Hu Wei, Dolsten Gabriel, Beroshvili Giorgi, Wang Eric Y, 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
Howard Hughes Medical Institute, Immunology Program, and Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Res Sq. 2025 May 14:rs.3.rs-6596747. doi: 10.21203/rs.3.rs-6596747/v1.
Regulatory T (Treg) cells, expressing the transcription factor Foxp3, are obligatory gatekeepers of the immune responsiveness. While Foxp3 essential role in Treg l differentiation is well established, the mechanisms by which Foxp3 governs the Treg-specific transcriptional network remain incompletely understood. Here, we employed a novel chemogenetic system of inducible, time-controlled degradation of Foxp3 protein to dissect its Treg stage stage-specific functions. While Foxp3 was indispensable for the establishment of the Treg transcriptional program and suppressive function during thymic Treg progenitors and newly generated peripheral Treg cells, degradation of Foxp3 in mature Treg cells resulted in unexpectedly minimal transcriptional changes largely limited to direct Foxp3 targets and largely preserved suppressive capacity. However, tumoral Treg cells were uniquely sensitive to Foxp3 degradation, which led to impaired suppressive function and tumor growth restraint absent pronounced adverse effects. These studies demonstrate context-dependent differential requirement for Foxp3 for Treg transcriptional and functional programs.
表达转录因子Foxp3的调节性T（Treg）细胞是免疫反应性的必需守门人。虽然Foxp3在Treg细胞分化中的重要作用已得到充分证实，但Foxp3调控Treg特异性转录网络的机制仍未完全了解。在这里，我们采用了一种新的化学遗传系统，可诱导、时间控制地降解Foxp3蛋白，以剖析其在Treg细胞阶段的特异性功能。虽然Foxp3对于胸腺Treg祖细胞和新产生的外周Treg细胞建立Treg转录程序和抑制功能是必不可少的，但成熟Treg细胞中Foxp3的降解导致出乎意料的最小转录变化，主要限于直接的Foxp3靶标，并且很大程度上保留了抑制能力。然而，肿瘤Treg细胞对Foxp3降解具有独特的敏感性，这导致抑制功能受损和肿瘤生长受限，而没有明显的不良影响。这些研究表明，Treg转录和功能程序对Foxp3的依赖性存在上下文差异。
