2. Academic Validation
  3. DDX55 safeguards naïve T cell homeostasis by suppressing activation-promoting transposable elements

DDX55 safeguards naïve T cell homeostasis by suppressing activation-promoting transposable elements

  • Sci Immunol. 2025 Sep 5;10(111):eadq0457. doi: 10.1126/sciimmunol.adq0457.
Mengyue Wu 1 2 3,  Kepan Linghu 1 2,  Qimin Yin 1 2 3,  Ping He 1 2,  Xinyang Yu 4,  Peng Hu 1 2,  Rongying He 1 2,  Qinyun Du 5,  Shengli Wang 4,  Xi Chen 1 2,  Shaohui Wang 5 6,  Xingyun Wu 3,  Mingfu Zhang 1 2,  Keren Peng 1 3,  Xiang Wang 1 2,  Juxiu Liu 1 2,  Dong Deng 1 2,  Guangchao Cao 7 8,  Kui Wang 3,  Xianli Meng 5,  Quanli Yang 4 7 8,  Dezhi Mu 1 2,  Zhinan Yin 7 8 9,  Lu Chen 1 2,  Jiyu Tong 1 2 10
Affiliations

Affiliations

  • 1 Laboratory of Epigenetics and Immunology, West China Institute of Women and Children's Health, NHC Key Laboratory of Chronobiology, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China.
  • 2 Department of Obstetric and Pediatric, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China.
  • 3 Department of Immunology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China.
  • 4 Zhuhai People's Hospital, Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University, Zhuhai, China.
  • 5 State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
  • 6 Qingdao Academy of Chinese Medicinal Sciences, Shandong University of Traditional Chinese Medicine, Qingdao, China.
  • 7 Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, China.
  • 8 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, China.
  • 9 Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital, Zhuhai Institute of Translational Medicine, Zhuhai Medical College of Jinan University, Zhuhai, China.
  • 10 Children's Medicine Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, China.
PMID: 40911696 DOI: 10.1126/sciimmunol.adq0457
Abstract

Naïve T cells are maintained in a homeostatic state to preserve a stable T cell pool with diverse T cell receptor (TCR) repertoires, ensuring preparedness for priming. However, the underlying mechanisms controlling naïve T cell homeostasis and priming remain unclear. Leveraging a machine learning-based functional genetic screen, we identified DEAD-box helicase 55 (Ddx55) as the top factor responsible for naïve T cell homeostasis. DDX55 was highly expressed in naïve T cells and suppressed enhancer- and promoter-like transposable elements (TEs) near T cell activation-associated genes. Ddx55 loss led to derepression of these TEs, resulting in TE-derived R loops and genomic instability, ultimately disrupting naïve T cell homeostasis and abolishing T cell proliferation. Mechanistically, DDX55-targeted TEs harbored myelocytomatosis oncogene (MYC)-binding motifs. DDX55 directly bound MYC and restricted its access to these TE loci, thereby preventing inappropriate TE activation in naïve T cells. Thus, naïve T cells exploit DDX55 as a vital regulator of T cell activation, ensuring their genomic stability and homeostatic maintenance.

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