The Journal of Experimental Medicine
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Published 7 January 2002. doi:10.1084/jem.20010659
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© Rockefeller University Press, 0022-1007/2002/1/59/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 1, January 7, 2002 59-70

Original Article

 Discrete Generation of Superoxide and Hydrogen Peroxide by T Cell Receptor Stimulation : Selective Regulation of Mitogen-Activated Protein Kinase Activation and Fas Ligand Expression



Satish Devadas1, Luba Zaritskaya1, Sue Goo Rhee2, Larry Oberley3 and Mark S. Williams1

1 Department of Immunology, Holland Laboratory, American Red Cross, Rockville, MD 20855
2 Laboratory of Cell Signaling, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
3 Free Radical and Radiation Biology Program, University of Iowa, Iowa City, IA 52242

Address correspondence to Dr. Mark S. Williams, Department of Immunology, Holland Lab, American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855. Phone: 301-738-0468; Fax: 301-517-0344; E-mail: willmark{at}usa.redcross.org

Receptor-stimulated generation of reactive oxygen species (ROS) has been shown to regulate signal transduction, and previous studies have suggested that T cell receptor (TCR) signals may involve or be sensitive to ROS. In this study, we have shown for the first time that TCR cross-linking induced rapid (within 15 min) generation of both hydrogen peroxide and superoxide anion, as defined with oxidation-sensitive dyes, selective pharmacologic antioxidants, and overexpression of specific antioxidant enzymes. Furthermore, the data suggest the novel observation that superoxide anion and hydrogen peroxide are produced separately by distinct TCR-stimulated pathways. Unexpectedly, TCR-stimulated activation of the Fas ligand (FasL) promoter and subsequent cell death was dependent upon superoxide anion, but independent of hydrogen peroxide, while nuclear factor of activated T cells (NFAT) activation or interleukin 2 transcription was independent of all ROS. Anti-CD3 induced phosphorylation of extracellular signal–regulated kinase (ERK)1/2 required hydrogen peroxide generation but was unaffected by superoxide anion. Thus, antigen receptor signaling induces generation of discrete species of oxidants that selectively regulate two distinct redox sensitive pathways, a proapoptotic (FasL) and a proliferative pathway (ERK).

Key Words: T lymphocytes • reactive oxygen species • signal transduction • genes, reporter • oxidoreductases


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