Intrahepatic Murine CD8 T-Cell Activation Associates With a Distinct Phenotype Leading to Bim-Dependent Death
| Autor: | Lauren E. Holz, Alex Bishop, Philippe Bouillet, Andreas Strasser, Patrick Bertolino, David G. Bowen, Geoffrey W. McCaughan, Lorraine A. O'Reilly, W. d’Avigdor, Volker Benseler |
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| Rok vydání: | 2008 |
| Předmět: |
Apoptosis
Mice Transgenic CD8-Positive T-Lymphocytes Biology Lymphocyte Activation Article Mice Interleukin 21 Immune system Antigen Proto-Oncogene Proteins Animals Cytotoxic T cell IL-2 receptor Antigen-presenting cell Bcl-2-Like Protein 11 Cell Death Hepatology Caspase 3 ZAP70 Interleukin-2 Receptor alpha Subunit Gastroenterology Membrane Proteins Cytotoxicity Tests Immunologic Intercellular Adhesion Molecule-1 Adoptive Transfer Liver Radiation Chimera Hepatocytes Cancer research Lymph Nodes Apoptosis Regulatory Proteins CD8 |
| Zdroj: | Gastroenterology. 135:989-997 |
| ISSN: | 0016-5085 |
| DOI: | 10.1053/j.gastro.2008.05.078 |
| Popis: | 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 CD25low CD54low 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. |
| Databáze: | OpenAIRE |
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