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Title: Elevated mitochondrial superoxide disrupts normal T cell development, impairing adaptive immune responses to an influenza challenge.

Authors: Case, Adam J; McGill, Jodi L; Tygrett, Lorraine T; Shirasawa, Takuji; Spitz, Douglas R; Waldschmidt, Thomas J; Legge, Kevin L; Domann, Frederick E

Published In Free Radic Biol Med, (2011 Feb 01)

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 (O(2)(•-)) 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.

PubMed ID: 21130157 Exiting the NIEHS site

MeSH Terms: Adaptive Immunity*; Animals; Apoptosis; Female; Gene Knockout Techniques; Influenza A Virus, H1N1 Subtype/immunology; Influenza A Virus, H1N1 Subtype/physiology*; Lymphocyte Count; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria/chemistry; Mitochondria/metabolism*; Orthomyxoviridae Infections/immunology; Orthomyxoviridae Infections/pathology; Oxidative Stress; Superoxide Dismutase/deficiency; Superoxide Dismutase/genetics; Superoxides/metabolism*; Superoxides/pharmacology; T-Lymphocytes/immunology; T-Lymphocytes/metabolism*; T-Lymphocytes/pathology

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