调节性T（Treg）细胞的主转录因子叉头盒蛋白P3（Foxp3）通过靶向某些基因进行激活或抑制来控制Treg细胞功能，但其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，否则这些基因在 T 细胞受体刺激（包括 Ifng）时会被 Foxp3 抑制。 Treg特异性IkE5缺失导致干扰素γ（IFN-γ）过度产生，从而破坏Foxp3表达的稳定性并损害Treg抑制功能，导致全身性自身免疫性疾病和强大的抗肿瘤免疫力。 Pomalidomide 可降解 IKZF1 和 IKZF3，诱导人 Treg 细胞中 IFN-γ 过量产生。从机制上讲，Foxp3-Ikzf1-Ikzf3 复合物与表观遗传共激活因子（例如 p300）竞争，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，并且可用于治疗自身免疫性疾病和癌症。版权所有 © 2024 Elsevier Inc. 保留所有权利。

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.Copyright © 2024 Elsevier Inc. All rights reserved.