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

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 Shen

doi:10.1126/science.adf8531

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

Science. 2024 Jan 26;383(6681):413-421. doi: 10.1126/science.adf8531. Epub 2024 Jan 25.

Authors

Dai Dai^#^{1

2

3}, Shuangshuang Gu^#¹, Xiaxia Han^#¹, Huihua Ding^{1

2}, Yang Jiang¹, Xiaoou Zhang^{4

5}, Chao Yao⁶, Soonmin Hong¹, Jinsong Zhang⁶, Yiwei Shen¹, Guojun Hou^{1

2}, Bo Qu^{1

2}, Haibo Zhou^{1

2}, Yuting Qin^{1

2}, Yuke He^{1

2}, Jianyang Ma^{1

2}, Zhihua Yin⁷, Zhizhong Ye⁷, Jie Qian¹, Qian Jiang⁸, Lihua Wu⁸, Qiang Guo¹, Sheng Chen¹, Chuanxin Huang⁹, Leah C Kottyan^{10

11}, Matthew T Weirauch^{10

11}, Carola G Vinuesa^{2

12}, Nan Shen^{1

2

3

7

10}

Affiliations

¹ Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.
² Centre for Personalised Immunology (CACPI), Shanghai Renji Hospital, SJTUSM, Shanghai, China.
³ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Renji Hospital, SJTUSM, Shanghai, China.
⁴ Shanghai Key Laboratory of Maternal and Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai, China.
⁵ Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
⁶ Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
⁷ Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China.
⁸ Department of Medical Genetics, Capital Institute of Pediatrics, Beijing, China.
⁹ Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, SJTUSM, Shanghai, China.
¹⁰ Center of Autoimmune Genomics and Etiology, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹¹ Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.
¹² Francis Crick Institute, London, UK.

^# Contributed equally.

PMID: 38271512
DOI: 10.1126/science.adf8531

Abstract

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.

MeSH terms

Aging / immunology
Animals
Autoimmunity* / genetics
B-Lymphocytes* / cytology
B-Lymphocytes* / metabolism
Cell Differentiation* / genetics
Cell Lineage / genetics
Disease Models, Animal
Female
Gene Expression Regulation*
Haploinsufficiency
Humans
Lupus Erythematosus, Systemic* / genetics
Lupus Erythematosus, Systemic* / immunology
MEF2 Transcription Factors / genetics
MEF2 Transcription Factors / metabolism
Mice
Zinc Finger E-box Binding Homeobox 2* / genetics
Zinc Finger E-box Binding Homeobox 2* / metabolism

Substances

MEF2 Transcription Factors
Mef2b protein, mouse
ZEB2 protein, human
ZEB2 protein, mouse
Zinc Finger E-box Binding Homeobox 2