title: Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein.
abstract: The immune response against hepatitis C virus (HCV) is rarely effective at clearing the virus, resulting in approximately 170 million chronic HCV infections worldwide. Here we report that ligation of an HCV receptor (CD81) inhibits natural killer (NK) cells. Cross-linking of CD81 by the major envelope protein of HCV (HCV-E2) or anti-CD81 antibodies blocks NK cell activation, cytokine production, cytotoxic granule release, and proliferation. This inhibitory effect was observed using both activated and resting NK cells. Conversely, on NK-like T cell clones, including those expressing NK cell inhibitory receptors, CD81 ligation delivered a costimulatory signal. Engagement of CD81 on NK cells blocks tyrosine phosphorylation through a mechanism which is distinct from the negative signaling pathways associated with NK cell inhibitory receptors for major histocompatibility complex class I. These results implicate HCV-E2-mediated inhibition of NK cells as an efficient HCV evasion strategy targeting the early antiviral activities of NK cells and allowing the virus to establish itself as a chronic infection.
authors.affiliation: IRIS, Department of Immunology, Chiron S.p.A., 53100 Siena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Crotta
authors.forename: Annalisa
authors.initials: A
authors.lastname: Stilla
authors.forename: Andreas
authors.initials: A
authors.lastname: Wack
authors.forename: Annalisa
authors.initials: A
authors.lastname: D'Andrea
authors.forename: Sandra
authors.initials: S
authors.lastname: Nuti
authors.forename: Ugo
authors.initials: U
authors.lastname: D'Oro
authors.forename: Marta
authors.initials: M
authors.lastname: Mosca
authors.forename: Franco
authors.initials: F
authors.lastname: Filliponi
authors.forename: R Maurizia
authors.initials: RM
authors.lastname: Brunetto
authors.forename: Ferruccio
authors.initials: F
authors.lastname: Bonino
authors.forename: Sergio
authors.initials: S
authors.lastname: Abrignani
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Valiante
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D016174:Hepacivirus / Q000276:immunology*; D006801:Humans; D007152:Immunologic Capping; D007376:Interleukin-2 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D008565:Membrane Proteins; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology; D011991:Receptors, Virus / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins / Q000276:immunology*
chemical_list: D015703:Antigens, CD; C554798:CD81 protein, human; D007376:Interleukin-2; D008024:Ligands; D008565:Membrane Proteins; D017452:Receptors, IgG; D011991:Receptors, Virus; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus; D011505:Protein-Tyrosine Kinases