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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=665793
• 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细胞主要以产生抗体的能力而闻名。但是，越来越多的文献已经表明，它们也可能通过各种抗体独立的机制（例如细胞因子的产生，共刺激和抗原表现）参与免疫反应。 B细胞可以分为三种不同的亚群：卵泡B细胞或B2细胞，先天样的边缘区B细胞（MZB）和B1 B细胞。卵泡B细胞是最突出的B细胞亚群，驻留在继发性和第三级淋巴机构的淋巴卵泡中。 MZB位于脾脏的边际区域，并具有结合免疫复合物，朝着脾白浆中迁移并将抗原转移到卵泡树突状细胞的能力。 B1 B细胞以其自然抗体的分泌而闻名。*******我们最近报道B细胞可以捕获原生动物的寄生虫Leishmania donovani。暴露于寄生虫后，B细胞会形成簇，并在富含IgM的口袋中固定Donovani L. donovani寄生虫。这种紧密的相互作用导致共刺激分子CD86和表面IgM的上调，在MyD88依赖性IL-10产生中，最终在48h后的细胞死亡中上调。 MyD88是大多数Toll样受体（TLR）使用的一种衔接蛋白，用于激活转录因子NFK-B和IRF转录因子家族。 B细胞中MyD88激活上游的途径尚不清楚。这些步骤的定义将需要更深入地了解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细胞亚群如何识别和对病原体的反应以及这种识别如何影响其功能。我们在此应用中的目标是表征多诺瓦乳杆菌和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细胞受体以及活化的下游途径的寄生虫识别； ii）寄生虫衍生的抗原的抗原呈递； iii）多诺瓦尼乳杆菌与各种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，敲除小鼠，共聚焦显微镜，流式细胞术以及几种生化技术将用于在体外实验中解剖各种激活途径。******* ******* **************************************************