title: NADPH oxidase controls phagosomal pH and antigen cross-presentation in human dendritic cells.
abstract: The phagocyte NADPH oxidase (NOX2) is critical for the bactericidal activity of phagocytic cells and plays a major role in innate immunity. We showed recently that NOX2 activity in mouse dendritic cells (DCs) prevents acidification of phagosomes, promoting antigen cross-presentation. In order to investigate the role of NOX2 in the regulation of the phagosomal pH in human DCs, we analyzed the production of reactive oxygen species (ROS) and the phagosomal/endosomal pH in monocyte-derived DCs and macrophages (M(diameter)s) from healthy donors or patients with chronic granulomatous disease (CGD). As expected, we found that human M(diameter)s acidify their phagosomes more efficiently than human DCs. Accordingly, the expression of the vacuolar proton ATPase (V-H(+)-ATPase) was higher in M(diameter)s than in DCs. Phagosomal ROS production, however, was also higher in M(diameter)s than in DCs, due to higher levels of gp91phox expression and recruitment to phagosomes. In contrast, in the absence of active NOX2, the phagosomal and endosomal pH decreased. Both in the presence of a NOX2 inhibitor and in DCs derived from patients with CGD, the cross-presentation of 2 model tumor antigens was impaired. We conclude that NOX2 activity participates in the regulation of the phagosomal and endosomal pH in human DCs, and is required for efficient antigen cross-presentation.
authors.affiliation: Inserm U653 Immunité et cancer, Institut Curie, Paris, France.
authors.forename: Adriana R
authors.initials: AR
authors.lastname: Mantegazza
authors.forename: Ariel
authors.initials: A
authors.lastname: Savina
authors.forename: Mónica
authors.initials: M
authors.lastname: Vermeulen
authors.forename: Laura
authors.initials: L
authors.lastname: Pérez
authors.forename: Jorge
authors.initials: J
authors.lastname: Geffner
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.forename: Sergio D
authors.initials: SD
authors.lastname: Rosenzweig
authors.forename: Florence
authors.initials: F
authors.lastname: Faure
authors.forename: Sebastián
authors.initials: S
authors.lastname: Amigorena
mesh_terms: D000136:Acid-Base Equilibrium / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017951:Antigen Presentation / Q000235:genetics*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D045142:Cross-Priming / Q000235:genetics*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010588:Phagosomes / Q000378:metabolism*; D055815:Young Adult
chemical_list: D008562:Membrane Glycoproteins; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases