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(申请人提供)：中枢神经系统(CNS)代表免疫特许权的位置。限制免疫介导的病理的可能性被认为是维持这一敏感组织的功能和寿命的关键，特别是考虑到其有限的再生能力。然而，在动态平衡条件下，免疫系统的细胞在中枢神经系统内被发现。调节性T(Treg)细胞是一组抑制性免疫细胞，通过阻止潜在致病免疫反应的激活而发挥作用。这些细胞在动态平衡条件下在许多组织中发挥关键作用，以防止人类和小鼠的自身免疫性疾病和死亡。我们在稳态条件下观察了中枢神经系统组织中的Treg细胞，并在此建议评估它们在稳态和西尼罗河病毒(West Nile Virus，WNV)神经致病感染期间的功能。为此，我们将利用我们实验室开发的几种遗传小鼠模型，这些模型允许在体内识别、分离和特异性消融Treg细胞，以及旨在防止它们进入中枢神经系统的模型。中枢神经系统内的Treg细胞将通过免疫荧光标记的表型标记和流式细胞术来表征，并评估其归巢到该组织所必需的分子的表达。利用在Treg细胞中仅表达人白喉毒素(DT)受体的小鼠，我将使用白喉毒素来耗尽Treg细胞，并通过评估效应器免疫细胞的表型和活性来检查中枢神经系统病理组织学。此外，还将利用CNS归巢分子中Treg细胞特异性缺陷的小鼠，以及将缺乏CNS归巢分子的小鼠的Treg细胞转移到T细胞缺陷小鼠身上，通过明确排除Treg细胞进入该组织来检查CNS中Treg细胞的功能。最后，我们观察到WNV感染的小鼠中枢神经系统内Treg细胞的聚集，我们知道这种病毒从中枢神经系统中清除是一个T细胞依赖的过程。因此，我们将评估感染西尼罗河病毒的小鼠的Treg细胞进入中枢神经系统的动态及其表型，并通过感染携带缺乏CNS归巢分子的Treg细胞的小鼠来探讨这种进入的机制。总之，这些实验将表征Treg细胞在动态平衡条件下进入CNS的功能和机制，以及这些细胞在CNS病毒免疫中的作用。