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.