A Molecular Theory of Germinal Centerb Cell Selection and Division

Michael Meyer-Hermann

doi:10.2139/ssrn.3712653

Abstract

Selection of B cells in germinal center (GC) reactions is pivotal to the generation of high affinity antibodies and memory B cells. Knowledge about B cell selection is limited and lacks global understanding. Here, we use current knowledge on molecular pathways of GC B cells to develop a theory of GC B cell selection and division based on the dynamics of molecular factors. Seemingly contradictory experiments are unified in a common concept by the separation of signals for B cell fate decision from signals controlling the number of B cell divisions. This novel concept of information processing in GCs replaces the conviction that the strength of a Tfh signals alone would control selection and subsequent division of B cells. Three versions of theories of B cell selection based on the concept of signal separation are proposed and experiments are predicted that allow to distinguish those. Understanding the encoding of information in molecular B cell states is critical for targeted immune interventions and the proposed theory implies that selection and division can be controlled independently in GC reactions.

Highlights

Germinal centers (GCs) are specialized environments in lymphoid tissues that give rise to high-affinity antibodies (Victora and Nussenzweig, 2012)
B cells (BCs) undergo somatic hypermutation in the GC-DZ, where BC division is dominant, while BC selection is concentrated in the GC-LZ, where native antigen is presented on follicular dendritic cells (FDCs) and cognate interactions with T follicular helper (Tfh) cells take place
A theory separating selection and division signals A spatio-temporal GC simulation framework was generated in which each BC, FDC, and Tfh cell is represented as an individual object (Meyer-Hermann et al, 2012, 2014, 2019; Binder and Meyer-Hermann, 2016)

Summary

Introduction

Germinal centers (GCs) are specialized environments in lymphoid tissues that give rise to high-affinity antibodies (Victora and Nussenzweig, 2012). The creation of new antibodies that previously did not exist in an organism was well described in many details, including GC morphology (Camacho et al, 1998), with dark and light zones (DZs and LZs), interzonal cell motility (Allen et al, 2007; Schwickert et al, 2007; Hauser et al, 2007; Figge et al, 2008), B cell (BC) mutation (MacLennan, 1994; Oprea et al, 2000), T follicular helper (Tfh) cell-dependent selection and division (Victora et al, 2010; Meyer-Hermann et al, 2012), and clonal diversity (Tas et al, 2016). BCs failing to do so activate apoptosis This theory of BC selection based on competition for Tfh cell help was supported by experimental findings (Allen et al, 2007; Victora et al, 2010) and forms the basis of the present investigation

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Conclusion