title: Lipid peroxidation causes endosomal antigen release for cross-presentation.
abstract: Dendritic cells (DCs) present foreign antigen in major histocompatibility complex (MHC) class I molecules to cytotoxic T cells in a process called cross-presentation. An important step in this process is the release of antigen from the lumen of endosomes into the cytosol, but the mechanism of this step is still unclear. In this study, we show that reactive oxygen species (ROS) produced by the NADPH-oxidase complex NOX2 cause lipid peroxidation, a membrane disrupting chain-reaction, which in turn results in antigen leakage from endosomes. Antigen leakage and cross-presentation were inhibited by blocking ROS production or scavenging radicals and induced when using a ROS-generating photosensitizer. Endosomal antigen release was impaired in DCs from chronic granulomatous disease (CGD) patients with dysfunctional NOX2. Thus, NOX2 induces antigen release from endosomes for cross-presentation by direct oxidation of endosomal lipids. This constitutes a new cellular function for ROS in regulating immune responses against pathogens and cancer.
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.
authors.forename: Ilse
authors.initials: I
authors.lastname: Dingjan
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.
authors.forename: Daniëlle Rj
authors.initials: DR
authors.lastname: Verboogen
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.
authors.forename: Laurent M
authors.initials: LM
authors.lastname: Paardekooper
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.
authors.forename: Natalia H
authors.initials: NH
authors.lastname: Revelo
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.
authors.forename: Simone P
authors.initials: SP
authors.lastname: Sittig
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Visser
authors.affiliation: Department of Chemistry, Bielefeld University, Bielefeld, 33501, Germany.
authors.forename: Gabriele Fischer von
authors.initials: GF
authors.lastname: Mollard
authors.affiliation: Department of Pediatrics, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.
authors.forename: Stefanie Sv
authors.initials: SS
authors.lastname: Henriet
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Ter Beest
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.
authors.forename: Geert
authors.initials: G
authors.lastname: van den Bogaart
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D045142:Cross-Priming; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D011992:Endosomes / Q000276:immunology / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D015870:Gene Expression; D006105:Granulomatous Disease, Chronic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells; D015227:Lipid Peroxidation / Q000187:drug effects / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000276:immunology*; D017319:Photosensitizing Agents / Q000494:pharmacology; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D024502:alpha-Tocopherol / Q000494:pharmacology
chemical_list: D016166:Free Radical Scavengers; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D017319:Photosensitizing Agents; D017382:Reactive Oxygen Species; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D024502:alpha-Tocopherol