Defining new BCR-antigen trafficking pathways

传染病每年夺走全球600多万人的生命。我们的免疫系统通过许多特殊细胞的协调行动对感染做出反应。B细胞是这种反应的一个关键组成部分，它会产生抗体来中和感染性病原体。激活B细胞对感染做出反应的细胞过程如果触发不当，可能会导致自身免疫或癌症。B细胞白血病是儿童最常见的恶性肿瘤之一，在发达国家发病率呈上升趋势。这些细胞过程是如何被调控的，目前尚不清楚。了解B细胞是如何被激活的，可以帮助我们设计更有效的疫苗，控制B细胞自身免疫，并找到治疗B细胞癌症的新方法。在感染后，B细胞通过其表面的受体(BCR)识别并吸收异物(抗原)。抗原与bcr的结合诱导了抗原-bcr复合体进入B细胞的信号传递和摄取。这种内化的抗原被运送到B细胞内的特定隔室，在那里它被处理并装载到其他免疫细胞识别的受体上。它们被输出回B细胞表面，在那里它们被T细胞识别，T细胞是另一种关键的免疫细胞类型。T细胞信号指示B细胞分裂和分化为产生抗体的细胞或记忆B细胞。这些步骤对于抗体介导的保护和对感染性病原体的长期免疫至关重要。B细胞摄取的抗原量及其在细胞中的运输决定了提供T细胞帮助的数量和质量。抗原从B细胞表面摄取和转运到处理室的机制尚不清楚。我之前的研究已经确定了一个与抗原摄取有关的蛋白质网络，其中大多数在B细胞中是未知的。其中一种名为SorLA的蛋白质已知可以调节免疫系统外细胞内蛋白质的运输。尽管它在B细胞淋巴瘤中过度表达，但它在B细胞中的作用尚未确定。我们的初步工作表明，SorLA被招募到内化的BCR抗原分子中，而SorLA的耗尽显着减少了BCR的摄取。此外，动物模型中SorLA的缺失降低了它们对免疫的反应，突显了SorLA在感染或接种疫苗后的免疫反应中的重要和生理相关的作用。在这里，我建议调查这一新的BCR贩运法规背后的机制。我们将删除SORL1，编码SorLA的基因，并测量它对B细胞信号和通过细胞的抗原运输的影响。我们将研究SorLA和已知的BCR摄取或激活成分之间的可能相互作用，以了解这些途径之间的协调。我们将量化B细胞表面抗原的数量和种类，以了解SorLA如何影响B细胞对T细胞帮助的竞争。此外，由于BCR在B细胞的发育过程中很重要，我们将研究BCR转运中断如何影响生物体中成熟B细胞的数量。最后，为了了解这种新的抗原摄取调节因子如何参与B细胞对免疫的反应，我们将分析B细胞的生长和分化为产生抗体或记忆B细胞以及产生高度特异的抗体。总之，这些研究将提供对B细胞抗原摄取及其调节的更全面的了解。这可能使我们能够设计出促进B细胞摄取和呈递的抗原，这对疫苗创新具有重要意义。它还将进一步加深我们对恶性B细胞中抗原摄取和呈递的了解-这一过程具有发现新的B细胞癌症治疗方法的尚未开发的潜力。

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.