2. Academic Validation
  3. Inhibition of LARP4-mediated quiescence exit of naive CD4+ T cells ameliorates autoimmune and allergic diseases

Inhibition of LARP4-mediated quiescence exit of naive CD4+ T cells ameliorates autoimmune and allergic diseases

  • Nat Biomed Eng. 2025 Oct 16. doi: 10.1038/s41551-025-01514-5.
Jian Zhou # 1,  Di Yang # 1,  Chao Han # 1,  Hui Dong # 1,  Shufeng Wang # 1,  Xiang Li 2,  Jun Hu 3,  Cui Wang 3,  Jie Luo 3,  Zhiyuan Wei 3,  Taiping Liu 4,  Shuai Xu 5,  Chen Xu 1,  Yiwei Zhang 1,  Xian Wang 6,  Yuanyu Deng 1,  Baiqing Li 1,  Ruihan Mao 1,  Mingyang Zhang 7,  Yi Sun 3,  Xinyuan Zhou 1,  Lilin Ye 1,  Bing Ni 8,  Jun Zhu 9,  Juan Li 10,  Jingbo Zhang 5,  Tingting Zhao 11,  Xiangmei Chen 12,  Rong Lin 13,  Yi Zhang 14,  Yuzhang Wu 15 16,  Yi Tian 17
Affiliations

Affiliations

  • 1 Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
  • 2 Departments of Physics and Anatomy and Cell Biology, The George Washington University, Washington, DC, USA.
  • 3 The First Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
  • 4 Department of Pathogenic Biology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
  • 5 The Second Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
  • 6 Department of Immunology, Medical College of Qingdao University, Qingdao, People's Republic of China.
  • 7 The Third Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
  • 8 Department of Pathophysiology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
  • 9 Shanghai Introncure Biotechnology, Inc., Shanghai, People's Republic of China.
  • 10 Department of Medical Genetics, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
  • 11 Chongqing International Institute for Immunology, Chongqing, People's Republic of China.
  • 12 Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China.
  • 13 Sanya People's Hospital, Sanya, China.
  • 14 Chongqing International Institute for Immunology, Chongqing, People's Republic of China. zhangyi@iiicq.vip.
  • 15 Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China. wuyuzhang@tmmu.edu.cn.
  • 16 Chongqing International Institute for Immunology, Chongqing, People's Republic of China. wuyuzhang@tmmu.edu.cn.
  • 17 Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China. tianyi@tmmu.edu.cn.
  • # Contributed equally.
PMID: 41102557 DOI: 10.1038/s41551-025-01514-5
Abstract

Naive T cells are maintained under a quiescent state, and their exit from quiescence is a hallmark of antigen stimulation. Here we identify the RNA binding protein La-related protein 4 (LARP4) as an important checkpoint regulator of quiescence exit in naive CD4+ T cells. Conditional knockout of LARP4 in naive CD4+ T cells leads to an enhanced quiescence state and/or dampened quiescence exit due to altered stability of several messenger RNAs important for T-cell activation. The differentiation of naive CD4+ T cells into helper T-cell subsets is also impaired after conditional knockout, leading to ameliorated autoimmune and allergic responses. Lastly, we design a peptide inhibitor of LARP4 (LIPEP), and treatment with LIPEP could perfectly mimic LARP4 deficiency and alleviate the severity of autoimmune and allergic diseases in the corresponding mouse models. Our study reveals a link between RNA stability and CD4+ T-cell homeostasis/adaptive activation, highlighting the potential of LARP4 as a preventative and therapeutic target for autoimmune and allergic diseases although at quite high doses.

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