Journal
FRONTIERS IN IMMUNOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2020.620716
Keywords
multiscale model; plasma cell differentiation; T follicular helper cell; CD40 signaling; germinal center
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Funding
- CASyM Exchange Research Grant
- COSMIC from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant [765158]
- Human Frontier Science Program 570 [RGP0033/2015]
- Marie Curie Actions (MSCA) [765158] Funding Source: Marie Curie Actions (MSCA)
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Germinal centers play a crucial role in the adaptive immune system by generating memory B cells and plasma cells that produce high affinity antibodies for effective immune protection. Cell-fate decisions in germinal centers involve various factors, including antigen, B-cell receptor affinity, T follicular helper cells, and transcription factors. Molecular modulations of the CD40 signaling pathway can influence the production of germinal center output cells.
Germinal centers play a key role in the adaptive immune system since they are able to produce memory B cells and plasma cells that produce high affinity antibodies for an effective immune protection. The mechanisms underlying cell-fate decisions are not well understood but asymmetric division of antigen, B-cell receptor affinity, interactions between B-cells and T follicular helper cells (triggering CD40 signaling), and regulatory interactions of transcription factors have all been proposed to play a role. In addition, a temporal switch from memory B-cell to plasma cell differentiation during the germinal center reaction has been shown. To investigate if antigen affinity-based Tfh cell help recapitulates the temporal switch we implemented a multiscale model that integrates cellular interactions with a core gene regulatory network comprising BCL6, IRF4, and BLIMP1. Using this model we show that affinity-based CD40 signaling in combination with asymmetric division of B-cells result in switch from memory B-cell to plasma cell generation during the course of the germinal center reaction. We also show that cell fate division is unlikely to be (solely) based on asymmetric division of Ag but that BLIMP1 is a more important factor. Altogether, our model enables to test the influence of molecular modulations of the CD40 signaling pathway on the production of germinal center output cells.
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