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: 8060859
• 负责人: Rachel Niec
• 金额: $ 4.62万
• 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/8060859
• 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; 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. PUBLIC HEALTH RELEVANCE: This proposed research training program has the potential to impact public health in the following ways. First, this research will provide insight into immune regulation within the central nervous system (CNS), potentially leading to improved understanding of how immune homeostasis is maintained within this tissue. Second, West Nile virus is a leading cause of infectious encephalitis worldwide; an appreciation for how the immune system works to limit pathology in this infection may impact therapy for this and other neuroinvasive diseases.

描述（由申请人提供）： 中枢神经系统（CNS）代表免疫赦免的部位。限制免疫介导的病理学的可能性被认为对于维持该敏感组织的功能和寿命至关重要，特别是考虑到其有限的再生能力。然而，免疫系统的细胞在稳态条件下在CNS内发现。调节性T（Treg）细胞是通过防止潜在致病性免疫应答的激活而起作用的免疫细胞的抑制性群体。这些细胞在许多组织中的稳态条件下发挥关键作用，以防止人类和小鼠的自身免疫性疾病和死亡。我们已经在稳态条件下观察到CNS组织内的Treg细胞，并在此提出在稳态和西尼罗河病毒（WNV）的神经致病性感染期间评估它们在该组织中的功能。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，以及设计用于防止其进入CNS的模型。CNS内的Treg细胞将通过表型标志物的免疫荧光标记和流式细胞术来表征，并评价其归巢至该组织所必需的分子的表达。使用仅在Treg细胞中表达人白喉毒素（DT）受体的小鼠，我将使用白喉毒素耗尽Treg细胞，并通过评价效应免疫细胞表型和活性来检查CNS病理组织学。此外，将通过使用具有CNS归巢分子中Treg细胞特异性缺陷的小鼠特异性地阻止Treg细胞进入该组织以及将Treg细胞从缺乏CNS归巢分子的小鼠转移到T细胞缺陷小鼠中来检查Treg细胞在CNS中的功能。最后，我们已经观察到Treg细胞在WNV感染小鼠的CNS内的积累，并且已知该病毒从CNS的清除是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的小鼠的CNS内的表型，并且将通过感染携带缺乏CNS归巢分子的Treg细胞的小鼠来探究这种进入的机制。总之，这些实验将表征Treg细胞在稳态条件下进入CNS内的功能和机制以及这些细胞在CNS病毒免疫中的作用。 公共卫生关系： 这项拟议的研究培训计划有可能以下列方式影响公共卫生。首先，这项研究将提供对中枢神经系统（CNS）内免疫调节的深入了解，可能导致对该组织内免疫稳态如何维持的更好理解。其次，西尼罗河病毒是全球感染性脑炎的主要原因;对免疫系统如何限制这种感染的病理学的认识可能会影响这种和其他神经侵袭性疾病的治疗。