Journal
NATURE
Volume 592, Issue 7852, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41586-021-03239-2
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Funding
- National Key R&D Program of China (Ministry of Science and Technology) [2018YFE0200300]
- National Natural Science Foundation of China [81621002, 31830023, 81761128019]
- Tsinghua-Peking Center for Life Sciences
- Beijing Municipal Science & Technology Commission
- Beijing Frontier Research Center for Biological Structure
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The study reveals a chemokine-mediated mechanism that links the amount of T cell help received by individual B cells recently to their subsequent ability to attract more help. By modulating the expression levels of chemokine CCL22, high-affinity GC B cells are ‘highlighted,’ leading to preferential help from T-FH cells.
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 (T-FH) cells and, consequently, receive more contact-dependent T cell help(1). As these GC B cells and T-FH cells do not maintain long-lasting contacts in the chaotic GC environment(2-4), 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 T-FH 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 T-FH 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 T-FH cells, our study reveals a principle of spatiotemporal orchestration of GC positive selection.
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