Homing and Homeostasis of Regulatory T cells

描述（由申请人提供）：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。Treg作为一种有效的自我反应性T细胞调节剂，代表了一种令人兴奋的治疗自身免疫性疾病的新方法，如1型糖尿病、多发性硬化症、类风湿性关节炎和慢性疾病。然而，作为了解Treg如何在体内控制自身免疫功能的先决条件，确定Treg定位的位置以及它们与哪些细胞类型相互作用是必不可少的。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、定位和调节器官特异性自身免疫能力之间的关系尚未得到实验探索。我们假设Treg必须定位于特定的淋巴组织和非淋巴组织并在其中起作用，以防止自身免疫；在这里，我们提出了一系列的实验来验证这一假设，并确定破坏Treg定位如何影响它们的功能能力，以防止系统性和器官特异性自身免疫（目标1）和它们的生存/稳态（目标2）。此外，我们将验证一个假设，即归巢受体表达定义了针对淋巴组织和非淋巴组织的Treg亚群，这些组织具有不同的功能和稳态特征（目的3）。确定Treg归巢与其控制自身免疫能力之间的关系，需要了解这些细胞在体内的功能，以及不同Treg群体如何在不同的位点起作用，以防止自身免疫的启动和/或进展。这对Treg在预防和治疗人类自身免疫性疾病和炎症性疾病方面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.