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

• Published in: Free radical biology & medicine 2011-02, Vol.50 (3), p.448-458
• Main Authors: Case, Adam J., McGill, Jodi L., Tygrett, Lorraine T., Shirasawa, Takuji, Spitz, Douglas R., Waldschmidt, Thomas J., Legge, Kevin L., Domann, Frederick E.
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; animal models; Animals; Antioxidants; Apoptosis; Cre/loxP; Danio rerio; Developmental biology; Drosophila; drugs; Female; Free radicals; Gene Knockout Techniques; Immunodeficiency; immunosuppression (physiological); Influenza; Influenza A virus; Influenza A Virus, H1N1 Subtype - immunology; Influenza A Virus, H1N1 Subtype - physiology; innate immunity; Lymphocyte Count; Male; mammals; Manganese superoxide dismutase; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - chemistry; Mitochondria - metabolism; Mouse; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - pathology; Oxidative Stress; phenotype; Superoxide; superoxide anion; superoxide dismutase; Superoxide Dismutase - deficiency; Superoxide Dismutase - genetics; Superoxides - metabolism; Superoxides - pharmacology; T-lymphocytes; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Transgenic
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2010.11.025

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•−) 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.