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.

Elena Merino Tejero,Fabien Crauste,Antoine H C Van Kampen,María Rodríguez Martínez,Philippe A Robert,Michael Meyer-Hermann,Jeroen E J Guikema,Danial Lashgari,Xuefeng Gao,Rodrigo García-Valiente,S Marieke Van Ham,Huub Hoefsloot

doi:10.3389/fimmu.2020.620716

Abstract

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.

Highlights

Germinal centers (GCs) are anatomical structures located inside B-cell follicles within secondary lymphoid organs that play an important role in the adaptive immune system [1, 2]
The scenario 1 model is based on the hypothesis that Ag-retaining (Ag+) cells differentiate to a mixture of plasma cells (PCs) and memory B-cells (MBCs) output cells
We presented a multiscale computational model integrating cellular and molecular mechanisms, operating at different time scales, to investigate output cell differentiation based on Ag status and/or B lymphocyte induced maturation protein 1 (BLIMP1) level

Summary

Introduction

Germinal centers (GCs) are anatomical structures located inside B-cell follicles within secondary lymphoid organs that play an important role in the adaptive immune system [1, 2]. Through subsequent rounds of cell proliferation, somatic hypermutation (SHM) and positive selection the B-cell receptor (BcR) is optimized for antigen (Ag) binding in a process called affinity maturation. This eventually results in the development of memory B-cells (MBCs) and plasma cells (PCs) that produce high affinity antibodies (Abs), which provide an effective immune protection. The Ag is processed by the CCs resulting in class II MHC-peptide complexes (pMHCII) presented to the Tfh cells. B cells compete in an affinity-dependent way for interaction with Tfh cells, facilitating CD40 and cytokine signaling to become positively selected. In this research we present a multiscale computational model (MSM) integrating molecular and cellular mechanisms to investigate PC differentiation

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Results

Conclusion