System-Level Scenarios for the Elucidation of T Cell-Mediated Germinal Center B Cell Differentiation

Niels J.M. Verstegen, Victor Ubels, Hans V. Westerhoff, S. Marieke van Ham, Matteo Barberis*

*Corresponding author for this work

    Research output: Contribution to JournalArticleAcademicpeer-review


    Germinal center (GC) reactions are vital to the correct functioning of the adaptive immune system, through formation of high affinity, class switched antibodies. GCs are transient anatomical structures in secondary lymphoid organs where specific B cells, after recognition of antigen and with T cell help, undergo class switching. Subsequently, B cells cycle between zones of proliferation and somatic hypermutation and zones where renewed antigen acquisition and T cell help allows for selection of high affinity B cells (affinity maturation). Eventually GC B cells first differentiate into long-lived memory B cells (MBC) and finally into plasma cells (PC) that partially migrate to the bone marrow to encapsulate into long-lived survival niches. The regulation of GC reactions is a highly dynamically coordinated process that occurs between various cells and molecules that change in their signals. Here, we present a system-level perspective of T cell-mediated GC B cell differentiation, presenting and discussing the experimental and computational efforts on the regulation of the GCs. We aim to integrate Systems Biology with B cell biology, to advance elucidation of the regulation of high-affinity, class switched antibody formation, thus to shed light on the delicate functioning of the adaptive immune system. Specifically, we: i) review experimental findings of internal and external factors driving various GC dynamics, such as GC initiation, maturation and GCBC fate determination; ii) draw comparisons between experimental observations and mathematical modeling investigations; and iii) discuss and reflect on current strategies of modeling efforts, to elucidate B cell behavior during the GC tract. Finally, perspectives are specifically given on to the areas where a Systems Biology approach may be useful to predict novel GCBC-T cell interaction dynamics.

    Original languageEnglish
    Article number734282
    Pages (from-to)1-19
    Number of pages19
    JournalFrontiers in Immunology
    Issue numberSeptember
    Early online date20 Sept 2021
    Publication statusPublished - Sept 2021

    Bibliographical note

    Publisher Copyright:
    © Copyright © 2021 Verstegen, Ubels, Westerhoff, van Ham and Barberis.

    Copyright 2021 Elsevier B.V., All rights reserved.


    This work was supported by the Systems Biology Grant of the University of Surrey to MB, and by the EU ERASMUS+ Traineeship Grant to MB (recipient VU).

    FundersFunder number
    University of Surrey


      • B cell recycling and differentiation
      • B cells
      • cytokines
      • mathematical modeling
      • memory B cell
      • plasma cell
      • systems biology
      • T follicular helper cells


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