title: Adenovirus E3/19K promotes evasion of NK cell recognition by intracellular sequestration of the NKG2D ligands major histocompatibility complex class I chain-related proteins A and B.
abstract: The adenovirus (Ad) early transcription unit 3 (E3) encodes multiple immunosubversive functions that are presumed to facilitate the establishment and persistence of infection. Indeed, the capacity of E3/19K to inhibit transport of HLA class I (HLA-I) to the cell surface, thereby preventing peptide presentation to CD8(+) T cells, has long been recognized as a paradigm for viral immune evasion. However, HLA-I downregulation has the potential to render Ad-infected cells vulnerable to natural killer (NK) cell recognition. Furthermore, expression of the immediate-early Ad gene E1A is associated with efficient induction of ligands for the key NK cell-activating receptor NKG2D. Here we show that while infection with wild-type Ad enhances synthesis of the NKG2D ligands, major histocompatibility complex class I chain-related proteins A and B (MICA and MICB), their expression on the cell surface is actively suppressed. Both MICA and MICB are retained within the endoplasmic reticulum as immature endoglycosidase H-sensitive forms. By analyzing a range of cell lines and viruses carrying mutated versions of the E3 gene region, E3/19K was identified as the gene responsible for this activity. The structural requirements within E3/19K necessary to sequester MICA/B and HLA-I are similar. In functional assays, deletion of E3/19K rendered Ad-infected cells more sensitive to NK cell recognition. We report the first NK evasion function in the Adenoviridae and describe a novel function for E3/19K. Thus, E3/19K has a dual function: inhibition of T-cell recognition and NK cell activation.
authors.affiliation: Department of Medical Microbiology, Cardiff University, Tenovus Building, Heath Park, Cardiff CF14 4XX, United Kingdom. WilkinsonGW1@cf.ac.uk
authors.forename: Brian P
authors.initials: BP
authors.lastname: McSharry
authors.forename: Hans-Gerhard
authors.initials: HG
authors.lastname: Burgert
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Owen
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Stanton
authors.forename: Virginie
authors.initials: V
authors.lastname: Prod'homme
authors.forename: Martina
authors.initials: M
authors.lastname: Sester
authors.forename: Katja
authors.initials: K
authors.lastname: Koebernick
authors.forename: Veronika
authors.initials: V
authors.lastname: Groh
authors.forename: Thomas
authors.initials: T
authors.lastname: Spies
authors.forename: Steven
authors.initials: S
authors.lastname: Cox
authors.forename: Ann-Margaret
authors.initials: AM
authors.lastname: Little
authors.forename: Eddie C Y
authors.initials: EC
authors.lastname: Wang
authors.forename: Peter
authors.initials: P
authors.lastname: Tomasec
authors.forename: Gavin W G
authors.initials: GW
authors.lastname: Wilkinson
mesh_terms: D017503:Adenovirus E3 Proteins / Q000276:immunology*; D000260:Adenoviruses, Human / Q000737:chemistry / Q000276:immunology*; D002451:Cell Compartmentation; D015870:Gene Expression; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007109:Immunity; D007694:Killer Cells, Natural / Q000276:immunology* / Q000821:virology; D008024:Ligands; D011971:Receptors, Immunologic / Q000276:immunology*; D055607:Receptors, Natural Killer Cell; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D017503:Adenovirus E3 Proteins; D015395:Histocompatibility Antigens Class I; D008024:Ligands; C099187:MHC class I-related chain A; C098080:MICB antigen; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell