Contribution of ASC Dynamics to Survival within the Bone Marrow

摘要 体液免疫是全世界所有疫苗接种活动的基础，也是最有效的疫苗接种活动之一。 公共卫生方面的进步，以减少疾病。体液免疫的关键是发展和长期 长寿命抗体分泌细胞(LLASCs)的存活。LLASCs驻留在骨髓(BM)中，可以提供 对特定病原体的终生保护。然而，一些疫苗接种只能导致暂时的 豁免权(几个月到几年)。因此，了解LLASC的生存方式可以帮助您深入了解如何改进 疫苗。 ASCs被认为停靠在一个静态的、支持性的利基环境中，在那里它们可以接收有利于生存的信号(IL-6，4月) 并产生抗体。对ASC-NICE的研究表明，许多类型的细胞支持ASCs 它们产生有利于生存的细胞因子的能力，以及它们在静态、共聚焦图像中与ASCs的密切联系。 然而，这些研究没有解决ASC如何在其利基内动态交互，也没有讨论ASC如何(也没有 新产生的或LLASC)竞争由利基提供的有限资源。因此，动力如何 影响ASC竞争、生存和长寿的因素尚不清楚。这个项目试图理解如何 ASCs的动态影响它们在BM中的竞争和生存。 在这个项目中，我将评估ASC如何在BM环境中进行交互。我将结合活体内的双光子 显微镜结合新的和经典的功能研究来研究促进动态ASC的因素 在他们的BM利基内的互动。我将确定影响ASC动态的因素，并分析如何 这种动态影响ASCs在骨髓中的长期存活和保留。这项工作将产生新的见解 BM的驻留细胞如何与其特定的生态位相互作用，并更好地了解BM ASC 利基市场。

Abstract Humoral immunity is the basis of all worldwide vaccination campaigns and has been one of the most effective public health advancements to curtail disease. Critical to humoral immunity is the development and long term survival of long-lived antibody secreting cells (LLASCs). LLASCs reside in the bone marrow (BM) and can confer protection towards specific pathogens for a lifetime. However, some vaccinations can only induce temporary immunity (months to a few years). Therefore, understanding how LLASCs survive can yield insight into improving vaccines. ASCs are thought to dock into a static, supportive niche where they can receive pro survival signals (IL-6, APRIL) and produce antibody. Studies of the ASC-niche have implicated a number of cell types in supporting ASCs due to their ability to produce pro survival cytokines and their close proximity to ASCs in static, confocal images. However, these studies do not address how ASCs dynamically interact within their niche nor how ASCs (either newly generated or LLASCs) compete for the limited resources provided by the niche. Therefore, how dynamics affect ASC competition, survival, and factor into longevity is not known. This project seeks to understand how the dynamics of ASCs affects their competition and survival in the BM. In this project I will assess how ASCs interact within the BM environment. I will combine intravital two photon microscopy with novel and classical functional studies to study the factors that promote dynamic ASC interactions within their BM niche. I will determine the factors that contribute to ASC dynamics and dissect how the dynamics affects long-term survival and retention of ASCs in the BM. This work will yield new insights into how resident cells of the BM interact with their specific niches and to a better understanding of the BM ASC niche.