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

Frontiers in Immunology

Antoine H. C. van Kampen¹  Huub Hoefsloot¹  Rodrigo García-Valiente²  Elena Merino Tejero²  Danial Lashgari²  Philippe A. Robert³  Xuefeng Gao⁴  Jeroen E. J. Guikema⁶  María Rodríguez Martínez⁷  Michael Meyer-Hermann⁸  S. Marieke van Ham⁹  Fabien Crauste^1,10 

[1] 0Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands;Bioinformatics Laboratory, Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam Institute for Infection and Immunity, Amsterdam, Netherlands;Department for Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany;Department of Hematology and Oncology, International Cancer Center, Shenzhen University General Hospital, Shenzhen University Health Science Center, Shenzhen, China;Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands;Department of Pathology, Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam University Medical Centers, Amsterdam, Netherlands;IBM Research Europe, Zürich, Switzerland;Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Braunschweig, Germany;Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands;Université de Paris, CNRS, MAP5 UMR 8145, Paris, France;

关键词: multiscale model;    plasma cell differentiation;    T follicular helper cell;    CD40 signaling;    germinal center;   

DOI  :  10.3389/fimmu.2020.620716

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown