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The transcription factor ZEB2 drives the formation of age-associated B cells.
journal contribution
posted on 2024-05-13, 10:04 authored by Dai Dai, Shuangshuang Gu, Xiaxia Han, Huihua Ding, Yang Jiang, Xiaoou Zhang, Chao Yao, Soonmin Hong, Jinsong Zhang, Yiwei Shen, Guojun Hou, Bo Qu, Haibo Zhou, Yuting Qin, Yuke He, Jianyang Ma, Zhihua Yin, Zhizhong Ye, Jie Qian, Qian Jiang, Lihua Wu, Qiang Guo, Sheng Chen, Chuanxin Huang, Leah C Kottyan, Matthew T Weirauch, Carola G Vinuesa, Nan ShenAge-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.
