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

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

Research output: Contribution to journalArticle

51 Scopus citations

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•-) 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.

Original languageEnglish (US)
Pages (from-to)448-458
Number of pages11
JournalFree Radical Biology and Medicine
Volume50
Issue number3
DOIs
Publication statusPublished - Feb 1 2011

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Keywords

  • Adaptive immunity
  • Antioxidants
  • Apoptosis
  • Cre/loxP
  • Developmental biology
  • Free radicals
  • Immunodeficiency
  • Influenza
  • Manganese superoxide dismutase
  • Mouse
  • Superoxide
  • Transgenic

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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