Intrahepatic murine CD8 T-cell activation associates with a distinct phenotype leading to Bim-dependent death.
OBJECTIVE
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.
Holz
Lauren E
LE
Centenary Institute, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and Faculty of Medicine, University of Sydney, Camperdown, New South Wales, Australia.
Benseler
Volker
V
Bowen
David G
DG
Bouillet
Philippe
P
Strasser
Andreas
A
O'Reilly
Lorraine
L
d'Avigdor
William M H
WM
Bishop
Alex G
AG
McCaughan
Geoffrey W
GW
Bertolino
Patrick
P
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D003601:Cytotoxicity Tests, Immunologic; D022781:Hepatocytes / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008099:Liver / Q000166:cytology / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011828:Radiation Chimera
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D018799:Intercellular Adhesion Molecule-1; D053148:Caspase 3