Abstract
Memory B cells and antibody-secreting plasma cells are generated within germinal centers during affinity maturation in which B-cell proliferation, selection, differentiation, and self-renewal play important roles. The mechanisms behind memory B cell and plasma cell differentiation in germinal centers are not well understood. However, it has been suggested that cell fate is (partially) determined by asymmetric cell division, which involves the unequal distribution of cellular components to both daughter cells. To investigate what level and/or probability of asymmetric segregation of several fate determinant molecules, such as the antigen and transcription factors (BCL6, IRF4, and BLIMP1) recapitulates the temporal switch and DZ-to-LZ ratio in the germinal center, we implemented a multiscale model that combines a core gene regulatory network for plasma cell differentiation with a model describing the cellular interactions and dynamics in the germinal center. Our simulations show that BLIMP1 driven plasma cell differentiation together with coupled asymmetric division of antigen and BLIMP1 with a large segregation between the daughter cells results in a germinal center DZ-to-LZ ratio and a temporal switch from memory B cells to plasma cells that have been observed in experiments.
Highlights
Memory B cells (MBCs) and antibody-secreting plasma cells (PCs) are generated within germinal centers (GCs) during affinity maturation in which B-cell proliferation, selection, differentiation, and self-renewal play important roles in the GC reaction (1)
To enable the investigation of cellular and molecular mechanisms involved in PC differentiation, we recently developed a multiscale model (MSM) (11) that integrates an agent-based model (ABM) of the GC reaction (5) with a gene regulatory network (GRN) involved in PC differentiation (12)
Based on a computational model of the GC, Meyer-Hermann and colleagues hypothesized that asymmetric division of Ag might play a role in PC differentiation, as this resulted in a dark zone (DZ)-to-LZ ratio in agreement with experimental data (5)
Summary
Memory B cells (MBCs) and antibody-secreting plasma cells (PCs) are generated within germinal centers (GCs) during affinity maturation in which B-cell proliferation, selection, differentiation, and self-renewal play important roles in the GC reaction (1). A more comprehensive computational model of the GC reaction predicted that asymmetric division of Ag might codetermine B-cell fate, since inclusion of this mechanism resulted in GC transzone migration rates and DZ-to-LZ ratio in agreement with experimental data (5, 6). In addition to asymmetric Ag division, in vitro studies have shown that other B-cell fate-altering molecules, such as transcriptional regulator B-cell lymphoma 6 (BCL6) and the receptor for interleukin-21 (IL-21R), segregate asymmetrically in approximately 44% of mitotic GC B cells (7). The same study suggested that CD40 signaling facilitates TF asymmetry by providing polarity cues to B cells. Other polarity cues [e.g., cell– cell contacts (8)], TFs [e.g., BLIMP1 transcription (9)], and signaling pathways [e.g., nuclear factor kappa B (Nf-kB)] may drive asymmetric division and/or B-cell fate
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