Trafficking and Function of Central Nervous System Resident Regulatory T Cells

中枢神经系统驻留调节 T 细胞的运输和功能

• 批准号: 8424309
• 负责人: Rachel Niec
• 金额: $ 2.8万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8424309
• 关键词: Ablation; Address; Arbovirus Encephalitis; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Blood - brain barrier anatomy; Cell physiology; Cells; Central Nervous System Infections; Central Nervous System Viral Diseases; Cessation of life; Characteristics; Diphtheria Toxin; Disease; Down-Regulation; Effector Cell; Evaluation; Experimental Autoimmune Encephalomyelitis; Flavivirus; Frequencies; Genetic; Homeostasis; Homing; Human; Human Herpesvirus 2; Immune; Immune response; Immune system; Immunity; Immunologic Surveillance; Infection; Infectious Encephalitis; Inflammation; Inflammatory; Label; Laboratories; Longevity; Mediating; Modeling; Multiple Sclerosis; Mus; Nervous System Physiology; Neuraxis; Pathology; Phenotype; Play; Population; Process; Public Health; Regulation; Regulatory T-Lymphocyte; Research; Research Training; Role; Signal Transduction; Site; T-Lymphocyte; Tissues; Training Programs; United States; Viral; Virus; Virus Diseases; West Nile virus; Work; diphtheria toxin receptor; immune activation; immune function; improved; in vivo; insight; model design; mouse model; neurotropic; pathogen; prevent; public health relevance; regenerative; research study; trafficking; transcription factor

DESCRIPTION (provided by applicant): The central nervous system (CNS) represents a site of immune privilege. Limiting the potential for immune mediated pathology is thought to be critical for maintained function and longevity of this sensitive tissue especially given its limited regenerative capacity. However, cells of the immune system are found within the CNS under homeostatic conditions. Regulatory T (Treg) cells are a suppressive population of immune cells that act by preventing activation of potentially pathogenic immune responses. These cells function critically under homeostatic conditions in a number of tissues to prevent autoimmune disease and death in humans and mice. We have observed Treg cells within the CNS tissue under homeostatic conditions and herein propose to evaluate their function in this tissue in the steady state and during neuropathogenic infection with West Nile virus (WNV). For this purpose, we will utilize several genetic mouse models developed in our laboratory, which allow for identification, isolation and specific ablation of Treg cells in vivo, as well as models designed to prevent their entry into the CNS. Treg cells within the CNS will be characterized by immunofluorescent labeling of phenotypic markers and flow cytometery and evaluated for expression of molecules essential for their homing to this tissue. Using mice that express the human diphtheria toxin (DT) receptor exclusively in Treg cells, I will use diphtheria toxin to deplete Treg cells and examine CNS pathology histological and via evaluation of effector immune cell phenotype and activity. In addition, the function of Treg cells in the CNS will be examined by specifically precluding their entry into this tissue using mice with Treg cell specific deficiency in CNS homing molecules and transfer of Treg cells from mice lacking CNS homing molecules into T cell deficient mice. Lastly, we have observed accumulation of Treg cells within the CNS of WNV infected mice and it is know that clearance of this virus from the CNS is a T cell dependent process. Thus, the dynamics of Treg cell entry and their phenotype within the CNS of mice infected with WNV will be evaluated and the mechanism of this entry will be interrogated through infection of mice harboring Treg cells lacking in CNS homing molecules. Together, these experiments will characterize the function and mechanism of entry of Treg cells within the CNS under homeostatic conditions and the role for these cells in CNS viral immunity.

描述（由申请人提供）：中枢神经系统（CNS）代表一个免疫特权部位。限制免疫介导病理学的潜力被认为对于维持该敏感组织的维持功能和寿命至关重要，特别是考虑到其再生能力有限。但是，在稳态条件下，在中枢神经系统内发现了免疫系统的细胞。调节性T（TREG）细胞是一种抑制免疫细胞的抑制群，可通过防止激活潜在的致病性免疫反应来起作用。这些细胞在许多组织中在稳态条件下进行批判性发挥作用，以防止人类和小鼠的自身免疫性疾病和死亡。我们已经在稳态条件下观察到CNS组织内的Treg细胞，并提出在稳态和西尼尼罗河病毒（WNV）中评估其在该组织中的功能。为此，我们将利用实验室中开发的几种遗传小鼠模型，这些模型允许对体内Treg细胞的识别，隔离和特定消融，以及旨在防止其进入中枢神经系统的模型。中枢神经系统内的Treg细胞的特征是表型标记和流式细胞仪的免疫荧光标记，并评估了对将其归归其为该组织所必需的分子的表达。使用专门在Treg细胞中表达人二半毒素（DT）受体的小鼠，我将使用白喉毒素耗尽Treg细胞并检查CNS病理学组织学并通过评估效应免疫细胞表型和活性。此外，将通过特异性排除在中枢神经系统中使用具有Treg细胞特异性缺乏症的小鼠，并从缺乏CNS归纳分子中的Treg细胞中转移Treg细胞特异性缺乏的小鼠来研究中枢神经系统中Treg细胞的功能。最后，我们观察到在WNV感染小鼠的中枢神经系统中的Treg细胞积累，并且知道该病毒从中枢神经系统中清除是T细胞依赖性过程。因此，将评估Treg细胞进入的动力学及其在感染WNV的小鼠中的表型的动力学，并将通过感染中CNS寄居分子缺乏Treg细胞的小鼠进行询问，并将评估该条目的机理。总之，这些实验将表征在稳态条件下Treg细胞进入中枢神经系统内的功能和机制，以及这些细胞在CNS病毒免疫中的作用。