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Cited by 178Systemic Lupus Erythematosus ResearchT-cell and B-cell ImmunologyGenomics and Chromatin Dynamics

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

Open access
Dai, Dai, Gu, Shuangshuang, Han, Xiaxia, Ding, Huihua, Jiang, Yang, Zhang, Xiaoou, Yao, Chao, Hong, Soonmin +20 more·2024·Science
DOI 10.1126/science.adf8531PMC PMC7616037

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Abstract

Abstract Age-associated B-cells (ABCs) accumulate during infection, aging and autoimmunity, contributing to lupus pathogenesis. Here, we screen for transcription factors driving ABC formation and find 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 TLR7-driven lupus, Zeb2 is essential for ABC formation and autoimmune pathology. Zeb2 binds to the +20kb intronic enhancer of Mef2b, 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 signaling, and treatment with the Jak1/3 inhibitor tofacitinib reduces ABC accumulation in autoimmune mice and patients. Zeb2 thus emerges as a driver of B-cell autoimmunity. One-Sentence Summary Zeb2 is essential for Age-associated B cells differentiation and function.

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  • ABCs are characterized by distinct gene expression profiles with expression of transcription factors T-BET, IRF5, and ZEB2.

    “ABCs are characterized by their distinct gene expression profiles with the expression of a set a transcription factor including T-BET, IRF5, and ZEB2 [73 -75].”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [73]

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Cited by

Sorted by citations

Authors
Dai, D., Gu, S., Han, X., Ding, H., Jiang, Y., Zhang, X., Yao, C., Hong, S., Zhang, J., Shen, Y., Hou, G., Qu, B., Zhou, H., Qin, Y., He, Y., Ma, J., Yin, Z., Ye, Z., Qian, J., Jiang, Q., Wu, L., Guo, Q., Chen, S., Huang, C., Kottyan, L. C., Weirauch, M. T., Vinuesa, C. G., & Shen, N.
Affiliations
  • Shanghai Jiao Tong University (CN)
  • Tongji University (CN)
  • Shanghai Institute of Nutrition and Health (CN)
  • Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China.
  • Fourth People's Hospital of Shenzhen (CN)
  • Capital Institute of Pediatrics (CN)
  • Ruijin Hospital (CN)
  • Cincinnati Children's Hospital Medical Center (US)
  • Australian National University (AU)
Corresponding author
  • Dai, Dai
  • Vinuesa, Carola G.
  • Shen, Nan
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2024-01-26
Volume
383
Issue
6681
Pages
413-421
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.adf8531
PMC
PMC7616037
OpenAlex
W4391215347
Cited by
178
References
4
Citations by year
2026: 76 · 2025: 67 · 2024: 29 · 2023: 4 · 2022: 2
FWCI
55.69
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Science (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by)
  • Figshare (submittedVersion, cc-by)
  • The Francis Crick Institute (cc-by)
Funders
  • Wellcome Trust (CC2228)
  • Francis Crick Institute (CC2228)
  • Cancer Research UK (CC2228)
  • National Natural Science Foundation of China (81901637, 82071843, 2005DKA21300, 31930037, 31630021)
  • Sanming Project of Medicine in Shenzhen (SZSM201602087)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR070549)
Topics
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
age-associated B cells, ZEB2, transcription factors, lupus, MEF2B, JAK/STAT signaling, CD11c, B cell-mediated autoimmunity, aging, haploinsufficiency
MeSH terms
Zinc Finger E-box Binding Homeobox 2, Aging, Animals, B-Lymphocytes, Cell Differentiation, Disease Models, Animal, Female, Gene Expression Regulation, Humans, Lupus Erythematosus, Systemic, Transcription Factors, Autoimmunity, Cell Lineage, Mice, Haploinsufficiency, MEF2 Transcription Factors

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