title: Presentation of a Conserved Adenoviral Epitope on HLA-C*0702 Allows Evasion of Natural Killer but Not T Cell Responses.
abstract: Infection with adenovirus is a major cause of infectious mortality in children following hematopoietic stem-cell transplantation. While adoptive transfer of epitope-specific T cells is a particularly effective therapeutic approach, there are few suitable adenoviral peptide epitopes described to date. Here, we describe the adenoviral peptide epitope FRKDVNMVL from hexon protein, and its variant FRKDVNMIL, that is restricted by human leukocyte antigen (HLA)-C*0702. Since HLA-C*0702 can be recognized by both T cells and natural killer (NK) cells, we characterized responses by both cell types. T cells specific for FRKDVNMVL were detected in peripheral blood mononuclear cells expanded from eight of ten healthy HLA-typed donors by peptide-HLA multimer staining, and could also be detected by cultured interferon γ ELISpot assays. Surprisingly, HLA-C*0702 was not downregulated during infection, in contrast to the marked downregulation of HLA-A*0201, suggesting that adenovirus cannot evade T cell responses to HLA-C*0702-restricted peptide epitopes. By contrast, NK responses were inhibited following adenoviral peptide presentation. Notably, presentation of the FRKDVNMVL peptide enhanced binding of HLA-C*0702 to the inhibitory receptor KIR2DL3 and decreased NK cytotoxic responses, suggesting that adenoviruses may use this peptide to evade NK responses. Given the immunodominance of FRKDVNMVL-specific T cell responses, apparent lack of HLA-C*0702 downregulation during infection, and the high frequency of this allotype, this peptide epitope may be particularly useful for adoptive T cell transfer therapy of adenovirus infection.
authors.affiliation: 1 Institute for Medical Virology, University Hospital Tübingen , Tübingen, Germany .
authors.forename: Anna
authors.initials: A
authors.lastname: Keib
authors.affiliation: 1 Institute for Medical Virology, University Hospital Tübingen , Tübingen, Germany .
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Günther
authors.affiliation: 2 Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich , Munich, Germany .
authors.forename: Benjamin
authors.initials: B
authors.lastname: Faist
authors.affiliation: 3 Institute of Virology, University Hospital Freiburg , Freiburg, Germany .
authors.forename: Anne
authors.initials: A
authors.lastname: Halenius
authors.affiliation: 2 Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich , Munich, Germany .|4 German Center for Infection Research (DZIF) , Partner Sites Tübingen and Munich, Germany .
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.affiliation: 2 Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich , Munich, Germany .|4 German Center for Infection Research (DZIF) , Partner Sites Tübingen and Munich, Germany .
authors.forename: Michael
authors.initials: M
authors.lastname: Neuenhahn
authors.affiliation: 1 Institute for Medical Virology, University Hospital Tübingen , Tübingen, Germany .
authors.forename: Gerhard
authors.initials: G
authors.lastname: Jahn
authors.affiliation: 1 Institute for Medical Virology, University Hospital Tübingen , Tübingen, Germany .|4 German Center for Infection Research (DZIF) , Partner Sites Tübingen and Munich, Germany .
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Dennehy
mesh_terms: D000260:Adenoviruses, Human / Q000276:immunology*; D017951:Antigen Presentation; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism*; D015236:HLA-C Antigens / Q000378:metabolism*; D006801:Humans; D057131:Immune Evasion; D007694:Killer Cells, Natural / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015236:HLA-C Antigens
keywords: adenovirus; adoptive transfer therapy; immunoevasion; peptide epitope