Journal
IMMUNOLOGY LETTERS
Volume 132, Issue 1-2, Pages 53-60Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.imlet.2010.05.008
Keywords
Indoleamine 2,3-dioxygenase; 3-Hydroxyanthranilic acid; T cells; Glutathione
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Funding
- Ministry of Health, Welfare and Family affairs, Republic of Korea [0920040]
- Inje University
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Tryptophan-derived metabolites, initiated by indoleamine 2,3-dioxygenase (IDO), preferentially induce activated T cell death, which is an important mechanism in IDO-mediated T cell suppression. However, the mechanism of this phenomenon remains unclear. We found that 3-hydroxyanthranilic acid (3-HAA), the most potent metabolite, selectively eliminated activated T cells, which were stimulated with the bacterial superantigen staphylococcal enterotoxin A (SEA), but not resting T cells, by inducing apoptosis. We observed 3-HAA-induced depletion of intracellular glutathione (GSH) in activated T cells. When GSH levels were maintained by addition of N-acetylcysteine (NAC) and GSH, 3-HAA-mediated T cell death was completely inhibited. This was associated with extrusion of GSH from activated T cells without increased reactive oxygen species (ROS) formation. Finally, we showed that administration of 3-HAA in mice after allogeneic bone marrow transplantation reduced acute graft-versus-host disease (GVHD) lethality by inhibition of alloreactive T cell expansion through intracellular GSH depletion. Our data suggest that direct depletion of intracellular GSH is the major mechanism of 3-HAA-mediated activated T cell death. (C) 2010 Elsevier B.V. All rights reserved.
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