Abstract：
The master transcription factor of regulatory T (Treg) cells, forkhead box protein P3 (Foxp3), controls Treg cell function by targeting certain genes for activation or repression, but the specific mechanisms by which it mediates this activation or repression under different conditions remain unclear. We found that Ikzf1 associates with Foxp3 via its exon 5 (IkE5) and that IkE5-deficient Treg cells highly expressed genes that would otherwise be repressed by Foxp3 upon T cell receptor stimulation, including Ifng. Treg-specific IkE5-deletion caused interferon-γ (IFN-γ) overproduction, which destabilized Foxp3 expression and impaired Treg suppressive function, leading to systemic autoimmune disease and strong anti-tumor immunity. Pomalidomide, which degrades IKZF1 and IKZF3, induced IFN-γ overproduction in human Treg cells. Mechanistically, the Foxp3-Ikzf1-Ikzf3 complex competed with epigenetic co-activators, such as p300, for binding to target gene loci via chromatin remodeling. Therefore, the Ikzf1 association with Foxp3 is essential for the gene-repressive function of Foxp3 and could be exploited to treat autoimmune disease and cancer.
摘要：
调节性T(Treg)细胞的主转录因子,叉头盒蛋白P3（Foxp3），通过针对某些基因的激活或抑制来控制Treg细胞功能，但在不同条件下介导这种激活或抑制的具体机制仍不清楚。我们发现Ikzf1通过其外显子5（IkE5）与Foxp3结合，并且IkE5缺陷的Treg细胞高度表达基因，否则这些基因会在T细胞受体刺激时被Foxp3抑制。包括Ifng.Treg特异性IkE5缺失导致干扰素-γ（IFN-γ）过度生产，导致Foxp3表达不稳定，Treg抑制功能受损，导致全身自身免疫性疾病和强大的抗肿瘤免疫力。波马度胺,其降解IKZF1和IKZF3,在人Treg细胞中诱导IFN-γ过量产生。机械上,Foxp3-Ikzf1-Ikzf3复合物与表观遗传共激活剂竞争，例如p300,用于通过染色质重塑与靶基因位点结合。因此,Ikzf1与Foxp3的关联对于Foxp3的基因抑制功能至关重要,可用于治疗自身免疫性疾病和癌症.
