The quantity of CD40 signaling determines the differentiation of B cells into functionally distinct memory cell subsets

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Abstract

In mice, memory B (B_mem) cells can be divided into two subpopulations: CD80^hi B_mem cells that preferentially differentiate into plasma cells and CD80^lo B_mem cells that become germinal center (GC) B cells during a recall response. We demonstrate that these distinct responses can be B cell-intrinsic and essentially independent of B-cell receptor (BCR) isotypes. Furthermore, we found that development of CD80^hi B_mem cells in the primary immune response requires follicular helper T cells, a relatively strong CD40 signal and a high affinity BCR on B cells, whereas development of CD80^lo B_mem cells does not. Quantitative differences in CD40 stimulation were enough to recapitulate the distinct B cell fate decisions in an in vitro culture system. The quantity of CD40 signaling appears to be translated into NF-kB activation followed by BATF upregulation to promote B_mem cell differentiation from GC B cells.

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All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1-7.

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Takuya Koike

Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan

Competing interests
The authors declare that no competing interests exist.
Koshi Harada

Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan

Competing interests
The authors declare that no competing interests exist.
Shu Horiuchi

Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan

Competing interests
The authors declare that no competing interests exist.
Daisuke Kitamura

Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan

For correspondence
kitamura@rs.noda.tus.ac.jp

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5195-0474

Funding

Japan Society for the Promotion of Science (16H05206)

Daisuke Kitamura

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were performed under protocols approved by the Animal Care and Use Committee of the Tokyo University of Science (Approval No.: S15021, S16019, S17004, S18018). All surgery was performed under Isoflurane anesthesia, and every effort was made to minimize suffering.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.