Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α.
Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α.
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DOI：
10.1038/nm.3868
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发表时间：
2015-06
期刊：
影响因子：
82.9
通讯作者：
Quintana, Francisco J.
中科院分区：
文献类型：
--
作者：
Mascanfroni, Ivan D.;Takenaka, Maisa C.;Yeste, Ada;Patel, Bonny;Wu, Yan;Kenison, Jessica E.;Siddiqui, Shafiuddin;Basso, Alexandre S.;Otterbein, Leo E.;Pardoll, Drew M.;Pan, Fan;Priel, Avner;Clish, Clary B.;Robson, Simon C.;Quintana, Francisco J.
我们对调节淋巴细胞代谢的途径以及代谢及其产物对免疫应答的影响的理解仍然有限。我们报道了由转录因子低氧诱导因子-1 α（HIF 1-α）和芳烃受体（AHR）控制的代谢程序支持1型调节（Tr 1）细胞的分化。HIF 1-α控制Tr 1细胞的早期代谢重编程。在以后的时间点，AHR促进HIF 1-α降解并控制Tr 1细胞代谢。与炎症相关的细胞外三磷酸腺苷（eATP）和缺氧通过HIF 1-α触发AHR失活并抑制Tr 1细胞分化。相反，CD 39通过消耗eATP促进Tr 1细胞分化。CD 39还通过与应答T细胞和抗原呈递细胞表达的CD 73合作产生腺苷而有助于Tr 1抑制活性。这些结果表明，HIF 1-α和AHR整合免疫，代谢和环境信号来调节免疫反应。
Our understanding of the pathways that regulate lymphocyte metabolism, as well as the effects of metabolism and its products on the immune response, is still limited. We report that a metabolic program controlled by the transcription factors hypoxia inducible factor-1α (HIF1-α) and aryl hydrocarbon receptor (AHR) supports the differentiation of type 1 regulatory (Tr1) cells. HIF1-α controls the early metabolic reprograming of Tr1 cells. At later time points, AHR promotes HIF1-α degradation and takes control of Tr1 cell metabolism. Extracellular adenosine triphosphate (eATP) and hypoxia, linked to inflammation, trigger AHR inactivation by HIF1-α and inhibit Tr1 cell differentiation. Conversely, CD39 promotes Tr1 cell differentiation by depleting eATP. CD39 also contributes to Tr1 suppressive activity by generating adenosine in cooperation with CD73 expressed by responder T cells and antigen presenting cells. These results suggest that HIF1-α and AHR integrate immunological, metabolic and environmental signals to regulate the immune response.
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