Immunosurveillance of the liver by intravascular effector CD8+ T cells

Luca G. Guidotti, Donato Inverso, Laura Sironi, Pietro Di Lucia, Jessica Fioravanti, Lucia Ganzer, Amleto Fiocchi, Maurizio Vacca, Roberto Aiolfi, Stefano Sammicheli, Marta Mainetti, Tiziana Cataudella, Andrea Raimondi, Gloria Gonzalez-Aseguinolaza, Ulrike Protzer, Zaverio M. Ruggeri, Francis V. Chisari, Masanori Isogawa, Giovanni Sitia, Matteo Iannacone

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)486-500
Number of pages15
JournalCell
Volume161
Issue number3
DOIs
Publication statusPublished - Apr 23 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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