Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion

Dimitra Peppa, Upkar S Gill, Gary Reynolds, Nicholas J W Easom, Laura J Pallett, Anna Schurich, Lorenzo Micco, Gaia Nebbia, Harsimran D Singh, David H Adams, Patrick T F Kennedy, Mala K Maini

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204 Citations (Scopus)


Antiviral T cell responses in hepatotropic viral infections such as hepatitis B virus (HBV) are profoundly diminished and prone to apoptotic deletion. In this study, we investigate whether the large population of activated NK cells in the human liver contributes to this process. We show that in vitro removal of NK cells augments circulating CD8(+) T cell responses directed against HBV, but not against well-controlled viruses, in patients with chronic hepatitis B (CHB). We find that NK cells can rapidly eliminate HBV-specific T cells in a contact-dependent manner. CD8(+) T cells in the liver microcirculation are visualized making intimate contact with NK cells, which are the main intrahepatic lymphocytes expressing TNF-related apoptosis-inducing ligand (TRAIL) in CHB. High-level expression of the TRAIL death receptor TRAIL-R2 is found to be a hallmark of T cells exposed to the milieu of the HBV-infected liver in patients with active disease. Up-regulation of TRAIL-R2 renders T cells susceptible to caspase-8-mediated apoptosis, from which they can be partially rescued by blockade of this death receptor pathway. Our findings demonstrate that NK cells can negatively regulate antiviral immunity in chronic HBV infection and illustrate a novel mechanism of T cell tolerance in the human liver.
Original languageEnglish
Pages (from-to)99-114
Number of pages16
JournalThe Journal of Experimental Medicine
Issue number1
Publication statusPublished - 14 Jan 2013


  • Adult
  • Aged
  • Apoptosis
  • CD8-Positive T-Lymphocytes
  • Case-Control Studies
  • Caspase 8
  • Hepatitis B, Chronic
  • Humans
  • Immune Tolerance
  • Killer Cells, Natural
  • Liver
  • Middle Aged
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • Up-Regulation
  • Young Adult


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