Elevated mitochondrial superoxide disrupts normal T cell development, impairing adaptive immune responses to an influenza challenge.
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.
Free Radical and Radiation Biology Program, Department of Radiation Oncology, Carver College of Medicine, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
Adam J
AJ
Case
Jodi L
JL
McGill
Lorraine T
LT
Tygrett
Takuji
T
Shirasawa
Douglas R
DR
Spitz
Thomas J
TJ
Waldschmidt
Kevin L
KL
Legge
Frederick E
FE
Domann
D056704:Adaptive Immunity; D000818:Animals; D017209:Apoptosis; D005260:Female; D055786:Gene Knockout Techniques; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology / Q000502:physiology*; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism*; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000473:pathology; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics; D013481:Superoxides / Q000378:metabolism* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000099156:Superoxide Dismutase 2
D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2