Mobilization and trafficking of central ILC progenitors

项目摘要 先天性淋巴样细胞（ILC）是外周组织的重要组成部分，通过调节组织稳态， 免疫和炎症。外周ILC人群随时间推移发生自发性和诱导性损耗 并且应当补充以保持它们的正常数量和子集组成。骨髓（BM）是 产生外周组织ILC祖细胞的主要位点。将ILC祖细胞递送到 外周组织中的ILC祖细胞的动员是从BM，这大概需要调节 ILC祖细胞从BM移出并最终运输到各种外周组织中。 不幸的是，我们几乎不了解各种ILC祖细胞是如何从BM动员的， 在稳态下特征性地分布于各种外周组织，以及这些过程是如何 在炎症条件下改变。本项目的总体目标是了解 BM ILC祖细胞的动员和运输。 在中央ILC祖细胞的动员和迁移方面出现了几个重要问题： 哪些祖细胞主要从BM迁移产生外周ILC亚群？他们是多潜能的吗 和/或承诺的祖先引发他们移民的机制和信号是什么？怎么 这些血液循环中的祖细胞进入不同的外周组织？是迁移机制 对于每个祖细胞亚群或组织部位是通用的还是特异性的？炎症信号是如何改变 ILC祖细胞的动员和迁移模式，以及我们是否可以控制致病组织中的ILC活性， 通过利用动员的BM ILC祖细胞或靶向它们的动员和迁移来改善条件？ 我们设计了以下具体目标来调查这些关于动员和 ILC祖细胞的贩运。目标1.确定保留与移民的基本机制 BM ILC祖细胞; Aim 2.研究BM ILC祖细胞的保留与迁移 由昼夜节律调节;目标3.识别调节保留与炎症信号。 BM ILC祖细胞的移出;目的4.确定归巢行为和贩运受体 移民的ILC祖先。该项目将产生关于外围ILC如何 系统由ILC祖细胞的动员和潜在的选择性运输到外周血中来调节。 组织中这些结果将大大提高我们对维护和管理 外周ILC，并将提供新的见解，治疗利用和控制ILC 祖先

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.