title: Immunosurveillance of the liver by intravascular effector CD8(+) T cells.
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.
authors.affiliation: 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.
authors.forename: Luca G
authors.initials: LG
authors.lastname: Guidotti
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy.
authors.forename: Donato
authors.initials: D
authors.lastname: Inverso
authors.affiliation: 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.
authors.forename: Laura
authors.initials: L
authors.lastname: Sironi
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Di Lucia
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Fioravanti
authors.affiliation: 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.
authors.forename: Lucia
authors.initials: L
authors.lastname: Ganzer
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Amleto
authors.initials: A
authors.lastname: Fiocchi
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Vacca
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Aiolfi
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Sammicheli
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Mainetti
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Cataudella
authors.affiliation: Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Raimondi
authors.affiliation: Gene Therapy and Gene Regulation Program, Center for Applied Medical Research, 31008 Pamplona, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Gonzalez-Aseguinolaza
authors.affiliation: Institute of Virology, Technical University of Munich, 81675 Munich, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Protzer
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Zaverio M
authors.initials: ZM
authors.lastname: Ruggeri
authors.affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Francis V
authors.initials: FV
authors.lastname: Chisari
authors.affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Masanori
authors.initials: M
authors.lastname: Isogawa
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sitia
authors.affiliation: 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.
authors.forename: Matteo
authors.initials: M
authors.lastname: Iannacone
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism; D006509:Hepatitis B / Q000276:immunology* / Q000473:pathology; D006515:Hepatitis B virus / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000276:immunology*; D008103:Liver Cirrhosis; D051379:Mice; D008810:Mice, Inbred C57BL; D015166:Monitoring, Immunologic; D010973:Platelet Adhesiveness; D013047:Specific Pathogen-Free Organisms
chemical_list: D006820:Hyaluronic Acid