From stability to dynamics: understanding molecular mechanisms of regulatory T cells through Foxp3 transcriptional dynamics.
From stability to dynamics: understanding molecular mechanisms of regulatory T cells through Foxp3 transcriptional dynamics.
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DOI：
10.1111/cei.13194
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发表时间：
2019-07
影响因子：
4.6
通讯作者：
Ono M
中科院分区：
文献类型：
--
作者：
Bending D;Ono M
对调节性T细胞（Treg）的研究集中在胸腺Treg作为免疫抑制性T细胞的稳定谱系，其分化由转录因子叉头盒蛋白3（Foxp3）控制。然而，这种谱系观点可能会限制关于Foxp3和Treg在体内作用的假设，特别是在临床环境和免疫疗法开发中。在这篇综述中，我们综合了一个新的视角Foxp3作为一个动态表达的基因的作用，从而重新审视Foxp3的转录调控的分子机制。特别是，我们通过开发细胞动力学和活性计时器（Tocky）系统介绍了Foxp3介导的T细胞调节研究的最新进展，并表明Foxp3转录动力学的研究可以揭示Treg体内分化和功能的时间变化。我们强调了Foxp3作为T细胞受体（TCR）信号传导下游基因的作用，并表明时间上持续的TCR信号启动Foxp3在自身反应性胸腺细胞中的转录。此外，我们还将Foxp3基因的自动调节转录回路作为巩固Treg分化和激活其抑制功能的机制。此外，我们还探索了Foxp3转录的表观遗传修饰和染色质结构的动态调节背后的潜在机制。最后，我们讨论了Treg分化和激活的时间变化的临床相关性。
Studies on regulatory T cells (Treg) have focused on thymic Treg as a stable lineage of immunosuppressive T cells, the differentiation of which is controlled by the transcription factor forkhead box protein 3 (Foxp3). This lineage perspective, however, may constrain hypotheses regarding the role of Foxp3 and Treg in vivo, particularly in clinical settings and immunotherapy development. In this review, we synthesize a new perspective on the role of Foxp3 as a dynamically expressed gene, and thereby revisit the molecular mechanisms for the transcriptional regulation of Foxp3. In particular, we introduce a recent advancement in the study of Foxp3‐mediated T cell regulation through the development of the Timer of cell kinetics and activity (Tocky) system, and show that the investigation of Foxp3 transcriptional dynamics can reveal temporal changes in the differentiation and function of Treg in vivo. We highlight the role of Foxp3 as a gene downstream of T cell receptor (TCR) signalling and show that temporally persistent TCR signals initiate Foxp3 transcription in self‐reactive thymocytes. In addition, we feature the autoregulatory transcriptional circuit for the Foxp3 gene as a mechanism for consolidating Treg differentiation and activating their suppressive functions. Furthermore, we explore the potential mechanisms behind the dynamic regulation of epigenetic modifications and chromatin architecture for Foxp3 transcription. Lastly, we discuss the clinical relevance of temporal changes in the differentiation and activation of Treg.