Inhibition of T cell proliferation by macrophage tryptophan catabolism.
Inhibition of T cell proliferation by macrophage tryptophan catabolism.
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DOI：
10.1084/jem.189.9.1363
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发表时间：
1999-05-03
期刊：
影响因子：
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通讯作者：
Mellor AL
中科院分区：
文献类型：
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作者：
Munn DH;Shafizadeh E;Attwood JT;Bondarev I;Pashine A;Mellor AL
我们最近发现，在小鼠妊娠期间，吲哚胺2，3-双加氧酶（IDO）的表达是防止母体T细胞对同种异体胎儿排斥所必需的。除了它们在妊娠中的作用之外，IDO表达细胞广泛分布在初级和次级淋巴器官中。在这里，我们表明，单核细胞的巨噬细胞集落刺激因子的影响下分化获得抑制T细胞增殖的能力，在体外通过快速和选择性降解色氨酸的IDO。通过T细胞衍生的信号IFN-γ和CD 40-配体的协同组合在巨噬细胞中诱导IDO。用色氨酸的1-甲基类似物抑制IDO防止了巨噬细胞介导的抑制。纯化的T细胞在Dahan缺陷条件下活化，能够合成蛋白质，进入细胞周期，并正常进展通过G1的初始阶段，包括IL-2受体的上调和IL-2的合成。然而，在没有色氨酸的情况下，细胞周期进程停止在中期G1停滞点。色氨酸恢复到停滞的细胞不足以允许进一步的细胞周期进展，也不足以通过CD 28进行共刺激。只有在色氨酸存在的情况下提供第二轮T细胞受体信号传导，T细胞才能退出停滞状态。这些数据揭示了一种新的机制，抗原呈递细胞可以通过色氨酸催化剂调节T细胞活化。我们推测IDO在体内通过某些抗原呈递细胞的表达允许它们抑制不需要的T细胞应答。
We have recently shown that expression of the enzyme indoleamine 2,3-dioxygenase (IDO) during murine pregnancy is required to prevent rejection of the allogeneic fetus by maternal T cells. In addition to their role in pregnancy, IDO-expressing cells are widely distributed in primary and secondary lymphoid organs. Here we show that monocytes that have differentiated under the influence of macrophage colony-stimulating factor acquire the ability to suppress T cell proliferation in vitro via rapid and selective degradation of tryptophan by IDO. IDO was induced in macrophages by a synergistic combination of the T cell–derived signals IFN-γ and CD40-ligand. Inhibition of IDO with the 1-methyl analogue of tryptophan prevented macrophage-mediated suppression. Purified T cells activated under tryptophan-deficient conditions were able to synthesize protein, enter the cell cycle, and progress normally through the initial stages of G1, including upregulation of IL-2 receptor and synthesis of IL-2. However, in the absence of tryptophan, cell cycle progression halted at a mid-G1 arrest point. Restoration of tryptophan to arrested cells was not sufficient to allow further cell cycle progression nor was costimulation via CD28. T cells could exit the arrested state only if a second round of T cell receptor signaling was provided in the presence of tryptophan. These data reveal a novel mechanism by which antigen-presenting cells can regulate T cell activation via tryptophan catabolism. We speculate that expression of IDO by certain antigen presenting cells in vivo allows them to suppress unwanted T cell responses.