Antigen-presenting and phagocytic functions of B cell subsets

B细胞主要以其产生抗体的能力而闻名。然而，越来越多的文献表明，它们也可能通过各种抗体非依赖性机制参与免疫应答，如细胞因子产生、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（MZ B）和B1 B细胞。滤泡B细胞是最主要的B细胞亚群，存在于二级和三级淋巴器官的淋巴滤泡中。MZB位于脾的边缘区，具有结合免疫复合物、向脾白色髓迁移以及将抗原转移至滤泡树突状细胞的能力。B1 B细胞以分泌天然抗体而闻名。我们最近报道，B细胞可以捕获原虫寄生虫杜氏利什曼原虫。一旦接触到寄生虫，B细胞就会形成簇，并将L. Donovani寄生虫在IgM丰富的口袋里。这种密切的相互作用导致共刺激分子CD 86和表面IgM的上调，导致MyD 88依赖性IL-10的产生，并最终导致48小时后的细胞死亡。MyD 88是大多数Toll样受体（TLR）用于激活转录因子NFk-B和转录因子IRF家族的衔接蛋白。MyD 88在B细胞中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它们的功能。我们的目的是在这个应用程序中的特征之间的相互作用L。donovani和B细胞，以了解多克隆B细胞活化的途径。特别是，我们将调查i）寄生虫识别各种toll样受体，补体受体，和B细胞受体，和激活的下游途径; ii）抗原呈递寄生虫衍生抗原;和iii）寄生虫捕获和表面之间的相互作用L。donovani和各种B细胞亚群。转基因寄生虫、基因敲除小鼠、共聚焦显微镜、流式细胞术和几种生化技术将用于在体外实验中剖析各种激活途径。这里确定的激活途径可以揭示其他病原体也可以用来激活B细胞并调节其功能的新策略。*

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.***