title: Manganese superoxide dismutase: a regulator of T cell activation-induced oxidative signaling and cell death.
abstract: Mitochondrial reactive oxygen species (ROS) are indispensible for T cell activation-induced expression of interleukin 2 (IL-2) and CD95 ligand (CD95L, FasL/Apo-1L) genes, and in turn, for CD95L-mediated activation-induced cell death (AICD). Here, we show that manganese superoxide dismutase (MnSOD/SOD2), a major mitochondrial antioxidative enzyme, constitutes an important control switch in the process of activation-induced oxidative signal generation in T cells. Analysis of the kinetics of T cell receptor (TCR)-triggered ROS production revealed a temporal association between higher MnSOD abundance/activity and a shut-down phase of oxidative signal generation. Transient or inducible MnSOD overexpression abrogated T cell activation-triggered mitochondrial ROS production as well as NF-κB- and AP-1-mediated transcription. Consequently, lowered expression of IL-2 and CD95L genes resulted in decreased IL-2 secretion and CD95L-dependent AICD. Moreover, upregulation of the mitochondrial MnSOD level is dependent on oxidation-sensitive transcription and not on the increase of mitochondrial mass. Thus, MnSOD-mediated negative feedback regulation of activation-induced mitochondrial ROS generation exemplifies a process of retrograde mitochondria-to-nucleus communication. Our finding underlines the critical role for MnSOD and mitochondria in the regulation of human T cell activation.
authors.affiliation: Division of Immunogenetics (D030), Tumor Immunology Program, German Cancer Research Center (DFKZ), Im Neuenheimer Feld 280, Heidelberg, Germany. m.kaminski@dkfz.de
authors.forename: Marcin Mikołaj
authors.initials: MM
authors.lastname: Kamiński
authors.forename: Daniel
authors.initials: D
authors.lastname: Röth
authors.forename: Sabine
authors.initials: S
authors.lastname: Sass
authors.forename: Sven Wolfgang
authors.initials: SW
authors.lastname: Sauer
authors.forename: Peter Heinrich
authors.initials: PH
authors.lastname: Krammer
authors.forename: Karsten
authors.initials: K
authors.lastname: Gülow
mesh_terms: D016923:Cell Death / Q000276:immunology; D053222:Fas Ligand Protein / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D008928:Mitochondria / Q000378:metabolism; D018448:Models, Immunological; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology; D014158:Transcription, Genetic
chemical_list: D053222:Fas Ligand Protein; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase