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Cell. 2015 Apr 23;161(3):486-500. doi: 10.1016/j.cell.2015.03.005. Epub 2015 Apr 16.

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

Author information

1
Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: guidotti.luca@hsr.it.
2
Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy.
3
Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Department of Physics, University of Milano Bicocca, 20126 Milan, Italy.
4
Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
5
Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
6
Gene Therapy and Gene Regulation Program, Center for Applied Medical Research, 31008 Pamplona, Spain.
7
Institute of Virology, Technical University of Munich, 81675 Munich, Germany.
8
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
9
Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.
10
Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy; Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. Electronic address: iannacone.matteo@hsr.it.

Abstract

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.

PMID:
25892224
DOI:
10.1016/j.cell.2015.03.005
[Indexed for MEDLINE]
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