PDF(Pubmed)
Abstract：
Nuclear factor Foxp3 determines regulatory T (Treg) cell fate and function via mechanisms that remain unclear. Here, we investigate the nature of Foxp3-mediated gene regulation in suppressing autoimmunity and antitumor immune response. Contrasting with previous models, we find that Foxp3-chromatin binding is regulated by Treg activation states, tumor microenvironment, and antigen and cytokine stimulations. Proteomics studies uncover dynamic proteins within Foxp3 proximity upon TCR or IL-2 receptor signaling in vitro, reflecting intricate interactions among Foxp3, signal transducers, and chromatin. Pharmacological inhibition and genetic knockdown experiments indicate that NFAT and AP-1 protein Batf are required for enhanced Foxp3-chromatin binding in activated Treg cells and tumor-infiltrating Treg cells to modulate target gene expression. Furthermore, mutations at the Foxp3 DNA-binding domain destabilize the Foxp3-chromatin association. These representative settings delineate context-dependent Foxp3-chromatin interaction, suggesting that Foxp3 associates with chromatin by hijacking DNA-binding proteins resulting from Treg activation or differentiation, which is stabilized by direct Foxp3-DNA binding, to dynamically regulate Treg cell function according to immunological contexts.
摘要：
核因子Foxp3通过尚不清楚的机制决定调节性T（Treg）细胞的命运和功能。这里,我们研究了Foxp3介导的基因调控在抑制自身免疫和抗肿瘤免疫反应中的本质。与以前的型号相比，我们发现Foxp3-染色质结合受Treg激活状态调节，肿瘤微环境,以及抗原和细胞因子刺激。蛋白质组学研究揭示了在体外TCR或IL-2受体信号传导时Foxp3附近的动态蛋白，反映了Foxp3，信号换能器，和染色质。药理学抑制和基因敲低实验表明,在活化的Treg细胞和肿瘤浸润的Treg细胞中增强的Foxp3-染色质结合以调节靶基因表达需要NFAT和AP-1蛋白Batf。此外，Foxp3DNA结合结构域的突变使Foxp3-染色质缔合不稳定。这些代表性的设置描述了上下文相关的Foxp3-染色质相互作用，提示Foxp3通过劫持Treg激活或分化产生的DNA结合蛋白与染色质结合，通过直接的Foxp3-DNA结合来稳定，根据免疫学背景动态调节Treg细胞功能。
