Mobilization and trafficking of central ILC progenitors

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PROJECT SUMMARY ILCs play essential roles in peripheral tissues by regulating tissue homeostasis, immunity and inflammation. Peripheral ILC populations undergo spontaneous and induced attrition over time and should be replenished to maintain their normal numbers and subset composition. The first step to deliver ILC progenitors into peripheral tissues is the mobilization of ILC progenitors from the central hematopoietic tissue, bone marrow (BM), and this presumably requires regulated emigration of ILC progenitors from the BM and their ultimate trafficking into various peripheral tissues. Unfortunately, we hardly understand how various ILC progenitors are mobilized from the BM and characteristically distributed to various peripheral tissues in steady state and how these processes are altered in inflammatory conditions. The overarching objective of this project is to understand the mobilization and trafficking of BM ILC progenitors. Several key questions arise in terms of the mobilization and migration of central ILC progenitors: Which progenitors dominantly emigrate from BM to generate peripheral ILC subsets in steady state? Are they multi- potential and/or committed progenitors? What are the mechanisms and signals that trigger their emigration? How do these progenitor cells in the blood circulation enter distinct peripheral tissues? Is the migration mechanism universal or specific for each progenitor subset or tissue site? How do inflammatory signals alter the mobilization and migration patterns of ILC progenitors, and can we control tissue ILC activity in pathogenic conditions by utilizing mobilized BM ILC progenitors or targeting their mobilization and migration? We devised the following specific aims to investigate these questions regarding the mobilization and trafficking of ILC progenitors. Aim 1. Identify the mechanism that mobilizes central ILC progenitors in steady state; Aim 2. Identify the mechanism by which central ILC progenitors are mobilized in inflammatory conditions; Aim 3. Identify potentially diverse mechanisms for the entrance of mobilized ILC progenitors into distinct peripheral tissues. The project will generate fundamental knowledge on how the peripheral ILC system is maintained and regulated by the mobilization and potentially selective trafficking of ILC progenitors into peripheral tissues. The outcomes will greatly enhance our understanding of the maintenance and regulation of peripheral ILCs and will provide novel insights into therapeutic utilization and control of ILC progenitors.