Immunosurveillance of the liver by intravascular effector CD8(+) T cells

Effector CD8(+) T cells (CD8 TE) play a key role during hepatotropic viral infections. Here, we used advanced imaging in mouse models of hepatitis B virus (HBV) pathogenesis to understand the mechanisms whereby these cells home to the liver, recognize antigens, and deploy effector functions. We show...

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Bibliographic Details
Published in:Cell 2015-04, Vol.161 (3), p.486-500
Main Authors: Guidotti, Luca G, Inverso, Donato, Sironi, Laura, Di Lucia, Pietro, Fioravanti, Jessica, Ganzer, Lucia, Fiocchi, Amleto, Vacca, Maurizio, Aiolfi, Roberto, Sammicheli, Stefano, Mainetti, Marta, Cataudella, Tiziana, Raimondi, Andrea, Gonzalez-Aseguinolaza, Gloria, Protzer, Ulrike, Ruggeri, Zaverio M, Chisari, Francis V, Isogawa, Masanori, Sitia, Giovanni, Iannacone, Matteo
Format: Article
Language:English
Subjects:
Animals
CD8-Positive T-Lymphocytes - immunology
Cell Movement
Endothelial Cells - metabolism
Hepatitis B - immunology
Hepatitis B - pathology
Hepatitis B virus - physiology
Hepatocytes - metabolism
Hyaluronic Acid - metabolism
Liver - cytology
Liver - immunology
Liver Cirrhosis
Mice
Mice, Inbred C57BL
Monitoring, Immunologic
Platelet Adhesiveness
Specific Pathogen-Free Organisms
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Summary:Effector CD8(+) T cells (CD8 TE) play a key role during hepatotropic viral infections. Here, we used advanced imaging in mouse models of hepatitis B virus (HBV) pathogenesis to understand the mechanisms whereby these cells home to the liver, recognize antigens, and deploy effector functions. We show that circulating CD8 TE arrest within liver sinusoids by docking onto platelets previously adhered to sinusoidal hyaluronan via CD44. After the initial arrest, CD8 TE actively crawl along liver sinusoids and probe sub-sinusoidal hepatocytes for the presence of antigens by extending cytoplasmic protrusions through endothelial fenestrae. Hepatocellular antigen recognition triggers effector functions in a diapedesis-independent manner and is inhibited by the processes of sinusoidal defenestration and capillarization that characterize liver fibrosis. These findings reveal the dynamic behavior whereby CD8 TE control hepatotropic pathogens and suggest how liver fibrosis might reduce CD8 TE immune surveillance toward infected or transformed hepatocytes.
ISSN:0092-8674
1097-4172
1097-4172
DOI:10.1016/j.cell.2015.03.005