Antigen-presenting and phagocytic functions of B cell subsets

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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.