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Coming of age: the formation and function of age-associated B cells

Cellular & Molecular Immunology volume 21, pages 311–312 (2024)Cite this article

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B cells are generated in the bone marrow during ontogeny and migrate to peripheral lymphoid organs, where they encounter antigens to elicit humoral immunity. During the past decade, many novel B-cell subsets with distinct phenotypes and functions have been identified, and among these subsets, age-associated B cells (ABCs) were first characterized as a B-cell subset that accumulates with age [1]. Emerging evidence has shown that ABCs are critically involved in various human diseases [2]. Recent studies have shown that ABCs are generated prior to germinal center formation and expand during the development of systemic lupus erythematosus (SLE) and viral infections [2,3,4]. Although ABCs reportedly rely on Toll-like receptor (TLR) signals and T-cell-derived cytokines, including IFN-γ and IL-21, for differentiation [1, 2, 5], how microenvironment signals drive the formation of ABCs is unclear. T-bet has been recognized as a key transcription factor (TF) for ABCs, but recent studies have shown that T-bet is dispensable for the generation of these cells [6]. Moreover, IRF5 is highly expressed in ABCs and regulates the functions of ABCs in systemic autoimmunity [7]. However, IRF5 has broad functions in many B-cell and T-cell subsets. Currently, elucidating the transcriptional regulation of ABCs is a major challenge.

In a recent paper published in Science, Dai et al. reported a novel TF, zinc finger E-box binding homeobox 2 (ZEB2), that specifically drives the formation of ABCs [8]. By using single-cell RNA sequencing (scRNA-seq) and CRISPR/Cas9–based screening strategies, the authors found that ZEB2 is required for human and mouse ABC differentiation in culture. These authors further demonstrated that ZEB2 is essential for ABC formation and pathogenicity during the development of lupus. Mechanistically, ZEB2 promotes ABC differentiation by directly inhibiting other effector B-cell subsets and inducing ABC signature phenotypes. ZEB2-mediated ABC complex formation is dependent on the JAK-STAT pathway, demonstrating the promising therapeutic potential of JAK inhibitors for treating ABC-associated human diseases. This study identified an essential function of ZEB2 in the formation and function of ABCs, providing convincing evidence for the identity of ABCs as an important B-cell subset.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82071817, 82171793, 82371803), the Shenzhen Science and Technology Program (YCYJ20210324114602008), the Jiangsu Provincial Key Research and Development Program (BE2023758), the Hong Kong Research Grants Council (17113319, 17103821), the RGC Theme-based Research Scheme (TRS) (T12-703/19-R) and the Centre for Oncology and Immunology under the Health@InnoHK Initiative funded by the Innovation and Technology Commission, Hong Kong, China. The figure was drawn with BioRender with the permission of the publication license.

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Authors and Affiliations

  1. Department of Laboratory Medicine, Institute of Medical Immunology of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, China

    Ke Rui

  2. Department of Rheumatology and Immunology, Nanjing First Hospital, Nanjing Medical University, Jiangsu, China

    Nan Che

  3. Centre for Infection and Immunity Studies, School of Medicine, The Sun Yat-sen University, Shenzhen, 518107, Guangdong, China

    Kongyang Ma

  4. Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China

    Hejian Zou

  5. Department of Pathology and Shenzhen Institute of Research and Innovation, HKU Shenzhen Hospital, The University of Hong Kong, Hong Kong, China

    Fan Xiao & Liwei Lu

  6. Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong, China

    Fan Xiao & Liwei Lu

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Correspondence to Fan Xiao or Liwei Lu.

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Rui, K., Che, N., Ma, K. et al. Coming of age: the formation and function of age-associated B cells. Cell Mol Immunol 21, 311–312 (2024). https://doi.org/10.1038/s41423-024-01143-z

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