GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase
GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase
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DOI：
10.1016/j.immuni.2005.03.013
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发表时间：
2005-05-01
期刊：
影响因子：
32.4
通讯作者：
Mellor, AL
中科院分区：
文献类型：
--
作者：
Munn, DH;Sharma, MD;Mellor, AL
吲哚胺2，3双加氧酶（IDO）分解代谢氨基酸色氨酸。表达IDO的免疫调节性树突状细胞（DC）已经涉及包括肿瘤、自身免疫和移植耐受在内的环境。然而，IDO调节T细胞应答的下游分子机制仍然未知。我们现在表明，IDO表达浆细胞样DC激活GCN 2激酶途径在响应T细胞。GCN 2是一种应激反应激酶，通过不带电荷的tRNA升高而激活。具有GCN 2的靶向破坏的T细胞在体外对IDO介导的增殖抑制不敏感。在体内，来自肿瘤引流淋巴结的IDO表达DC不抑制GCN 2敲除T细胞的增殖。IDO诱导应答野生型T细胞的深刻无能，但GCN 2敲除细胞对IDO诱导的无能是难治的。我们假设GCN 2在T细胞中充当分子传感器，使它们能够检测和响应IDO产生的条件。
Indoleamine 2,3 dioxygenase (IDO) catabolizes the amino acid tryptophan. IDO-expressing immunoregulatory dendritic cells (DCs) have been implicated in settings including tumors, autoimmunity, and transplant tolerance. However, the downstream molecular mechanisms by which IDO functions to regulate T cell responses remain unknown. We now show that IDO-expressing plasmacytoid DCs activate the GCN2 kinase pathway in responding T cells. GCN2 is a stress-response kinase that is activated by elevations in uncharged tRNA. T cells with a targeted disruption of GCN2 were not susceptible to IDO-mediated suppression of proliferation in vitro. In vivo, proliferation of GCN2-knockout T cells was not inhibited by IDO-expressing DCs from tumor-draining lymph nodes. IDO induced profound anergy in responding wild-type T cells, but GCN2-knockout cells were refractory to IDO-induced anergy. We hypothesize that GCN2 acts as a molecular sensor in T cells, allowing them to detect and respond to conditions created by IDO.