The cell biology of marginal zone B cells: filopodial networks as an immune sensing apparatus

边缘区 B 细胞的细胞生物学：丝状伪足网络作为免疫传感装置

• 批准号: RGPIN-2017-04862
• 负责人: Gold, Michael
• 金额: $ 1.89万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=711270
• 关键词: cell; biology; marginal; zone; cells

Cells, organs, and organisms must respond to changes in their environment. The immune system is an excellent model of how sensing and alerting functions are integrated. Innate immune cells such as macrophages have receptors on their surface that capture pathogens, recognize microbial components as danger signals, and initiate immediate protective responses. If the infection is not cleared, T- and B-lymphocytes of the adaptive immune system are activated to generate more potent and specific responses (e.g. antibodies). Key intermediates are innate-like lymphocytes such as marginal zone B cells (MZBs), which detect pathogens, alert adaptive immune cells, and provide protection until the adaptive immune system is activated. MZBs reside at sites where the blood or lymph enters lymphoid organs. They express B cell receptors (BCR) that bind specific parts of foreign molecules (antigens [Ags]), as well as Toll-like receptors (TLRs) that bind microbial danger signals. The activation of MZBs by Ags and microbial components causes them to secrete antibodies that recognize broad classes of microbes. However, MZBs also play a key role in alerting other cells of the immune system. They capture Ags via the BCR and other receptors (CD21, CD36) on their surface. This allows them to promote the activation of T cells as well as circulating B cells that make highly specific antibodies. Although MZBs are important early responders, their cell biology has not been studied because they are few in number and no MZB cell lines exist. My lab has developed expertise in studying MZBs using single cell microscopy and our goal is to elucidate the mechanisms that allow them to be effective sensing/alerting cells. We found that MZBs rapidly extend a network of long, thin membrane protrusions called filopodia. This resembles the dendritic network of sensory neurons. We hypothesize that the MZB filopodial network (FilNet) is a sensory apparatus that is specialized for detecting microbes and acquiring Ags. The factors that regulate MZB FilNet formation are not known and its role as a sensory and Ag-acquisition apparatus has not been explored. The objectives of this proposal are to test the following hypotheses: (1) Sensory receptors (BCR, TLRs) and Ag acquisition receptors (BCRs, CD21, CD36) are present on MZB filopodia (2) Adhesion molecules, TLRs, hormones that MZBs are normally exposed to, and inflammatory mediators regulate the formation of MZB FilNets. (3) MZB filopodia can acquire Ags via multiple receptors (4) Low levels of Ag-induced BCR signaling cause the expansion of MZB FilNets so that the cells can scan for more Ag in order to become activated; high levels of Ag-induced BCR signaling cause retraction of the MZB FilNet as the cell prepares to divide and secrete antibodies. Finding from these studies could have broad implications for understanding how sensing/alerting cells are specialized to carry out their functions.

细胞、器官和生物体必须对环境的变化做出反应。免疫系统是感知和警报功能如何整合的一个极好的模型。巨噬细胞等先天免疫细胞表面有受体，可捕捉病原体，识别微生物成分为危险信号，并启动即时保护性反应。如果感染没有清除，适应性免疫系统的T和B淋巴细胞被激活，以产生更有效和特异的反应(例如抗体)。关键的中间体是先天的类淋巴细胞，如边缘区B细胞(MZB)，它们检测病原体，向适应性免疫细胞发出警报，并提供保护，直到适应性免疫系统被激活。 MZB位于血液或淋巴进入淋巴器官的部位。它们表达结合外来分子(抗原[AGS])特定部分的B细胞受体(BCR)，以及结合微生物危险信号的Toll样受体(TLRs)。MZB被AGS和微生物成分激活，导致它们分泌抗体，识别广泛的微生物类别。然而，MZB在提醒免疫系统的其他细胞方面也发挥着关键作用。它们通过BCR和表面的其他受体(CD21、CD36)捕获AGS。这使得它们能够促进T细胞和循环B细胞的激活，这些细胞产生高度特异的抗体。虽然MZB是重要的早期应答细胞，但由于其数量较少，且不存在MZB细胞系，其细胞生物学尚未得到研究。我的实验室已经发展出使用单细胞显微镜研究MZB的专业知识，我们的目标是阐明使MZB成为有效的传感/警报细胞的机制。 我们发现，MZB迅速延伸出一种名为丝状足的长而薄的膜突起网络。这类似于感觉神经元的树突网络。我们假设MZB丝状径向网络(FilNet)是一种专门用于检测微生物和获取AGS的感觉器官。调控MZB FilNet形成的因素尚不清楚，其作为感官和Ag获取装置的作用也未被探索。 这项提议的目标是检验以下假设： (1)感觉受体(BCR，TLRs)和抗原获得受体(BCR，CD21，CD36)存在于MZB丝状伪足上 (2)黏附分子、TLR、MZB正常接触的激素和炎症介质调节MZB滤网的形成。 (3)MZB丝状伪足可通过多种受体获得AGS (4)低水平的Ag诱导的BCR信号导致MZB FilNet的扩张，使细胞能够扫描更多的Ag以激活；高水平的Ag诱导的BCR信号导致MZB FilNet在细胞准备分裂和分泌抗体时收缩。 这些研究的发现可能会对理解感知/警报细胞是如何专门执行其功能具有广泛的意义。