美国纪念斯隆-凯特琳癌症中心Alexander Y. Rudensky团队取得一项新突破。他们的最新研究提出了调节性T细胞中转录因子Foxp3表达的时间和环境依赖性要求。这一研究成果发表在2025年10月8日出版的国际学术期刊《自然—免疫学》上。

利用一种新的体内诱导Foxp3蛋白降解的化学发生系统，该研究团队发现Foxp3对于新生成的Treg细胞的转录和功能程序的建立是必不可少的，而成熟的Treg细胞中Foxp3的缺失在稳态下只会导致很小的功能和转录变化。成熟Treg细胞中foxp3依赖性程序的这种弹性是在出乎意料的长时间内获得的；然而，在严重炎症的情况下，Foxp3的缺失导致Treg细胞转录组和适应度的明显扰动。

此外，肿瘤Treg细胞对Foxp3降解具有独特的敏感性，这导致其抑制功能受损，在没有明显不良反应的情况下肿瘤缩小。这些研究表明Foxp3对Treg转录和功能程序的差异需求依赖于环境。

据悉，表达转录因子Foxp3的调节性T （Treg）细胞是免疫反应的强制性守门人，但Foxp3调控Treg转录网络的机制尚不完全清楚。

附：英文原文

Title: Temporal and context-dependent requirements for the transcription factor Foxp3 expression in regulatory T cells

Author: Hu, Wei, Dolsten, Gabriel A., Wang, Eric Y., Beroshvili, Giorgi, Wang, Zhong-Min, Ghelani, Aazam P., Uhl, Lion F. K., Bou-Puerto, Regina, Huang, Xiao, Michaels, Anthony J., Hoyos, Beatrice E., Jin, Wenjie, Pritykin, Yuri, Rudensky, Alexander Y.

Issue&Volume: 2025-10-08

Abstract: Regulatory T (Treg) cells, expressing the transcription factor Foxp3, are obligatory gatekeepers of immune responsiveness, yet the mechanisms by which Foxp3 governs the Treg transcriptional network remain incompletely understood. Using a novel chemogenetic system of inducible Foxp3 protein degradation in vivo, we found that while Foxp3 was indispensable for the establishment of transcriptional and functional programs of newly generated Treg cells, Foxp3 loss in mature Treg cells resulted in minimal functional and transcriptional changes under steady state. This resilience of the Foxp3-dependent program in mature Treg cells was acquired over an unexpectedly long timescale; however, in settings of severe inflammation, Foxp3 loss led to a pronounced perturbation of Treg cell transcriptome and fitness. Furthermore, tumoral Treg cells were uniquely sensitive to Foxp3 degradation, which led to impairment in their suppressive function and tumor shrinkage in the absence of pronounced adverse effects. These studies demonstrate a context-dependent differential requirement for Foxp3 for Treg transcriptional and functional programs.

DOI: 10.1038/s41590-025-02295-4

Source: https://www.nature.com/articles/s41590-025-02295-4