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

Jian Zhou, Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Di Yang, Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Chao Han, Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Hui Dong, Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Shufeng Wang, Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Xiang Li, Departments of Physics and Anatomy and Cell Biology, The George Washington University, Washington, DC, USA.
Jun Hu, The First Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Cui Wang, The First Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Jie Luo, The First Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Zhiyuan Wei, The First Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Taiping Liu, Department of Pathogenic Biology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Shuai Xu, The Second Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Chen Xu, Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Yiwei Zhang, Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Xian Wang, Department of Immunology, Medical College of Qingdao University, Qingdao, People's Republic of China.
Yuanyu Deng, Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Baiqing Li, Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Ruihan Mao, Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Mingyang Zhang, The Third Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Yi Sun, The First Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Xinyuan Zhou, Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Lilin Ye, Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Bing Ni, Department of Pathophysiology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Jun Zhu, Shanghai Introncure Biotechnology, Inc., Shanghai, People's Republic of China.
Juan Li, Department of Medical Genetics, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Jingbo Zhang, The Second Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
Tingting Zhao, Chongqing International Institute for Immunology, Chongqing, People's Republic of China.
Xiangmei Chen, 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.
Rong Lin, Sanya People's Hospital, Sanya, China.
Yi Zhang, Chongqing International Institute for Immunology, Chongqing, People's Republic of China. zhangyi@iiicq.vip.
Yuzhang Wu, Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China. wuyuzhang@tmmu.edu.cn.
Yi Tian, Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China. tianyi@tmmu.edu.cn.

Document Type

Journal Article

Publication Date

10-16-2025

Journal

Nature biomedical engineering

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.

Department

Anatomy and Regenerative Biology

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