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Affinity-coupled CCL22 promotes positive selection in germinal centres

Author

Listed:
  • Bo Liu

    (Tsinghua University
    Tsinghua University
    Tsinghua University)

  • Yihan Lin

    (Tsinghua University
    Tsinghua University
    Tsinghua University)

  • Jiacong Yan

    (Tsinghua University
    Tsinghua University
    Tsinghua University)

  • Jiacheng Yao

    (Tsinghua University
    Tsinghua University)

  • Dan Liu

    (Tsinghua University
    Tsinghua University
    Tsinghua University)

  • Weiwei Ma

    (Tsinghua University
    Tsinghua University
    Tsinghua University)

  • Jianbin Wang

    (Tsinghua University)

  • Wanli Liu

    (Tsinghua University
    Tsinghua University
    Tsinghua University)

  • Chengshuo Wang

    (Capital Medical University)

  • Luo Zhang

    (Capital Medical University)

  • Hai Qi

    (Tsinghua University
    Tsinghua University
    Tsinghua University
    Tsinghua University)

Abstract

Antibody affinity maturation depends on positive selection in germinal centres (GCs) of rare B cell clones that acquire higher-affinity B cell receptors via somatic hypermutation, present more antigen to follicular helper T (TFH) cells and, consequently, receive more contact-dependent T cell help1. As these GC B cells and TFH cells do not maintain long-lasting contacts in the chaotic GC environment2–4, it is unclear how sufficient T cell help is cumulatively focused onto those rare clones. Here we show that, upon stimulation of CD40, GC B cells upregulate the chemokine CCL22 and to a lesser extent CCL17. By engaging the chemokine receptor CCR4 on TFH cells, CCL22 and CCL17 can attract multiple helper cells from a distance, thus increasing the chance of productive help. During a GC response, B cells that acquire higher antigen-binding affinities express higher levels of CCL22, which in turn ‘highlight’ these high-affinity GC B cells. Acute increase or blockade of TFH cells helps to rapidly increase or decrease CCL22 expression by GC B cells, respectively. Therefore, a chemokine-based intercellular reaction circuit links the amount of T cell help that individual B cells have received recently to their subsequent ability to attract more help. When CCL22 and CCL17 are ablated in B cells, GCs form but B cells are not affinity-matured efficiently. When competing with wild-type B cells in the same reaction, B cells lacking CCL22 and CCL17 receive less T cell help to maintain GC participation or develop into bone-marrow plasma cells. By uncovering a chemokine-mediated mechanism that highlights affinity-improved B cells for preferential help from TFH cells, our study reveals a principle of spatiotemporal orchestration of GC positive selection.

Suggested Citation

  • Bo Liu & Yihan Lin & Jiacong Yan & Jiacheng Yao & Dan Liu & Weiwei Ma & Jianbin Wang & Wanli Liu & Chengshuo Wang & Luo Zhang & Hai Qi, 2021. "Affinity-coupled CCL22 promotes positive selection in germinal centres," Nature, Nature, vol. 592(7852), pages 133-137, April.
  • Handle: RePEc:nat:nature:v:592:y:2021:i:7852:d:10.1038_s41586-021-03239-2
    DOI: 10.1038/s41586-021-03239-2
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    Cited by:

    1. Javier Rodríguez-Ubreva & Anna Arutyunyan & Marc Jan Bonder & Lucía Del Pino-Molina & Stephen J. Clark & Carlos de la Calle-Fabregat & Luz Garcia-Alonso & Louis-François Handfield & Laura Ciudad & Edu, 2022. "Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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