Wang Xianghong, Lin Rong, Li Dehai, Ye Weiyuan, Yang Zhe, Wu Niujian, Wen Qiong, Tan Jingyi, Sun Chuanchuan, Yin Zhinan, Lu Hongyun, Yang Hengwen
Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (The Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai 519000, China; Department of Endocrinology and Metabolism, Zhuhai People's Hospital (The Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University), Zhuhai 519000, China.
Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (The Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai 519000, China.
Int Immunopharmacol. 2025 Feb 20;148:114100. doi: 10.1016/j.intimp.2025.114100. Epub 2025 Jan 26.
Previous studies have established that γδ T cells play a significant role in liver fibrosis. However, their specific functions and mechanisms in fibrotic liver tissue remain unclear. Using online microarray expression profiles, we observed that USF3 was upregulated in patients with liver fibrosis and was associated with immune cells. Additionally, increases in the expression of USF3 correlated with elevated levels of interferon-gamma (IFN-γ) in γδ T cells. However, the regulatory impact of USF3 on T cells, particularly in relation to fibrosis, has not been sufficiently elucidated. In this study, we employed conditional knockout mice (USF3; CD2-cre) to investigate the role of USF3 in γδ T cells. The conditional knockout of USF3 resulted in an increase in both the number and proliferation of γδ T cells, which was associated with mTOR signaling pathway activation. The absence of USF3 significantly enhanced the expression of Eomes in γδ T cells, leading to an increase in IFN-γ production. Importantly, liver fibrosis was alleviated in USF3 conditional knockout mice, which was potentially linked to the enhanced proliferation of γδ T cells and the elevated expression of cytotoxic molecules, including IFN-γ. In summary, targeting USF3 in γδ T cells may represent a promising immunotherapeutic approach for liver fibrosis.
先前的研究已证实γδ T细胞在肝纤维化中发挥重要作用。然而，它们在纤维化肝组织中的具体功能和机制仍不清楚。通过在线微阵列表达谱，我们观察到USF3在肝纤维化患者中上调，且与免疫细胞相关。此外，USF3表达的增加与γδ T细胞中干扰素-γ（IFN-γ）水平的升高相关。然而，USF3对T细胞的调节作用，特别是与纤维化相关的调节作用，尚未得到充分阐明。在本研究中，我们使用条件性敲除小鼠（USF3；CD2-cre）来研究USF3在γδ T细胞中的作用。USF3的条件性敲除导致γδ T细胞数量和增殖增加，这与mTOR信号通路激活有关。USF3的缺失显著增强了γδ T细胞中Eomes的表达，导致IFN-γ产生增加。重要的是，USF3条件性敲除小鼠的肝纤维化得到缓解，这可能与γδ T细胞增殖增强和包括IFN-γ在内的细胞毒性分子表达升高有关。总之，靶向γδ T细胞中的USF3可能是一种有前景的肝纤维化免疫治疗方法。
