%A Merino Tejero,Elena %A Lashgari,Danial %A García-Valiente,Rodrigo %A Gao,Xuefeng %A Crauste,Fabien %A Robert,Philippe A. %A Meyer-Hermann,Michael %A Martínez,María Rodríguez %A van Ham,S. Marieke %A Guikema,Jeroen E. J. %A Hoefsloot,Huub %A van Kampen,Antoine H. C. %D 2021 %J Frontiers in Immunology %C %F %G English %K Multiscale model,Plasma cell differentiation,T follicular helper cell,CD40 signaling,Germinal Center %Q %R 10.3389/fimmu.2020.620716 %W %L %M %P %7 %8 2021-February-05 %9 Original Research %+ Antoine H. C. van Kampen,Bioinformatics Laboratory, Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam Institute for Infection and Immunity,Netherlands,10289316@frontiersin.org %+ Antoine H. C. van Kampen,Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam,Netherlands,10289316@frontiersin.org %# %! Multiscale modelling of germinal center %* %< %T 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 %U https://www.frontiersin.org/articles/10.3389/fimmu.2020.620716 %V 11 %0 JOURNAL ARTICLE %@ 1664-3224 %X 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.