HMGB1 couples LEF1 to regulate B cell immunity.
- 2025-09-23
- JCI insight 10(20)
- Qiuyue Chen
- Ziyin Zhang
- Nanshu Xiang
- Li Luo
- Xin Dai
- Danqing Kang
- Lu Yang
- Yingzi Zhu
- Jiang Chang
- Yukai Jing
- Na Li
- Qianglin Chen
- Panpan Jiang
- Ju Liu
- Yanmei Huang
- Heather Miller
- Xinyuan Zhou
- Fang Zheng
- Quan Gong
- Chaohong Liu
- PubMed: 40985892
- DOI: 10.1172/jci.insight.187002
Study Design
- Population
- conditional Hmgb1 knockout mice
- Methods
- Conditional deletion of Hmgb1 in B cells; assessed B cell populations, BCR signaling, gene expression, actin reorganization
- Funding
- Unclear
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.