| First Author | Holz LE | Year | 2008 |
| Journal | Gastroenterology | Volume | 135 |
| Issue | 3 | Pages | 989-97 |
| PubMed ID | 18619445 | Mgi Jnum | J:141863 |
| Mgi Id | MGI:3819908 | Doi | 10.1053/j.gastro.2008.05.078 |
| Citation | Holz LE, et al. (2008) Intrahepatic murine CD8 T-cell activation associates with a distinct phenotype leading to Bim-dependent death. Gastroenterology 135(3):989-97 |
| abstractText | 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. |
