Gu Qianchong, Zhao Xiufeng, Guo Jie, Jin Qiuzhu, Wang Ting, Xu Wei, Li Liping, Zhang Jianhua, Zhang Wei, Hong Sheng, Zhang Fuping, Hou Baidong, Zhou Xuyu
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Science (CAS), Beijing 100101, China; Department of Savaid Medical School, University of Chinese Academy of Sciences (CAS), Beijing 100049, China.
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Science (CAS), Beijing 100101, China.
Cell Rep. 2023 Aug 29;42(8):112877. doi: 10.1016/j.celrep.2023.112877. Epub 2023 Jul 26.
Foxp3 is the master transcription factor for regulatory T cells (Tregs). Alternative splicing of human Foxp3 results in the expression of two isoforms: the full length and an exon 2-deleted protein. Here, AlphaFold2 predictions and in vitro experiments demonstrate that the N-terminal domain of Foxp3 inhibits DNA binding by moving toward the C terminus and that this movement is mediated by exon 2. Consequently, we find that Foxp3Δ2-bearing thymus-derived Tregs (tTregs) in the peripheral lymphoid organ are less sensitive to T cell receptor (TCR) stimulation due to the enhanced binding of Foxp3Δ2 to the Batf promoter and are hyporesponsive to interleukin-2 (IL-2). In contrast, among RORγt peripherally induced Tregs (pTregs) in the large intestine, Foxp3Δ2 pTregs express many more RORγt-related genes, conferring a competitive advantage. Together, our results reveal that alternative splicing of exon 2 generates an active form of Foxp3, which plays a differential role in regulating tTreg and pTreg homeostasis.
Foxp3是调节性T细胞（Tregs）的主要转录因子。人类Foxp3的可变剪接导致两种异构体的表达：全长蛋白和缺失外显子2的蛋白。在此，AlphaFold2预测和体外实验表明，Foxp3的N端结构域通过向C端移动来抑制DNA结合，并且这种移动由外显子2介导。因此，我们发现外周淋巴器官中携带Foxp3Δ2的胸腺来源的Tregs（tTregs）对T细胞受体（TCR）刺激的敏感性较低，这是由于Foxp3Δ2与Batf启动子的结合增强，并且对白细胞介素-2（IL-2）反应低下。相反，在大肠中RORγt外周诱导的Tregs（pTregs）中，Foxp3Δ2 pTregs表达更多与RORγt相关的基因，从而赋予竞争优势。总之，我们的结果表明外显子2的可变剪接产生了一种活性形式的Foxp3，它在调节tTreg和pTreg稳态中发挥不同作用。
