Homing and Homeostasis of Regulatory T cells

描述（由申请方提供）：本研究的目的是确定归巢受体的特定组合如何控制CD4 + CD25+调节性T细胞（Treg）的定位和功能。作为自身反应性T细胞的有效调节剂，Treg代表了治疗自身免疫性疾病如1型糖尿病、多发性硬化、类风湿性关节炎和Chron病的令人兴奋的新治疗方法。然而，作为了解Treg如何在体内发挥作用以控制自身免疫的先决条件，确定Treg定位于何处以及它们与哪些细胞类型相互作用是至关重要的。虽然Treg表达淋巴细胞归巢受体的多样性和异质性模式，但它们的归巢受体表达、它们的定位和它们调节器官特异性自身免疫的能力之间的关系尚未被实验探索。我们假设Treg必须定位于特定的淋巴组织和非淋巴组织中并在其中发挥作用，以防止自身免疫;在这里，我们提出了一系列实验来验证这一假设，并确定破坏Treg定位如何影响其功能能力，以防止系统性和器官特异性自身免疫（目的1）及其生存/稳态（目的2）。此外，我们将检验归巢受体表达定义靶向具有不同功能和稳态特征的淋巴组织与非淋巴组织的Treg亚群的假设（目的3）。需要确定Treg归巢与其控制自身免疫的能力之间的关系，以了解这些细胞在体内的功能，以及不同的Treg群体如何在不同的位点发挥作用，以防止自身免疫的起始和/或进展。这对Treg在预防和治疗人类自身免疫性和炎症性疾病的临床应用具有明确和直接的意义。

DESCRIPTION (provided by applicant): The objective of this study is to determine how specific combinations of homing receptors control the localization and function of CD4+CD25+ regulatory T cells (Treg). As potent modulators of self-reactive T cells, Treg represent an exciting new therapeutic approach for the treatment of autoimmune disorders such as type 1 diabetes, multiple sclerosis, rheumatoid arthritis and Chron's disease. However, as a prerequisite to understanding how Treg function in vivo to control autoimmunity, it is essential to determine where Treg localize and what cell types they interact with. While Treg express diverse and heterogeneous patterns of lymphocyte homing receptors, the relationship between their homing receptor expression, their localization, and their ability to modulate organ-specific autoimmunity has not been explored experimentally. We hypothesize that Treg must localize to and function within specific lymphoid and non-lymphoid tissues in order to prevent autoimmunity; Here we propose a series of experiments to test this hypothesis, and determine how disrupting Treg localization impacts their functional ability to prevent systemic and organ-specific autoimmunity (aim 1) and their survival/homeostasis (aim 2). In addition, we will test the hypothesis that homing receptor expression defines Treg subsets targeted to lymphoid vs. non-lymphoid tissues that have distinct functional and homeostatic characteristics (aim 3). Determining the relationship between Treg homing and their ability to control autoimmunity is required to understand where these cells function in vivo, and how diverse populations of Treg may function at distinct sites to prevent the initiation and/or progression of autoimmunity. This has clear and direct implications in the clinical application of Treg to the prevention and treatment of human autoimmune and inflammatory diseases.