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

Takuya Koike1, Koshi Harada1, Shu Horiuchi1

  • 1Division of Molecular Biology, Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Noda, Japan.

Elife
|June 22, 2019
PubMed

Insights

Memory B cells diverge into plasma cell precursors (CD80hi) or germinal center B cells (CD80lo). This divergence is B-cell-intrinsic, driven by CD40 signaling strength, influencing immune memory.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Memory B cells (Bmem) are crucial for adaptive immunity, providing rapid and enhanced responses upon secondary antigen exposure.
  • Existing understanding suggests heterogeneity within Bmem populations, but the intrinsic mechanisms governing their distinct recall responses are not fully elucidated.
  • The role of B-cell receptor (BCR) isotypes and T cell help in directing Bmem cell fates requires further clarification.

Purpose of the Study:

  • To investigate the B-cell-intrinsic mechanisms that dictate the divergent fates of memory B cell subpopulations.
  • To determine the influence of CD40 signaling quantity and B-cell receptor affinity on Bmem cell differentiation pathways.
  • To elucidate the molecular signaling cascade, including NF-κB and BATF, involved in Bmem cell fate decisions.

Main Methods:

  • Analysis of distinct mouse memory B cell subpopulations (CD80hi and CD80lo) during primary and recall immune responses.
  • In vitro culture systems to assess Bmem cell differentiation under varying CD40 stimulation levels.
  • Quantitative assessment of BCR affinity and T cell (follicular helper T cells) involvement in Bmem development.

Main Results:

  • Memory B cells differentiate into CD80hi (plasma cell precursors) or CD80lo (germinal center B cells) subpopulations, independent of BCR isotype.
  • Development of CD80hi Bmem cells requires follicular helper T cells, strong CD40 signaling, and high-affinity BCRs, while CD80lo development does not.
  • Differential CD40 signaling quantitatively recapitulates distinct B cell fates in vitro, mediated by NF-κB activation and BATF upregulation.

Conclusions:

  • CD40 signaling strength is a critical B-cell-intrinsic factor determining memory B cell fate decisions.
  • A quantitative difference in CD40 stimulation translates into distinct downstream signaling pathways, promoting either plasma cell differentiation or germinal center re-entry.
  • This study reveals a key regulatory mechanism for generating diverse antibody-producing cell populations crucial for effective adaptive immunity.

Keywords:
germinal centerimmune responseimmunologyinflammationmemory B cellsmouseplasma cellsrecall response

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