Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10738699 | Free Radical Biology and Medicine | 2011 | 11 Pages |
Abstract
Reactive oxygen species (ROS) are critical in a broad spectrum of cellular processes including signaling, tumor progression, and innate immunity. The essential nature of ROS signaling in the immune systems of Drosophila and zebrafish has been demonstrated; however, the role of ROS, if any, in mammalian adaptive immune system development and function remains unknown. This work provides the first clear demonstration that thymus-specific elevation of mitochondrial superoxide (O2
- â) disrupts normal T cell development and impairs the function of the mammalian adaptive immune system. To assess the effect of elevated mitochondrial superoxide in the developing thymus, we used a T-cell-specific knockout of manganese superoxide dismutase (i.e., SOD2) and have thus established a murine model to examine the role of mitochondrial superoxide in T cell development. Conditional loss of SOD2 led to increased superoxide, apoptosis, and developmental defects in the T cell population, resulting in immunodeficiency and susceptibility to the influenza A virus H1N1. This phenotype was rescued with mitochondrially targeted superoxide-scavenging drugs. These findings demonstrate that loss of regulated levels of mitochondrial superoxide lead to aberrant T cell development and function, and further suggest that manipulations of mitochondrial superoxide levels may significantly alter clinical outcomes resulting from viral infection.
- â) disrupts normal T cell development and impairs the function of the mammalian adaptive immune system. To assess the effect of elevated mitochondrial superoxide in the developing thymus, we used a T-cell-specific knockout of manganese superoxide dismutase (i.e., SOD2) and have thus established a murine model to examine the role of mitochondrial superoxide in T cell development. Conditional loss of SOD2 led to increased superoxide, apoptosis, and developmental defects in the T cell population, resulting in immunodeficiency and susceptibility to the influenza A virus H1N1. This phenotype was rescued with mitochondrially targeted superoxide-scavenging drugs. These findings demonstrate that loss of regulated levels of mitochondrial superoxide lead to aberrant T cell development and function, and further suggest that manipulations of mitochondrial superoxide levels may significantly alter clinical outcomes resulting from viral infection.
Keywords
dihydrodichlorofluorescein diacetateHBSSRNSDCFH-DANBTIFN-γSOD1SOD2IAVMFISOD3LCKPBSCre/loxPO2•−ONOO−ROSnitroblue tetrazoliumAntioxidantsInfluenzaadaptive immunityTeminterferon-γTransgenictumor necrosis factor-αApoptosisdihydroethidiumFree radicalsHydroxyl radicalDevelopmental biologySuperoxideextracellular superoxide dismutasemanganese superoxide dismutaseTNF-αPhosphate-buffered salinecopper/zinc superoxide dismutaseMousemean fluorescence intensityTransmission electron microscopyDHEInfluenza A virusPeroxynitriteImmunodeficiencyreactive nitrogen speciesReactive oxygen species•OH
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Authors
Adam J. Case, Jodi L. McGill, Lorraine T. Tygrett, Takuji Shirasawa, Douglas R. Spitz, Thomas J. Waldschmidt, Kevin L. Legge, Frederick E. Domann,