Tolerogenic Phenotype of IFN-γ-Induced IDO+ Dendritic Cells Is Maintained via an Autocrine IDO-Kynurenine/AhR-IDO Loop
Tolerogenic Phenotype of IFN-γ-Induced IDO+ Dendritic Cells Is Maintained via an Autocrine IDO-Kynurenine/AhR-IDO Loop
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DOI：
10.4049/jimmunol.1502615
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发表时间：
2016-08-01
影响因子：
4.4
通讯作者：
Egilmez, Nejat K.
中科院分区：
文献类型：
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作者：
Li, Qingsheng;Harden, Jamie L.;Egilmez, Nejat K.
先前的研究表明，IL-12驱动的抗肿瘤活性被树突状细胞（DC）功能从免疫原性活性快速转换为致耐受性活性所短路。该过程依赖于IFN-γ，并且致耐受性表型由IDO赋予。对IL-12加GM-CSF处理的荷瘤小鼠的肿瘤引流淋巴结中的IDO+ DC的扩展监测显示，尽管IFN-γ诱导是短暂的，但DC中的IDO表达是长期维持的。开发了模拟IFN-γ介导的DC功能变化的体外系统，以剖析IL-12后DC中持续IDO表达的分子基础。用IFN-γ和CD 40 L刺激DC导致IDO 1和IDO 2转录的快速诱导，并再现了从免疫原性到致耐受性活性的体内转换。发现IDO表达的长期维持不依赖于外源性和自分泌IFN-γ或次级细胞因子TGF-β、TNF-α和IL-6。相反，IDO酶活性和IFN-γ诱导的AhR表达都是体外和体内持续IDO转录所需的。向其中IDO活性被阻断的DC培养物中添加色氨酸分解代谢物犬尿氨酸恢复了野生型DC中的长期IDO表达，但在AhR缺陷型DC中没有，确立了犬尿氨酸-AhR途径在维持致耐受性DC中的IDO表达中的中心作用。这些发现进一步阐明了IL-12后调节反弹的细胞和分子生物学，并提供了对反馈抑制机制如何长期占主导地位的见解。
Previous studies demonstrated that IL-12-driven antitumor activity is short-circuited by a rapid switch in dendritic cell (DC) function from immunogenic to tolerogenic activity. This process was dependent on IFN-gamma and the tolerogenic phenotype was conferred by IDO. Extended monitoring of IDO+ DC in the tumor-draining lymph nodes of IL-12 plus GM-CSF-treated tumor-bearing mice revealed that whereas IFN-gamma induction was transient, IDO expression in DC was maintained long-term. An in vitro system modeling the IFN-gamma-mediated change in DC function was developed to dissect the molecular basis of persistent IDO expression in post-IL-12 DC. Stimulation of DC with IFN-gamma and CD40L resulted in rapid induction of IDO1 and IDO2 transcription and recapitulated the in vivo switch from immunogenic to tolerogenic activity. Long-term maintenance of IDO expression was found to be independent of exogenous and autocrine IFN-gamma, or the secondary cytokines TGF-beta, TNF-alpha, and IL-6. In contrast, both IDO enzymatic activity and IFN-gamma-induced AhR expression were required for continued IDO transcription in vitro and in vivo. Addition of the tryptophan catabolite kynurenine to DC cultures in which IDO activity was blocked restored longterm IDO expression in wild-type DC but not in AhR-deficient DC, establishing the central role of the kynurenine-AhR pathway in maintaining IDO expression in tolerogenic DC. These findings shed further light on the cellular and molecular biology of the post-IL-12 regulatory rebound and provide insight into how feedback inhibitory mechanisms dominate in the long-term.