Antigen-presenting and phagocytic functions of B cell subsets

B 细胞亚群的抗原呈递和吞噬功能

• 批准号: RGPIN-2015-04714
• 负责人: Stager, Simona
• 金额: $ 2.19万
• 依托单位: Institut national de la recherche scientifique
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=683350
• 关键词: Antigen; presenting; phagocytic; functions; cell

B-cells are mostly known for their capacity to produce antibodies. However, an increasing body of literature has now shown that they may also participate in the immune response by various antibody-independent mechanisms, such as cytokine production, co-stimulation, and antigen presentation. B-cells can be divided in three different subpopulations: follicular B cells or B2 cells, innate-like marginal zone B-cells (MZB), and B1 B-cells. Follicular B cells are the most prominent B-cell subpopulation and reside in lymphoid follicles of secondary and tertiary lymphoid organs. MZB are located in the marginal zone of the spleen and are endowed with the capacity to bind immune complexes, migrate towards the splenic white pulp, and transfer antigen to follicular dendritic cells. B1 B-cells are known for their secretion of natural antibodies.*******We have recently reported that B cells can capture the protozoan parasite Leishmania donovani. Upon exposure to the parasite, B cells form clusters and hold L. donovani parasites in IgM-rich pockets. This close interaction results in the upregulation of the costimulatory molecule CD86 and of surface IgM, in a MyD88-dependent IL-10 production, and eventually in cell death after 48h. MyD88 is an adapter protein used by most Toll-Like Receptors (TLRs) to activate the transcription factors NFk-B and the IRF family of transcription factors. The pathways upstream of MyD88 activation in B-cells are as yet unknown. Definition of these steps will require a deeper understanding of how B cells interact with the parasite.*******The overall goal of our research is to understand how various B cell subpopulations recognize and react to pathogens, and how this recognition affects their function. Our objective in this application is to characterize the interaction between L. donovani and B cells in order to understand the pathways of polyclonal B cell activation. Particularly, we will investigate i) parasite recognition by various toll-like receptors, complement receptors, and the B cell receptor, and the activated downstream pathways; ii) antigen-presentation of parasite-derived antigens; and iii) parasite capture and surface interaction between L. donovani and various B cell subpopulations. Transgenic parasites, knock-out mice, confocal microscopy, flow cytometry, and several biochemical techniques will be used to dissect the various activation pathways in in vitro experiments.*******The activation pathways identified here could uncover novel strategies that may also be used by other pathogens to activate B cells and modulate their functions.***

B 细胞因其产生抗体的能力而闻名。然而，现在越来越多的文献表明，它们还可能通过各种不依赖于抗体的机制参与免疫反应，例如细胞因子的产生、共刺激和抗原呈递。 B 细胞可分为三个不同的亚群：滤泡 B 细胞或 B2 细胞、先天样边缘区 B 细胞 (MZB) 和 B1 B 细胞。滤泡 B 细胞是最重要的 B 细胞亚群，存在于二级和三级淋巴器官的淋巴滤泡中。 MZB 位于脾脏边缘区，具有结合免疫复合物、向脾白髓迁移以及将抗原转移至滤泡树突细胞的能力。 B1 B 细胞以其分泌天然抗体而闻名。********我们最近报道，B 细胞可以捕获原生动物寄生虫杜氏利什曼原虫。接触寄生虫后，B 细胞会形成簇，并将杜氏乳杆菌寄生虫保留在富含 IgM 的细胞袋中。这种密切的相互作用导致共刺激分子 CD86 和表面 IgM 的上调，导致 MyD88 依赖性 IL-10 的产生，并最终导致 48 小时后细胞死亡。 MyD88 是大多数 Toll 样受体 (TLR) 用来激活转录因子 NFk-B 和 IRF 转录因子家族的衔接蛋白。 B 细胞中 MyD88 激活的上游途径尚不清楚。这些步骤的定义需要更深入地了解 B 细胞如何与寄生虫相互作用。********我们研究的总体目标是了解各种 B 细胞亚群如何识别病原体并对其做出反应，以及这种识别如何影响他们的功能。我们在此应用中的目标是表征杜氏乳杆菌和 B 细胞之间的相互作用，以了解多克隆 B 细胞激活的途径。特别是，我们将研究 i) 各种 Toll 样受体、补体受体和 B 细胞受体对寄生虫的识别，以及激活的下游途径； ii) 寄生虫衍生抗原的抗原呈递； iii) 杜氏乳杆菌和各种 B 细胞亚群之间的寄生虫捕获和表面相互作用。转基因寄生虫、基因敲除小鼠、共聚焦显微镜、流式细胞术和多种生化技术将用于剖析体外实验中的各种激活途径。********这里确定的激活途径可能会揭示可能的新策略也可被其他病原体用来激活 B 细胞并调节其功能。***