Journal
BLOOD
Volume 112, Issue 12, Pages 4712-4722Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-01-134791
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Funding
- Ligue National de Lutte contre le Cancer
- Welcome Trust
- Biotechnology and Biological Sciences Research Council
- Fondation Bettencourt
- Association pour la Recherche contre le Cancer
- EC [LSBH-CT-2004-512074, LSHC-CT-2006-518234]
- ARC
- Institut Curie, France
- Inserm and the Marie Curie Fellowship
- CONICET
- Agencia Nacional de Promocion Cientfica y Tecnologica, Argentina
- National Institutes of Health (NIH)/Fogarty International Center (FIC)/Global Research Initiative Program (GRIP) [R01 TW006644]
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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 monocytederived DCs and macrophages (MOs) from healthy donors or patients with chronic granulomatous disease (CGD). As expected, we found that human MOs acidify their phagosomes more efficiently than human DCs. Accordingly, the expression of the vacuolar proton ATPase (V-H+-ATPase) was higher in MOs than in DCs. Phagosomal ROS production, however, was also higher in MOs 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. (Blood. 2008; 112: 4712-4722)
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