Affinity-coupled CCL22 promotes positive selection in germinal centres

Bo Liu, Yihan Lin, Jiacong Yan, Jiacheng Yao, Dan Liu, Weiwei Ma, Jianbin Wang, Wanli Liu, Chengshuo Wang, Luo Zhang and Hai Qi ()
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Bo Liu: Tsinghua University
Yihan Lin: Tsinghua University
Jiacong Yan: Tsinghua University
Jiacheng Yao: Tsinghua University
Dan Liu: Tsinghua University
Weiwei Ma: Tsinghua University
Jianbin Wang: Tsinghua University
Wanli Liu: Tsinghua University
Chengshuo Wang: Capital Medical University
Luo Zhang: Capital Medical University
Hai Qi: Tsinghua University

Nature, 2021, vol. 592, issue 7852, 133-137

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03239-2

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