Expression and regulation of immune-modulatory enzyme indoleamine 2,3-dioxygenase (IDO) by human airway epithelial cells and its effect on T cell activation.
Expression and regulation of immune-modulatory enzyme indoleamine 2,3-dioxygenase (IDO) by human airway epithelial cells and its effect on T cell activation.
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DOI：
10.18632/oncotarget.11586
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发表时间：
2016-09-06
期刊：
影响因子：
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通讯作者：
Ghaemmaghami AM
中科院分区：
文献类型：
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作者：
Aldajani WA;Salazar F;Sewell HF;Knox A;Ghaemmaghami AM
吲哚胺 2,3-双加氧酶 (IDO) 催化色氨酸的降解，色氨酸通过调节一系列代谢物（通常称为犬尿氨酸）的产生，在免疫抑制中发挥关键作用。越来越清楚的是，上皮细胞（EC）通过产生细胞因子、趋化因子和抗微生物介质来调节免疫细胞的功能，在维持肺稳态方面发挥着积极作用。在本研究中，我们评估了稳态条件下人类原代 EC 和 EC 系中 IDO 活性和表达的调节以及对细菌和过敏刺激的反应。我们还研究了 IDO 表达在人气道 EC 中的潜在免疫调节功能。我们的数据清楚地表明，气道内皮细胞产生 IDO，它在响应过敏原和 TLR 配体时下调，而在响应 IFN-γ 时上调。通过基因沉默，我们进一步证明 IDO 在 EC 介导的 T 细胞抗原特异性和多克隆增殖抑制中发挥着关键作用。有趣的是，我们的数据还表明，ECs 因模仿细菌或病毒感染的不同 TLR 激动剂而失去了对 T 细胞激活的抑制作用。总之，我们的工作提供了对 IDO 在 EC 中如何调节的理解，并证明“静息”EC 可以以 IDO 依赖性方式抑制 T 细胞激活。这些数据为 EC 如何通过产生 IDO 影响下游先天性和适应性反应提供了新的见解，作为其维持气道免疫稳态功能的一部分。
Indoleamine 2,3-dioxygenase (IDO) catalyzes the degradation of tryptophan, which plays a critical role in immune suppression through regulating the production of a series of metabolites that are generally referred to as kynurenines. It has become increasingly clear that epithelial cells (ECs) play an active role in maintaining lung homeostasis by modulating the function of immune cells via producing cytokines, chemokines, and anti-microbial mediators. In this study we assessed the regulation of IDO activity and expression in human primary ECs and EC lines under steady state conditions and in response to bacterial and allergenic stimuli. We also investigated the potential immune modulatory functions of IDO expression in human airway ECs. Our data clearly show that airway ECs produce IDO, which is down-regulated in response to allergens and TLR ligands while up-regulated in response to IFN-γ. Using gene silencing, we further demonstrate that IDO plays a key role in the EC-mediated suppression of antigen-specific and polyclonal proliferation of T cells. Interestingly, our data also show that ECs lose their inhibitory effect on T cell activation in response to different TLR agonists mimicking bacterial or viral infections. In conclusion, our work provides an understanding of how IDO is regulated in ECs as well as demonstrates that “resting” ECs can suppress T cell activation in an IDO dependent manner. These data provide new insight into how ECs, through the production of IDO, can influence downstream innate and adaptive responses as part of their function in maintaining immune homeostasis in the airways.