,Volume 135,Issue #3,Page 989-997
- Journal Title
- GASTROENTEROLOGY
- Publication Type
- Journal Article
- Abstract
- Background & Aims: Chronic infections by hepatotropic viruses such as hepatitis B and C are generally associated with an impaired CD8 T-cell immune response that is unable to clear the virus. The liver is increasingly recognized as an alternative site in which primary activation of CD8 T cells takes place, a property that might explain its role in inducing tolerance. However, the molecular mechanism by which intrahepatically activated T cells become tolerant is unknown. Here, we investigated the phenotype and fate of naive CD8 T cells activated by hepatocytes in vivo. Methods: Transgenic mouse models in which the antigen is expressed in lymph nodes and/or in the liver were adoptively transferred with naive CD8 T cells specific for the hepatic antigen. Results: Liver-activated CD8 T cells displayed poor effector functions and a unique CD25(low) CD54(low) phenotype. This phenotype was associated with increased expression of the proapoptotic protein Bim and caspase-3, demonstrating that these cells are programmed to die following intrahepatic activation. Importantly, we show that T cells deficient for Bim survived following intrahepatic activation. Conclusions: This study identifies Bim for the first time as a critical initiator of T-cell death in the liver. Thus, strategies inhibiting the up-regulation of this molecule could potentially be used to rescue CD8 T cells, clear the virus, and reverse the outcome of viral chronic infections affecting the liver.
- Publisher
- W B SAUNDERS CO-ELSEVIER INC
- Keywords
- CHRONIC HEPATITIS-C; SELF-ANTIGEN; PERIPHERAL DELETION; CROSS-PRESENTATION; LIVER TOLERANCE; TRANSGENIC MICE; INFECTION; HEPATOCYTES; EXPRESSION; DIFFERENTIATION
- Publisher's Version
- https://doi.org/10.1053/j.gastro.2008.05.078
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2008-09-01 12:00:00