B cells selection in Germinal center

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Date

2024-02

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University of Birmingham

Abstract

Vaccination triggers the long-term production of high-affinity antibodies. Germinal centers (GCs) are sites within lymphoid tissues where B cells undergo clonal expansion and affinity maturation during T cell-dependent antibody responses. However, the regulation of affinity-matured B cell selection within GCs remains poorly understood. In this study, we examined the roles of antibody secretion and feedback in GC regulation using various mouse models: those incapable of secreting IgM or undergoing class-switching (IgMi), those unable to undergo affinity maturation or class-switching (AIDKO), and those restricted to producing and secreting IgG1 antibodies (IgG1M). Following immunisation with a T cell-dependent (TD) antigen, IgMi and AIDKO mice exhibited an increased percentage of GC B cells. In contrast, the percentage of GC B cells in IgG1M mice was reduced compared to wild-type mice. Introducing antibody feedback by injecting antigen-specific IgM into IgMi or AIDKO mice slightly reduced the proportion of GC B cells. It was shown that more stringent antibody feedback strongly inhibits B-Tfh cell interactions. The Nr4a3-Tocky reporter system is unstable fluorescent protein that changes fluorescence from blue to red and can record the timing of TCR signalling. It was utilized to track interactions between GC B cells and Tfh cells in mice with altered B cell receptors (IgMg1 and IgG1M mice) or absence of affinity maturation (AIDKO mice). IgMg1 enhances interaction with and activation of Tfh cells, also reflected by higher Tfh frequencies. Additionally, testing expression of Nr4a3-blue and red forms of the reporter reveals an increase in newly activated Tfh cells in IgMg1 and IgG1M versus wildtype mice after immunisation. There was no change in Nr4a3-reporter expression in Tfh cells of AID-deficient mice, indicating unaffected Tfh cell activation in AID-deficient GCs. This work gives insight, by using mouse models with altered antibody feedback, into how IgM and IgG1 antibody secretion shapes GC developments and how altering BCR isotypes and signalling regulates Tfh cell activity through antigen presentation within the GC.

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B cells, Germinal center, Affinity maturation

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