Defining new BCR-antigen trafficking pathways

点击翻译按钮获取中文摘要

Infectious diseases claim over 6 million lives a year worldwide. Our immune system responds to infections through the coordinated action of many specialised cells. B cells are one critical component of this response, producing antibodies to neutralise infectious agents. The cellular processes which activate B cells to respond to infection can result in autoimmunity or cancer if triggered inappropriately. B cell leukaemia is one of the most prevalent malignancies in children with increasing incidence in developed countries. How these cellular processes are regulated remains unclear. Understanding how B cells are activated can help us to design more efficient vaccines, control B cell autoimmunity and identify new therapies for B cell cancers. Upon infection, B cells recognise and take up foreign agents (antigen) through a receptor on their surface (BCR). Binding of antigen to the BCR induces signalling and uptake of the antigen-BCR complex into the B cell. This internalised antigen is transported to specific compartments within the B cells, where it is processed and loaded onto receptors recognised by other immune cells. These are exported back to the B cell surface, where they are recognised by T cells, another crucial immune cell type. T cell signals instruct the B cells to divide and differentiate into either antibody-producing cells or memory B cells. These steps are essential for antibody-mediated protection and long-term immunity to the infectious agent. The amount of antigen taken up by the B cell, and its trafficking through the cell, determine the quantity and quality of T cell help provided. The mechanisms of antigen uptake and trafficking from the B cell surface to processing compartments are unclear. My previous research has identified a network of proteins involved in antigen uptake, most of which are unknown in B cells. One of these proteins, SORLA, is known to regulate intracellular trafficking of proteins in cells outside the immune system. Its role in B cells has not been defined though it is overexpressed in B cell lymphomas. Our preliminary work suggests SORLA is recruited to the internalised BCR-antigen molecules and SORLA depletion significantly reduces BCR uptake. Further, deletion of SORLA in animal models reduced their response to immunisation, highlighting an important and physiologically relevant role for SORLA in the immune response following infection or vaccination. Here, I propose to investigate the mechanisms behind this novel BCR trafficking regulation. We will delete SORL1, the gene encoding SORLA, and measure the effect on B cell signalling and antigen trafficking through the cell. We will investigate possible interactions between SORLA and known BCR uptake or activation components to understand the coordination between these pathways. We will quantify the amount and variety of antigens presented on the B cell surface, to understand how SORLA affects B cell competition for T cell help. Further, since the BCR is important during the development of B cells, we will investigate how disrupted BCR trafficking affects the number of mature B cells in an organism. Finally, to understand how this new regulator of antigen uptake is involved in the B cell response to immunisation, we will analyse B cell growth and differentiation into antibody-producing or memory B cells and production of highly specific antibodies. Together, these studies will provide a more complete understanding of B cell antigen uptake and its regulation. This could allow us to engineer antigens that promote uptake and presentation by B cells, which has important implications for vaccine innovation. It will also further our knowledge of antigen uptake and presentation in malignant B cells - a process with untapped potential for discovery of new B cell cancer therapies.