A Stochastic Model of the Germinal Center Integrating Local Antigen Competition, Individualistic T–B Interactions, and B Cell Receptor Signaling

Abstract

The germinal center (GC) reaction underlies productive humoral immunity by orchestrating competition-based affinity maturation to produce plasma cells and memory B cells. T cells are limiting in this process. How B cells integrate signals from T cells and BCRs to make fate decisions while subjected to a cyclic selection process is not clear. In this article, we present a spatiotemporally resolved stochastic model that describes cell behaviors as rate-limited stochastic reactions. We hypothesize a signal integrator protein integrates follicular helper T (Tfh)- and Ag-derived signals to drive different B cell fates in a probabilistic manner and a dedicated module of Tfh interaction promoting factors control the efficiency of contact-dependent Tfh help delivery to B cells. Without assuming deterministic affinity-based decisions or temporal event sequence, this model recapitulates GC characteristics, highlights the importance of efficient T cell help delivery during individual contacts with B cells and intercellular positive feedback for affinity maturation, reveals the possibility that antagonism between BCR signaling and T cell help accelerates affinity maturation, and suggests that the dichotomy between affinity and magnitude of GC reaction can be avoided by tuning the efficiency of contact-dependent help delivery during reiterative T–B interactions.

Linking signaling and selection in the germinal center

“…118 While the affinitydependence of the strength or quality of this signal for the B cell has not been investigated directly, it is reasonable to think that higher affinity cells will get a stronger signal with possibly more induction termined. 118 While the affinitydependence of the strength or quality of this signal for the B cell has not been investigated directly, it is reasonable to think that higher affinity cells will get a stronger signal with possibly more induction termined.…”

“…Indeed, theoretical considerations suggest that such positive feedback is necessary to enhance affinity selection. 118 While the affinitydependence of the strength or quality of this signal for the B cell has not been investigated directly, it is reasonable to think that higher affinity cells will get a stronger signal with possibly more induction of c-Myc as a consequence. Both antibody staining and a c-Myc-GFP reporter have revealed a relatively broad distribution of c-Myc levels in the GCBC that do express the protein, consistent with a diversity in strength of "positive selection" encounters in vivo.…”

Calculating germinal centre reactions

“…Several GCs in parallel [24,30,35] Several consecutive exposures [24,35] Spatially resolved GC [33,34,42] Shape space sequence [33,34,50] Co-evolving epitopes [49] Binary sequence [35,49] Sequence-free [40,41,48,52,54] Seeding by memory B cells [24,35] Stochastic differential equations [49] ODE-based simulation [41,48,54] Agent-based simulation [24,33,34,35,50,40] Class-switching [54] Molecular detail of T-B interaction [33,34] Full AA alphabet sequence [24,43] Role for plasma B cells [49,54,30] Treatment of Ab CDR and FWR regions [24,52] Rugged fitness landscape [30] Several epitopes simultaneously [30,35,48,50,53] Role for memory B cells [35,24] ...…”

Germinal center B cells separate signals for selection and division like compact discs

“…However, a realistic theory of BC selection has to properly describe GCs permissive of low affinity BCs (Kuraoka et al, 2016;Silver et al, 2018) still allowing for efficient affinity maturation, diversity of GC clonal dominance (Tas et al, 2016) still allowing for clonal bursts, Tfh signal-dependent DND upon selection without losing the relevance of BCR signaling for selection, and also reflect extreme stimulation settings like antigen-uptake via the DEC205-receptor . A consistent theory, explaining these seemingly conflicting GC properties does not exist (Oprea & Perelson, 1997;Zhang & Shakhnovich, 2010;Meyer-Hermann et al, 2012;Wang et al, 2016;de Boer & Perelson, 2017;Meyer-Hermann, 2019).…”