A temporally dynamic Foxp3 autoregulatory transcriptional circuit controls the effector Treg programme.
A temporally dynamic Foxp3 autoregulatory transcriptional circuit controls the effector Treg programme.
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DOI：
10.15252/embj.201899013
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发表时间：
2018-08-15
期刊：
影响因子：
--
通讯作者：
Ono M
中科院分区：
文献类型：
--
作者：
Bending D;Paduraru A;Ducker CB;Prieto Martín P;Crompton T;Ono M
调节性T细胞（Treg）是免疫应答的负调节因子;然而，在T细胞应答期间，Foxp 3转录是否以及如何在外周中被诱导和调节还知之甚少。使用Foxp 3-Timer的细胞动力学和活动（Tocky）小鼠，报告了真实的-时间Foxp 3表达，我们表明，新的Foxp 3表达的流量和Foxp 3转录的速率在炎症过程中增加。Foxp 3转录的这些持续动力学决定了效应Treg程序，并且依赖于Foxp 3自身调节转录回路。持续的Foxp 3转录活性控制共抑制分子的表达，包括CTLA-4和效应Treg标签基因。使用RNA-seq，我们根据它们与Foxp 3转录的时间动力学的关系鉴定了两组表面蛋白，并且我们证明了通过免疫疗法操纵Foxp 3动力学的原理：抗TNFRII抗体促进新的Foxp 3通量，抗OX 40抗体靶向高频Foxp 3表达子。总的来说，我们的研究剖析了Foxp 3驱动的T细胞调节背后的时间依赖性机制，并建立了Foxp 3 ‐Tocky系统作为研究T细胞免疫疗法背后机制的工具。
Regulatory T cells (Treg) are negative regulators of the immune response; however, it is poorly understood whether and how Foxp3 transcription is induced and regulated in the periphery during T‐cell responses. Using Foxp3‐Timer of cell kinetics and activity (Tocky) mice, which report real‐time Foxp3 expression, we show that the flux of new Foxp3 expressors and the rate of Foxp3 transcription are increased during inflammation. These persistent dynamics of Foxp3 transcription determine the effector Treg programme and are dependent on a Foxp3 autoregulatory transcriptional circuit. Persistent Foxp3 transcriptional activity controls the expression of coinhibitory molecules, including CTLA‐4 and effector Treg signature genes. Using RNA‐seq, we identify two groups of surface proteins based on their relationship to the temporal dynamics of Foxp3 transcription, and we show proof of principle for the manipulation of Foxp3 dynamics by immunotherapy: new Foxp3 flux is promoted by anti‐TNFRII antibody, and high‐frequency Foxp3 expressors are targeted by anti‐OX40 antibody. Collectively, our study dissects time‐dependent mechanisms behind Foxp3‐driven T‐cell regulation and establishes the Foxp3‐Tocky system as a tool to investigate the mechanisms behind T‐cell immunotherapies.
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控制FOXP3基因座中的顺式元素对调节T细胞身份的遗传控制。
影响因子：
64.5
作者：
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影响因子：
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32.4
作者：
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通讯作者：
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