Modelling Two Possible Mechanisms for the Regulation of the Germinal Center Dynamics

Abstract

Research on the germinal center has tried to unravel the mechanisms that control its dynamics. In this study we focus on the termination of the germinal center reaction, which is still an open problem. We propose two hypothetical biological mechanisms that may be responsible for the control of germinal center dynamics and analyze them through mathematical models. The first one is based on the differentiation of follicular dendritic cells and/or T cells. Interaction of these cells in the differentiated state with germinal center B cells would promote B cell differentiation into memory B cells and Ab-forming cells, ending the germinal center reaction. The second mechanism applies only to a scenario without recycling and consists of the decay of a hypothetical proliferation signal for centroblasts that limits the number of cell divisions. Each of the models makes predictions that can be experimentally tested.

Regulation of the Germinal Center Reaction by Foxp3+ Follicular Regulatory T Cells

“…A potential mechanism for this could be the presence within the polyclonal follicular T cell population in GCs of some regulatory T cells with specificity for ubiquitous self-antigens. In agreement with that, theoretical modeling points to processes related to T cell proliferation as being the dominant steps in the GC dynamics (15). We thus propose the hypothesis that there are regulatory mechanisms affecting Ag-specific T FH cells to prevent overly intense GCRs and/or production of autoantibodies.…”

“…These data suggest that T F regs derive predominantly from natural Tregs, whereas T FH cells are not amenable to TGF-bdependent conversion into Foxp3 + regulatory cells. hypothesis proposes that signaling from T cells is the responsible for GC termination (15). After observing an increase in T F reg numbers in the GC toward the end of the GCR, we suggest a wider scenario whereby this cell population has a role in controlling the magnitude and duration of the GCR.…”

Broad Volume Distributions Indicate Nonsynchronized Growth and Suggest Sudden Collapses of Germinal Center B Cell Populations

“…This distribution is by no means a Gaussian distribution. The importance of this finding is substantial, because mathematical models of affinity maturation often rate a selection mechanism successful only if every single iGC simulation run reproduces the average eGC kinetics as closely as possible (27)(28)(29)(30)(31). This is equivalent to narrow GC volume distributions.…”

Germinal centres seen through the mathematical eye: B-cell models on the catwalk

“…More intuitive termination signals are dynamic changes of the B-cell differentiation rate [43] (e.g. mediated by FDCsignalling), of the cell cycle time [36] or a limitation of the number of cell divisions [44]. Infectious antigen can provoke prolonged GC reactions [45].…”