Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites.
Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites.
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DOI：
10.1084/jem.20020052
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发表时间：
2002-08-19
期刊：
影响因子：
--
通讯作者：
Opelz G
中科院分区：
文献类型：
--
作者：
Terness P;Bauer TM;Röse L;Dufter C;Watzlik A;Simon H;Opelz G
吲哚胺2，3-双加氧酶（IDO）是一种参与色氨酸催化的酶，在某些细胞和组织中表达，特别是在淋巴器官的抗原呈递细胞和胎盘中。研究表明，IDO可能通过抑制同种异体反应性T细胞来防止妊娠期间胎儿的排斥反应，并表明IDO在抗原呈递细胞中的表达可能控制自身反应性免疫应答。色氨酸是细胞增殖所需的必需氨基酸，据报道色氨酸的降解是IDO诱导的T细胞抑制的机制。因为我们想研究IDO表达树突状细胞（DC）对同种异体T细胞的作用，所以将人IDO基因插入腺病毒载体中并在DC中表达。转基因DC降低色氨酸的浓度，增加色氨酸的主要代谢物犬尿氨酸的浓度，并在体外抑制同种异体T细胞增殖。犬尿氨酸、3-羟基犬尿氨酸和3-羟基邻氨基苯甲酸，但没有其他IDO诱导的色氨酸代谢物，抑制T细胞应答，抑制作用是累加的。T细胞一旦停止增殖，就不能再被刺激。增殖抑制可能是由于T细胞死亡，因为抑制性色氨酸催化剂对CD 3+细胞产生细胞毒性作用。这种作用优先影响活化的T细胞，并随着暴露时间逐渐增加。除T细胞外，B和自然杀伤（NK）细胞也被杀死，而DC不受影响。我们的研究结果揭示了DC介导的抑制机制，并为IDO活性明显增加的重要生物学过程提供了解释，例如保护胎儿在妊娠期间免受排斥反应，以及HIV感染患者可能的T细胞死亡。
Indoleamine 2,3-dioxygenase (IDO), an enzyme involved in the catabolism of tryptophan, is expressed in certain cells and tissues, particularly in antigen-presenting cells of lymphoid organs and in the placenta. It was shown that IDO prevents rejection of the fetus during pregnancy, probably by inhibiting alloreactive T cells, and it was suggested that IDO-expression in antigen-presenting cells may control autoreactive immune responses. Degradation of tryptophan, an essential amino acid required for cell proliferation, was reported to be the mechanism of IDO-induced T cell suppression. Because we wanted to study the action of IDO-expressing dendritic cells (DCs) on allogeneic T cells, the human IDO gene was inserted into an adenoviral vector and expressed in DCs. Transgenic DCs decreased the concentration of tryptophan, increased the concentration of kynurenine, the main tryptophan metabolite, and suppressed allogeneic T cell proliferation in vitro. Kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid, but no other IDO-induced tryptophan metabolites, suppressed the T cell response, the suppressive effects being additive. T cells, once stopped in their proliferation, could not be restimulated. Inhibition of proliferation was likely due to T cell death because suppressive tryptophan catabolites exerted a cytotoxic action on CD3+ cells. This action preferentially affected activated T cells and increased gradually with exposure time. In addition to T cells, B and natural killer (NK) cells were also killed, whereas DCs were not affected. Our findings shed light on suppressive mechanisms mediated by DCs and provide an explanation for important biological processes in which IDO activity apparently is increased, such as protection of the fetus from rejection during pregnancy and possibly T cell death in HIV-infected patients.
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影响因子：
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作者：
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发表时间：
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期刊：
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