Lipid peroxidation causes endosomal antigen release for cross-presentation

Sci Rep. 2016 Feb 24;6:22064. doi: 10.1038/srep22064.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation
  • Cross-Priming*
  • Dendritic Cells / cytology
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Endosomes / immunology
  • Endosomes / metabolism
  • Free Radical Scavengers / pharmacology
  • Gene Expression
  • Granulomatous Disease, Chronic / immunology*
  • Granulomatous Disease, Chronic / metabolism
  • Granulomatous Disease, Chronic / pathology
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / immunology
  • Humans
  • Jurkat Cells
  • Lipid Peroxidation / drug effects
  • Lipid Peroxidation / immunology*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology*
  • Mice
  • Mice, Inbred C57BL
  • NADPH Oxidase 2
  • NADPH Oxidases / genetics
  • NADPH Oxidases / immunology*
  • Photosensitizing Agents / pharmacology
  • Primary Cell Culture
  • Reactive Oxygen Species / antagonists & inhibitors
  • Reactive Oxygen Species / immunology
  • Reactive Oxygen Species / metabolism
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology*
  • alpha-Tocopherol / pharmacology

Substances

  • Free Radical Scavengers
  • Histocompatibility Antigens Class I
  • Membrane Glycoproteins
  • Photosensitizing Agents
  • Reactive Oxygen Species
  • CYBB protein, human
  • NADPH Oxidase 2
  • NADPH Oxidases
  • alpha-Tocopherol