Contribution of ASC Dynamics to Survival within the Bone Marrow

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.