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Multiscale Modeling of Germinal Center Recapitulates the Temporal Transition From Memory B Cells to Plasma Cells Differentiation as Regulated by Antigen Affinity-Based Tfh Cell Help
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 ant...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892951/ https://www.ncbi.nlm.nih.gov/pubmed/33613551 http://dx.doi.org/10.3389/fimmu.2020.620716 |
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author | Merino Tejero, Elena Lashgari, Danial García-Valiente, Rodrigo Gao, Xuefeng Crauste, Fabien Robert, Philippe A. Meyer-Hermann, Michael Martínez, María Rodríguez van Ham, S. Marieke Guikema, Jeroen E. J. Hoefsloot, Huub van Kampen, Antoine H. C. |
author_facet | Merino Tejero, Elena Lashgari, Danial García-Valiente, Rodrigo Gao, Xuefeng Crauste, Fabien Robert, Philippe A. Meyer-Hermann, Michael Martínez, María Rodríguez van Ham, S. Marieke Guikema, Jeroen E. J. Hoefsloot, Huub van Kampen, Antoine H. C. |
author_sort | Merino Tejero, Elena |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7892951 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-78929512021-02-20 Multiscale Modeling of Germinal Center Recapitulates the Temporal Transition From Memory B Cells to Plasma Cells Differentiation as Regulated by Antigen Affinity-Based Tfh Cell Help Merino Tejero, Elena Lashgari, Danial García-Valiente, Rodrigo Gao, Xuefeng Crauste, Fabien Robert, Philippe A. Meyer-Hermann, Michael Martínez, María Rodríguez van Ham, S. Marieke Guikema, Jeroen E. J. Hoefsloot, Huub van Kampen, Antoine H. C. Front Immunol Immunology 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. Frontiers Media S.A. 2021-02-05 /pmc/articles/PMC7892951/ /pubmed/33613551 http://dx.doi.org/10.3389/fimmu.2020.620716 Text en Copyright © 2021 Merino Tejero, Lashgari, García-Valiente, Gao, Crauste, Robert, Meyer-Hermann, Martínez, van Ham, Guikema, Hoefsloot and van Kampen http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Merino Tejero, Elena Lashgari, Danial García-Valiente, Rodrigo Gao, Xuefeng Crauste, Fabien Robert, Philippe A. Meyer-Hermann, Michael Martínez, María Rodríguez van Ham, S. Marieke Guikema, Jeroen E. J. Hoefsloot, Huub van Kampen, Antoine H. C. Multiscale Modeling of Germinal Center Recapitulates the Temporal Transition From Memory B Cells to Plasma Cells Differentiation as Regulated by Antigen Affinity-Based Tfh Cell Help |
title | Multiscale Modeling of Germinal Center Recapitulates the Temporal Transition From Memory B Cells to Plasma Cells Differentiation as Regulated by Antigen Affinity-Based Tfh Cell Help |
title_full | Multiscale Modeling of Germinal Center Recapitulates the Temporal Transition From Memory B Cells to Plasma Cells Differentiation as Regulated by Antigen Affinity-Based Tfh Cell Help |
title_fullStr | Multiscale Modeling of Germinal Center Recapitulates the Temporal Transition From Memory B Cells to Plasma Cells Differentiation as Regulated by Antigen Affinity-Based Tfh Cell Help |
title_full_unstemmed | Multiscale Modeling of Germinal Center Recapitulates the Temporal Transition From Memory B Cells to Plasma Cells Differentiation as Regulated by Antigen Affinity-Based Tfh Cell Help |
title_short | Multiscale Modeling of Germinal Center Recapitulates the Temporal Transition From Memory B Cells to Plasma Cells Differentiation as Regulated by Antigen Affinity-Based Tfh Cell Help |
title_sort | multiscale modeling of germinal center recapitulates the temporal transition from memory b cells to plasma cells differentiation as regulated by antigen affinity-based tfh cell help |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892951/ https://www.ncbi.nlm.nih.gov/pubmed/33613551 http://dx.doi.org/10.3389/fimmu.2020.620716 |
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