PROJECT SUMMARY Innate lymphoid cells (ILCs) are an essential part of 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. Bone marrow (BM) is the major site that produces ILC progenitors for peripheral tissues. The first step to deliver ILC progenitors into peripheral tissues is the mobilization of ILC progenitors from the 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 important questions arise in terms of the mobilization and migration of central ILC progenitors: Which progenitors dominantly emigrate from BM to generate peripheral ILC subsets? 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 underlying mechanism for the retention vs. emigration of BM ILC progenitors; Aim 2. Investigate how the retention vs. emigration of BM ILC progenitors is regulated by the circadian rhythm; Aim 3. Identify inflammatory signals that regulate the retention vs. emigration of BM ILC progenitors; Aim 4. Identify the homing behavior and trafficking receptors of emigrated ILC progenitors. The project will generate fundamental knowledge on how the peripheral ILC system is 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.