A temporally dynamic Foxp3 autoregulatory transcriptional circuit controls the effector Treg programme
A temporally dynamic Foxp3 autoregulatory transcriptional circuit controls the effector Treg programme
复制标题
时间动态 Foxp3 自动调节转录电路控制效应 Treg 程序
DOI：
10.1101/238386
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Bending D
中科院分区：
文献类型：
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作者：
Bending D
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，外周中Foxp 3转录是否以及如何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，报告真实的-timeFoxp 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。这些持续的动态ofFoxp 3转录决定了效应Treg程序，并依赖于Foxp 3的自动调节转录电路。PersistentFoxp 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：新的Foxp 3通量由抗TNFRII抗体促进，高频Foxp 3表达子由抗OX 40抗体靶向。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 howFoxp3transcription is induced and regulated in the periphery during T‐cell responses. UsingFoxp3‐Timer of cell kinetics and activity (Tocky) mice, which report real‐timeFoxp3expression,we show that the flux of newFoxp3expressors and the rate ofFoxp3transcription are increased during inflammation. These persistent dynamics ofFoxp3transcription determine the effector Treg programme and are dependent on a Foxp3 autoregulatory transcriptional circuit. PersistentFoxp3transcriptional 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 ofFoxp3transcription, and we show proof of principle for the manipulation ofFoxp3dynamics by immunotherapy: newFoxp3flux is promoted by anti‐TNFRII antibody, and high‐frequencyFoxp3expressors are targeted by anti‐OX40 antibody. Collectively, our study dissects time‐dependent mechanisms behind Foxp3‐driven T‐cell regulation and establishes theFoxp3‐Tocky system as a tool to investigate the mechanisms behind T‐cell immunotherapies.