Tryptophan metabolite 3-hydroxyanthranilic acid selectively induces activated T cell death via intracellular GSH depletion.
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.
Lee
Sun-Mi
SM
Department of Microbiology and Immunology, Inje University College of Medicine, Busan 614-735, Republic of Korea.
Lee
Young-Suk
YS
Choi
Jae-Hyeog
JH
Park
Sae-Gwang
SG
Choi
Il-Whan
IW
Joo
Young-Don
YD
Lee
Won-Sik
WS
Lee
Jeong-Nyeo
JN
Choi
Inhak
I
Seo
Su-Kil
SK
D015095:3-Hydroxyanthranilic Acid / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D016923:Cell Death / Q000187:drug effects*; D004768:Enterotoxins / Q000276:immunology; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous / Q000009:adverse effects; D014364:Tryptophan / Q000378:metabolism*
D004768:Enterotoxins; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D015095:3-Hydroxyanthranilic Acid; C026066:enterotoxin A, Staphylococcal; D014364:Tryptophan; D005978:Glutathione