日本大阪大学Shimon Sakaguchi、Kenji Ichiyama课题组的最新研究发现，转录因子Ikzf1与叉头盒蛋白 P3（Foxp3）联合抑制调节性T（Treg）细胞的基因表达，限制自身免疫和抗肿瘤免疫。相关论文于2024年8月6日发表在《免疫》杂志上。

研究发现，Ikzf1通过其第5个外显子（IkE5）与Foxp3结合，缺失IkE5的Treg细胞高表达在T细胞受体刺激时被Foxp3抑制的基因，包括Ifng。Treg特异性IkE5缺失会导致干扰素-γ（IFN-γ）过度产生，从而破坏Foxp3表达的稳定性并破坏Treg的抑制功能，导致全身性自身免疫病和强大的抗肿瘤免疫。

Pomalidomide能降解IKZF1和IKZF3，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p300等表观遗传共激活因子竞争结合到靶基因位点。因此，Ikzf1与Foxp3的结合对于Foxp3的基因抑制功能至关重要，可将其作为治疗自身免疫性疾病和癌症的潜在靶点。

据介绍，Treg细胞的主转录因子Foxp3通过靶向激活，或抑制某些基因来调控Treg细胞的功能，但它在不同条件下介导这种激活或抑制的具体机制仍不清楚。

附：英文原文

Title: Transcription factor Ikzf1 associates with Foxp3 to repress gene expression in Treg cells and limit autoimmunity and anti-tumor immunity

Author: Kenji Ichiyama, Jia Long, Yusuke Kobayashi, Yuji Horita, Takeshi Kinoshita, Yamami Nakamura, Chizuko Kominami, Katia Georgopoulos, Shimon Sakaguchi

Issue&Volume: 2024-08-06

Abstract: The master transcription factor of regulatory T (Treg) cells, forkhead box proteinP3 (Foxp3), controls Treg cell function by targeting certain genes for activationor repression, but the specific mechanisms by which it mediates this activation orrepression under different conditions remain unclear. We found that Ikzf1 associateswith Foxp3 via its exon 5 (IkE5) and that IkE5-deficient Treg cells highly expressed genes that would otherwise be repressed byFoxp3 upon T cell receptor stimulation, including Ifng. Treg-specific IkE5-deletion caused interferon-γ (IFN-γ) overproduction, which destabilized Foxp3 expressionand impaired Treg suppressive function, leading to systemic autoimmune disease andstrong anti-tumor immunity. Pomalidomide, which degrades IKZF1 and IKZF3, inducedIFN-γ overproduction in human Treg cells. Mechanistically, the Foxp3-Ikzf1-Ikzf3 complexcompeted with epigenetic co-activators, such as p300, for binding to target gene locivia chromatin remodeling. Therefore, the Ikzf1 association with Foxp3 is essentialfor the gene-repressive function of Foxp3 and could be exploited to treat autoimmunedisease and cancer.

DOI: 10.1016/j.immuni.2024.07.010

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00359-5