title: Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion.
abstract: 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.
authors.affiliation: Division of Infection and Immunity and Centre for Sexual Health and HIV Research, University College London, London NW3 2PF, UK.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Peppa
authors.forename: Upkar S
authors.initials: US
authors.lastname: Gill
authors.forename: Gary
authors.initials: G
authors.lastname: Reynolds
authors.forename: Nicholas J W
authors.initials: NJ
authors.lastname: Easom
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Pallett
authors.forename: Anna
authors.initials: A
authors.lastname: Schurich
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Micco
authors.forename: Gaia
authors.initials: G
authors.lastname: Nebbia
authors.forename: Harsimran D
authors.initials: HD
authors.lastname: Singh
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
authors.forename: Patrick T F
authors.initials: PT
authors.lastname: Kennedy
authors.forename: Mala K
authors.initials: MK
authors.lastname: Maini
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D016022:Case-Control Studies; D053181:Caspase 8 / Q000378:metabolism; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000821:virology; D008875:Middle Aged; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D053181:Caspase 8