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Gastroenterology. 2008 Sep;135(3):989-97. doi: 10.1053/j.gastro.2008.05.078. Epub 2008 Jul 9.

Intrahepatic murine CD8 T-cell activation associates with a distinct phenotype leading to Bim-dependent death.

Author information

1
Centenary Institute, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and Faculty of Medicine, University of Sydney, Camperdown, New South Wales, Australia.

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 naïve 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 naïve 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.

PMID:
18619445
PMCID:
PMC2956118
DOI:
10.1053/j.gastro.2008.05.078
[Indexed for MEDLINE]
Free PMC Article
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