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BCR-intrinsic regulation of memory B cell responses

BCR-记忆 B 细胞反应的内在调节

基本信息

批准号：
216884376
负责人：
Dr. Niklas Engels
金额：
--
依托单位：
Institut für Zelluläre und Molekulare Immunologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/216884376?language=en
关键词：
BCR intrinsic regulation memory cell

项目摘要

The production of antibodies by B lymphocytes is controlled by signals from the B cell antigen recep-tor (BCR). Following the activation of naïve B cells, primary immune responses are characterised by the production of immunoglobulin M (IgM) antibodies. Secondary responses are dominated by IgG antibodies secreted upon activation of Ig class-switched memory B cells. We recently showed that the antigen receptors of class-switched B cells expressing mIgG- or mIgE-containing BCRs possess a conserved tyrosine-based signalling motif that is not present in mIgM- or mIgD-containing BCRs on naïve cells. This motif, termed immunoglobulin tail tyrosine (ITT), amplifies signals from the mIgG- and mIgE-BCR by recruiting a signalling complex that is organised by the adaptor protein Grb2. One of the central aims of our project is to investigate the role of ITT signalling for secondary antibody responses in the mouse. To this end we have generated two novel knock-in mouse strains possessing tyrosine-to-phenylalanine (Y to F) substitutions in the ITTs of mIgG1 or mIgE. The immunological competence of these mice will be analysed in detail. Furthermore, we will determine the contribution of individual signalling components as well as entire signalling networks for the maintenance and/or activation of Ig class-switched memory B cells. This part will be promoted by two technical advances. First, we will perform a comprehensive determination of the global B cell phosphoproteome by quantitative mass spectrometry. Second, we will establish novel fluorescent biosensors to study signalling events in scarce populations of primary memory B cells. Collectively, genetically engineered mouse mutants in combination with novel tools for signal transduction research will provide a basis towards the elucidation of a molecular signal signature of memory B cells.

B淋巴细胞产生抗体受B细胞抗原受体(BCR)信号的控制。在幼稚B细胞被激活后，初级免疫反应的特征是产生免疫球蛋白M(IgM)抗体。二次反应主要由Ig类转换型记忆B细胞激活时分泌的抗体所主导。我们最近发现，表达含有MIGG或MIGE的BCR的类转换B细胞的抗原受体具有一个保守的基于酪氨酸的信号基序，这是幼稚细胞上含有mIgM或mIgD的BCR所不存在的。这个基序被称为免疫球蛋白尾部酪氨酸(ITT)，通过招募由接头蛋白Grb2组织的信号复合体来放大来自MIGG-和MIGE-BCR的信号。我们项目的中心目标之一是研究ITT信号在小鼠二次抗体反应中的作用。为此，我们产生了两个新的敲入小鼠品系，它们在mIgG1或MIGE的ITTS中具有酪氨酸到苯丙氨酸(Y到F)的替代。这些小鼠的免疫能力将被详细分析。此外，我们将确定单个信令组件以及整个信令网络对Ig类交换存储B细胞的维护和/或激活的贡献。这一部分将通过两项技术进步来推动。首先，我们将用定量质谱法对全球B细胞磷酸蛋白质组进行全面的测定。其次，我们将建立新的荧光生物传感器来研究初级记忆B细胞稀缺群体中的信号事件。总的来说，基因工程小鼠突变体与信号转导研究的新工具相结合，将为阐明记忆B细胞的分子信号特征提供基础。