Department of Microbiology and Immunology, Inje University College of Medicine, Busan 614-735, Republic of Korea.
Immunol Lett. 2010 Aug 16;132(1-2):53-60. doi: 10.1016/j.imlet.2010.05.008. Epub 2010 Jun 4.
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.
色氨酸衍生代谢物，由吲哚胺 2,3-双加氧酶（IDO）启动，优先诱导活化 T 细胞死亡，这是 IDO 介导的 T 细胞抑制的重要机制。然而，这种现象的机制尚不清楚。我们发现，最有效的代谢物 3-羟基犬尿氨酸（3-HAA）通过诱导细胞凋亡，选择性地消除了由细菌超抗原金黄色葡萄球菌肠毒素 A（SEA）刺激的活化 T 细胞，但不会消除静止的 T 细胞。我们观察到 3-HAA 诱导活化 T 细胞内谷胱甘肽（GSH）耗竭。当通过添加 N-乙酰半胱氨酸（NAC）和 GSH 来维持 GSH 水平时，3-HAA 介导的 T 细胞死亡完全被抑制。这与 GSH 从活化 T 细胞中排出而没有增加活性氧（ROS）形成有关。最后，我们表明，在同种异体骨髓移植后，在小鼠中给予 3-HAA 通过细胞内 GSH 耗竭抑制同种反应性 T 细胞扩增，从而降低急性移植物抗宿主病（GVHD）的致死率。我们的数据表明，细胞内 GSH 的直接耗竭是 3-HAA 介导的活化 T 细胞死亡的主要机制。
