The transcription factor ZEB2 drives the formation of age-associated B cells

• 成果类型: Article
• 署名作者: Dai, Dai; Gu, Shuangshuang; Han, Xiaxia; Ding, Huihua; Jiang, Yang; Zhang, Xiaoou; Yao, Chao; Hong, Soonmin; Zhang, Jinsong; Shen, Yiwei; Hou, Guojun; Qu, Bo; Zhou, Haibo; Qin, Yuting; He, Yuke; Ma, Jianyang; Yin, Zhihua; Ye, Zhizhong; Qian, Jie; Jiang, Qian; Wu, Lihua; Guo, Qiang; Chen, Sheng; Huang, Chuanxin; Kottyan, Leah C.; Weirauch, Matthew T.; Vinuesa, Carola G.; Shen, Nan
• 署名单位: Shanghai Jiao Tong University; Shanghai Jiao Tong University; Shanghai Jiao Tong University; Tongji University; Chinese Academy of Sciences; Shanghai Institute of Nutrition & Health, CAS; University of Chinese Academy of Sciences, CAS; Capital Institute of Pediatrics (CIP); Shanghai Jiao Tong University; Chinese Academy of Sciences; University System of Ohio; University of Cincinnati; Cincinnati Children's Hospital Medical Center; University System of Ohio; University of Cincinnati; Francis Crick Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10623
• DOI: 10.1126/science.adf8531
• 发表日期: 2024-01-26
• 页码: 413-421
• 关键词: t-bet; ifn-gamma; differentiation; expression; alignment; genes

摘要

Age-associated B cells (ABCs) accumulate during infection, aging, and autoimmunity, contributing to lupus pathogenesis. In this study, we screened for transcription factors driving ABC formation and found that zinc finger E-box binding homeobox 2 (ZEB2) is required for human and mouse ABC differentiation in vitro. ABCs are reduced in ZEB2 haploinsufficient individuals and in mice lacking Zeb2 in B cells. In mice with toll-like receptor 7 (TLR7)-driven lupus, ZEB2 is essential for ABC formation and autoimmune pathology. ZEB2 binds to +20-kb myocyte enhancer factor 2b (Mef2b)'s intronic enhancer, repressing MEF2B-mediated germinal center B cell differentiation and promoting ABC formation. ZEB2 also targets genes important for ABC specification and function, including Itgax. ZEB2-driven ABC differentiation requires JAK-STAT (Janus kinase-signal transducer and activator of transcription), and treatment with JAK1/3 inhibitor reduces ABC accumulation in autoimmune mice and patients. Thus, ZEB2 emerges as a driver of B cell autoimmunity.