Primary and memory B cell responses to Qβ-VLP in mice

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ZABEL, Franziska, 2014. Primary and memory B cell responses to Qβ-VLP in mice

@phdthesis{Zabel2014Prima-27511, title={Primary and memory B cell responses to Qβ-VLP in mice}, year={2014}, author={Zabel, Franziska}, address={Konstanz}, school={Universität Konstanz} }

Zabel, Franziska Extensive studies have been undertaken to describe naïve B cells differentiating into memory B cells at a cellular and molecular level. However, relatively little is known about the fate of memory B cells upon antigen re-encounter. We have previously established a system based on virus-like particles (VLPs) which allows to track VLP-specific B cells by flow cytometry as well as histology. Using allotype markers, it is possible to adoptively transfer memory B cells into a naïve mouse and track responses of naïve and memory B cells as well as antibody responses in the same mouse under physiological conditions.<br />In contrast to previous reports using proteins, we have observed that VLP-specific memory B cells did not efficiently proliferate but quickly differentiated into plasma cells upon cognate antigen challenge. This was paralleled by an early onset of a strong humoral IgG response. Also upon tracking of distinct memory B cell populations, neither IgM+ nor IgG+ memory B cells proliferated extensively or entered germinal centers. Remarkably, plasma cells derived from memory B cells preferentially homed to the bone marrow early and produced superior amounts of antibody compared to plasma cells generated during the primary B cell response. Indeed, secondary plasma cells produced about 5 times more antibody than the corresponding primary plasma cells residing in the bone marrow. Hence, viral like particles provided a sufficient strong stimulus to drive terminal differentiation of memory B cells into highly effective secondary plasma cells preferentially homing the bone marrow. From a physiological point of view this may be explained by the immediate need for protective IgG antibodies in the presence of systemic viral particles.<br />Interestingly, memory B cells failed to respond after multiple rounds of stimulation by cognate antigen, as the majority of Abs was only produced by memory derived secondary plasma cells after the first boost. In contrast, after second boost the humoral response was dominated by plasma cells derived from first-round memory B cells of the host. Under these conditions, the memory B cell pool was replaced by a new wave of memory B cells derived from primary B cells. Thus, memory B cells generated during a secondary response were largely derived from naïve B cells and may therefore harbor slightly different specificities than the concomitantly produced antibodies. As a consequence, the B cell response may remain dynamic and antigenic sub-specificities encountered during the primary response are not endlessly carried forward preventing adaptation of the B cell responses to newly emerging variants.<br /><br /><br />We further investigated the role of CD4+ T helper cells during memory B cell responses. Here, we observed a graded T helper cell dependence. Proliferation of class-switched memory B cell followed by rapid generation of plasma cells and early IgG responses were generally highly T cell dependent. In contrast, late plasma cell generation as well as late IgG responses were mostly T helper cell independent. From a physiological point of view, this may reflect the goal of the immune system to rid pathogens that are present for extended time periods even at the risk of raising T cell independent memory IgG responses.<br /><br /><br />All observations and conclusions made in this study may be representative for many VLPs and viral particles, as we assessed the majority of experiments with two different VLPs.<br /><br /><br />These insights are important for our general understanding of B cell responses and may be of value for improving vaccination regimens to optimize generation of long-lived plasma cells. Zabel, Franziska 2014-04-07T13:39:35Z Primäre B Zell- und B Zell-Gedächtnisantworten auf Qβ-VLP in Mäusen deposit-license Primary and memory B cell responses to Qβ-VLP in mice 2014 eng

Dateiabrufe seit 01.10.2014 (Informationen über die Zugriffsstatistik)

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