2. Academic Validation
  3. HMGB1 couples LEF1 to regulate B cell immunity

HMGB1 couples LEF1 to regulate B cell immunity

  • JCI Insight. 2025 Sep 23;10(18):e187002. doi: 10.1172/jci.insight.187002.
Qiuyue Chen 1 2,  Ziyin Zhang 2,  Nanshu Xiang 2,  Li Luo 2,  Xin Dai 2,  Danqing Kang 2,  Lu Yang 2,  Yingzi Zhu 3,  Jiang Chang 2,  Yukai Jing 2,  Na Li 1,  Qianglin Chen 1,  Panpan Jiang 2,  Ju Liu 2,  Yanmei Huang 2,  Heather Miller 4,  Xinyuan Zhou 5,  Fang Zheng 6,  Quan Gong 1,  Chaohong Liu 2
Affiliations

Affiliations

  • 1 Clinical Molecular Immunology Center, Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China.
  • 2 Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4 Department of Intracellular Pathogens, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
  • 5 Institute of Immunology, Army Medical University, Chongqing, China.
  • 6 Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
PMID: 40985892 DOI: 10.1172/jci.insight.187002
Abstract

Secreted high mobility group box protein 1 (HMGB1) regulates the adaptive immune response and acts as a biosensor for cells undergoing necrosis, stress, and inflammatory stimulation. However, its role in B cells remains enigmatic. Here, we demonstrate that HMGB1 is critical for peripheral B cell homeostasis and humoral immunity. Conditional deletion of Hmgb1 in B cells led to expanded marginal zone B cells, reduced B1a cells, and impaired antigen-specific antibody responses. Mechanistically, HMGB1 deficiency enhanced proximal and distal B cell receptor (BCR) signaling, probably via increased CD21 expression, which lowered the BCR activation threshold. This phenotype was linked to reduced lymphoid enhancer-binding factor 1 (LEF1) levels, a Wnt-responsive transcription factor, as HMGB1 directly bound the Lef1 promoter to sustain its transcription, thereby repressing Cd21. Furthermore, HMGB1 constrained actin reorganization by suppressing the MST1/DOCK8/WASP axis, which feedback-modulated BCR clustering and signalosome recruitment. Collectively, HMGB1 ensures optimal BCR signaling by transcriptionally and cytoskeletally tuning activation thresholds, highlighting its dual role as a nuclear regulator and cytoskeletal modulator in B cell immunity.

Keywords

Cell biology; Development; Immunology; Signal transduction.

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