Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
Immunity. 2024 Sep 10;57(9):2043-2060.e10. doi: 10.1016/j.immuni.2024.07.010. Epub 2024 Aug 6.
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.
调节性 T (Treg) 细胞的主转录因子叉头框蛋白 P3 (Foxp3) 通过靶向某些基因的激活或抑制来控制 Treg 细胞的功能，但在不同条件下它介导这种激活或抑制的确切机制仍不清楚。我们发现，Ikzf1 通过其外显子 5（IkE5）与 Foxp3 相互作用，并且缺乏 IkE5 的 Treg 细胞高表达那些原本会在 T 细胞受体刺激下被 Foxp3 抑制的基因，包括 Ifng。Treg 细胞特异性的 IkE5 缺失导致干扰素-γ (IFN-γ) 过度产生，这破坏了 Foxp3 的表达并损害了 Treg 的抑制功能，导致全身性自身免疫疾病和强烈的抗肿瘤免疫。来那度胺，它能降解 IKZF1 和 IKZF3，可诱导人 Treg 细胞中 IFN-γ 的过度产生。从机制上讲，Foxp3-Ikzf1-Ikzf3 复合物通过染色质重塑与表观遗传共激活因子（如 p300）竞争结合靶基因座。因此，Ikzf1 与 Foxp3 的结合对于 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。
