2. Academic Validation
  3. Modulation of γδ T cells by USF3: Implications for liver fibrosis and immune regulation

Modulation of γδ T cells by USF3: Implications for liver fibrosis and immune regulation

  • Int Immunopharmacol. 2025 Feb 20:148:114100. doi: 10.1016/j.intimp.2025.114100.
Xianghong Wang 1,  Rong Lin 2,  Dehai Li 3,  Weiyuan Ye 4,  Zhe Yang 5,  Niujian Wu 5,  Qiong Wen 2,  Jingyi Tan 2,  Chuanchuan Sun 6,  Zhinan Yin 7,  Hongyun Lu 8,  Hengwen Yang 9
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Tianjian Laboratory of Advanced Biomedical Sciences, Institute of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450001, China.
  • 4 Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, China.
  • 5 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.
  • 6 Department of Nephrology, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China.
  • 7 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; State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, China. Electronic address: tzhinan@jnu.edu.cn.
  • 8 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. Electronic address: luhongyun@jnu.edu.cn.
  • 9 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; State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, China. Electronic address: hengwenyang@jnu.edu.cn.
PMID: 39870010 DOI: 10.1016/j.intimp.2025.114100
Abstract

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 (USF3f/f; 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.

Keywords

Eomes; Hepatic fibrosis; USF3; γδ T cells.

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