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

被引：37

作者：

Dai, Dai ^{[1
,2
,3
]}

Gu, Shuangshuang ^{[1
]}

Han, Xiaxia ^{[1
]}

Ding, Huihua ^{[1
,2
]}

Jiang, Yang ^{[1
]}

Zhang, Xiaoou ^{[4
,5
]}

Yao, Chao ^{[6
]}

Hong, Soonmin ^{[1
]}

Zhang, Jinsong ^{[6
]}

Shen, Yiwei ^{[1
]}

Hou, Guojun ^{[1
,2
]}

Qu, Bo ^{[1
,2
]}

Zhou, Haibo ^{[1
,2
]}

Qin, Yuting ^{[1
,2
]}

He, Yuke ^{[1
,2
]}

Ma, Jianyang ^{[1
,2
]}

Yin, Zhihua ^{[7
]}

Ye, Zhizhong ^{[7
]}

Qian, Jie ^{[1
]}

Jiang, Qian ^{[8
]}

Wu, Lihua ^{[8
]}

Guo, Qiang ^{[1
]}

Chen, Sheng ^{[1
]}

Huang, Chuanxin ^{[9
]}

Kottyan, Leah C. ^{[10
,11
]}

Weirauch, Matthew T. ^{[10
,11
]}

Vinuesa, Carola G. ^{[2
,12
]}

Shen, Nan ^{[1
,2
,3
,7
,10
]}

机构：

[1] Shanghai Jiao Tong Univ, Shanghai Renji Hosp, Shanghai Inst Rheumatol, Sch Med SJTUSM, Shanghai, Peoples R China

[2] SJTUSM, Shanghai Renji Hosp, Ctr Personalised Immunol CACPI, Shanghai, Peoples R China

[3] SJTUSM, Shanghai Renji Hosp, Shanghai Canc Inst, State Key Lab Oncogenes & Related Genes, Shanghai, Peoples R China

[4] Shanghai First Matern & Infant Hosp, Clin & Translat Res Ctr, Shanghai Key Lab Maternal & Fetal Med, Shanghai, Peoples R China

[5] Tongji Univ, Frontier Sci Ctr Stem Cell Res, Sch Life Sci & Technol, Shanghai, Peoples R China

[6] Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Nutr & Hlth, Shanghai, Peoples R China

[7] Shenzhen Futian Hosp Rheumat Dis, Shenzhen, Peoples R China

[8] Capital Inst Pediat, Dept Med Genet, Beijing, Peoples R China

[9] SJTUSM, Ruijin Hosp, Shanghai Inst Immunol, Ctr Immune Related Dis, Shanghai, Peoples R China

[10] Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol, Div Human Genet, Cincinnati, OH 45229 USA

[11] Univ Cincinnati, Dept Pediat, Cincinnati, OH USA

[12] Francis Crick Inst, London, England

来源：

SCIENCE | 2024年 / 383卷 / 6681期

基金：

中国国家自然科学基金;

关键词：

T-BET; IFN-GAMMA; DIFFERENTIATION; EXPRESSION; ALIGNMENT; GENES;

D O I：

10.1126/science.adf8531

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

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.

引用

页码：413 / 421

页数：9

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