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

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 to individual interactions and lacks global understanding. Here, seemingly contradictory experiments are unified in a common concept by separation of signals for the frequency of fate decision from the strength of cell division, which can then be controlled independently, similar to the separation of frequency and amplitude in digital audio signals. Based on this concept of information processing, three theories of B cell selection are developed that can be distinguish by predicted experiments drawn from computer simulations. Understanding encoding of information in molecular states is critical for targeted immune interventions.

Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells

“…5, F–H ). To extrapolate the loss of inertial proliferative capacity among Ccnd3 +/− GC B cells from our direct competition data, we simulated this experiment in silico using a previously published agent-based model of GC selection that includes T cell control over the number of cell cycles carried a B cell undergoes upon positive selection ( Meyer-Hermann, 2020 Preprint ; Meyer-Hermann et al, 2012 ). We modeled loss of Ccnd3 expression as a reduction in the maximum number of divisions a Ccnd3 +/− GC B cell can complete upon positive selection.…”

“…For mathematical modeling to reproduce the percentage of the Ccnd3 +/− GC B cells during the GC reaction described in vivo, we used a previously reported agent-based model for simulating the GC reaction with the DisseD framework ( Meyer-Hermann, 2020 Preprint ), with modifications. Specifically, the in silico simulation was initiated with 50% WT and 50% Ccnd3 +/− B cells, for which the maximum number of divisions executed in response to Tfh cell help was fixed to a decreasing series of percentages (80%, 76%, 72%, 71%, 60%, and 50%) of the maximum number allowed to the WT B cells, with the function regulating the number of divisions modified accordingly ( Fig.…”

Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells

“…5F-H). To extrapolate the loss of inertial proliferative capacity among Ccnd3 +/− GC B cells from our direct competition data, we simulated this experiment in silico using a previously published agent-based model of GC selection that includes T cell control over the number of cell cycles carried a B cell undergoes upon positive selection (Meyer-Hermann, 2020; Meyer-Hermann et al, 2012). We modeled loss of Ccnd3 expression as a reduction in the maximum number of divisions a Ccnd3 +/− GC B cell can complete upon positive selection.…”

“…For mathematical modelling to reproduce the percentage of the Ccnd3 +/− GC B cells during the GC reaction described in vivo, we used a previously reported agent-based model for simulating the GC reaction with the DisseD framework (Meyer-Hermann, 2020), with modifications. Specifically, the in silico simulation was initiated with 50% WT and 50% Ccnd3 +/− B cells, for which the maximum number of divisions executed in response to Tfh help was fixed to a decreasing series of percentages (80, 76, 72, 71, 60, 50%) of the maximum number allowed to the WT B cells, with the function regulating the number of divisions modified accordingly (Fig.…”