title: Redox remodeling allows and controls B-cell activation and differentiation.
abstract: During their differentiation to antibody-secreting plasma cells, B lymphocytes undergo dramatic changes in metabolism, structure, and function. Here we show that this transition entails extensive intra- and extracellular redox changes. Lipopolysaccharide (LPS)-driven activation and differentiation of naïve murine B splenocytes is paralleled by increased production of reactive oxygen species (ROS) from different sources, followed by a strong antioxidant response. This response includes upregulation of thioredoxin and of the cystine transporter xCT, and increased production and extracellular release of nonprotein thiols, mainly glutathione (GSH) and cysteine. Although ROS levels are higher in late-differentiating B cells, an early oxidative step is likely required to start the differentiation program, because inhibition of NADPH oxidase-dependent early ROS production impairs B-cell activation and differentiation. Addition of reducing agents such as 2-ME results in increased IgM secretion per cell, suggesting that the antioxidant response not only is aimed at restoring the redox homeostasis but also plays a functional role. A highly reduced environment coincident with the presence of large ROS-producing cells is observed in histologic sections of spleens from immunized mice, indicating that the redox modifications observed in LPS-induced B-cell differentiation in vitro occur also in vivo during physiologic immune responses.
authors.affiliation: National Cancer Research Institute, Genova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Vené
authors.forename: Laura
authors.initials: L
authors.lastname: Delfino
authors.forename: Patrizia
authors.initials: P
authors.lastname: Castellani
authors.forename: Enrica
authors.initials: E
authors.lastname: Balza
authors.forename: Milena
authors.initials: M
authors.lastname: Bertolotti
authors.forename: Roberto
authors.initials: R
authors.lastname: Sitia
authors.forename: Anna
authors.initials: A
authors.lastname: Rubartelli
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018448:Models, Immunological; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000975:Antioxidants; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species