Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division
Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division
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DOI：
10.1046/j.1365-2567.2002.01526.x
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发表时间：
2002-12-01
期刊：
影响因子：
6.4
通讯作者：
Mellor, AL
中科院分区：
文献类型：
--
作者：
Lee, GK;Park, HJ;Mellor, AL
表达吲哚胺 2,3-双加氧酶 (IDO)（一种分解色氨酸的酶）的细胞可在体外防止 T 细胞增殖，抑制妊娠期间母体抗胎儿免疫，并抑制 T 细胞介导的对肿瘤相关抗原的反应。为了研究这些现象的机制基础，我们在化学成分确定的无色氨酸培养基中激活了幼稚小鼠 T 细胞。在这些条件下，T 细胞表达 CD25 和 CD69，并进入 G0/G1 期的前 12 小时，但不表达 CD71、细胞周期蛋白 D3、cdk4，开始 DNA 合成或分化为细胞毒性效应细胞。此外，由于色氨酸剥夺而生长停滞的活化T细胞在暴露于抗Fas抗体时表现出通过细胞凋亡而死亡的倾向增强。细胞凋亡受到 caspase 抑制剂的抑制，并且当 T 细胞源自 Fas 缺陷小鼠时未观察到细胞凋亡。这些发现表明，在缺乏游离色氨酸的情况下激活的 T 细胞进入细胞周期，但细胞周期进程在 G1 中期停止，T 细胞变得容易通过凋亡而死亡，部分是通过 Fas 介导的信号传导。因此，表达IDO和Fas配体的成熟抗原呈递细胞可以通过阻断T细胞周期进程和通过快速诱导T细胞活化诱导局部组织微环境中的细胞死亡来诱导抗原特异性T细胞耐受。
Cells expressing indoleamine 2,3-dioxygenase (IDO), an enzyme which catabolizes tryptophan, prevent T-cell proliferation in vitro, suppress maternal antifetal immunity during pregnancy and inhibit T-cell-mediated responses to tumour-associated antigens. To examine the mechanistic basis of these phenomena we activated naive murine T cells in chemically defined tryptophan-free media. Under these conditions T cells expressed CD25 and CD69 and progressed through the first 12 hr of G0/G1 phase but did not express CD71, cyclin D3, cdk4, begin DNA synthesis, or differentiate into cytotoxic effector cells. In addition, activated T cells with their growth arrested by tryptophan deprivation exhibited enhanced tendencies to die via apoptosis when exposed to anti-Fas antibodies. Apoptosis was inhibited by caspase inhibitor and was not observed when T cells originated from Fas-deficient mice. These findings suggest that T cells activated in the absence of free tryptophan entered the cell cycle but cell cycle progression ceased in mid-G1 phase and T cells became susceptible to death via apoptosis, in part though Fas-mediated signalling. Thus, mature antigen-presenting cells expressing IDO and Fas-ligand may induce antigen-specific T-cell tolerance by blocking T-cell cycle progression and by rapid induction of T-cell activation induced cell death in local tissue microenvironments.