The Regulation of T Cell Exhaustion by Adhesion Molecules

粘附分子对 T 细胞耗竭的调节

• 批准号: 8416362
• 负责人: Allan J Zajac
• 金额: $ 21.98万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416362
• 关键词: Ablation; Activities of Daily Living; Acute; Animal Model; Antigen-Presenting Cells; Antigens; Automobile Driving; CD8B1 gene; Cell Adhesion Molecules; Cell physiology; Cells; Chronic; Data; Development; Effector Cell; Epitopes; Evaluation; Event; Foundations; HIV; HIV-1; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Host Defense; Immunity; Immunization; Immunologic Memory; Infection; Intercellular adhesion molecule 1; Interleukin-10; Life; Lymphocyte Function-Associated Antigen-1; Lymphocytic choriomeningitis virus; Maintenance; Mediating; Memory; Methods; Mus; Pathway interactions; Phase; Phenotype; Play; Population; Publishing; Research Design; Role; Signal Transduction; System; T cell differentiation; T cell regulation; T cell response; T memory cell; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Variant; Viral; Viral Load result; Virus; Virus Diseases; base; cell type; cytokine; exhaust; exhaustion; functional restoration; improved; insight; novel; novel therapeutic intervention; novel therapeutics; pathogen; receptor; response; tumor

DESCRIPTION (provided by applicant): During chronic infections such as those caused by HIV-1, hepatitis C virus, and lymphocytic choriomeningitis virus, as well as during tumor outgrowth, antigen-specific CD8 T cells often progressively lose function in a step-wise manner. This loss of functional capacity, termed T cell exhaustion, represents an extreme state of differentiation which is characterized by an inability to elaborate key anti-viral effector activites and, in severe cases, culminates in deletion of the CD8 T cells. Defining how and why exhaustion develops, as well as determining the regulatory mechanisms that maintain this state, are significant as this may permit the development of new strategies to enhance immunity to infections which are difficult to control. This exploratory proposal is built on a foundation of preliminary data from acute infection studies showing that if ICAM-1 is not expressed, then there is greatly enhanced retention of virus-specific effector phenotype CD8 T cells well into the memory phase, even though the infection is cleared. This is significant as preserving this population during chronic viral infections may impede the development of exhaustion and favor viral control. Nevertheless, virtually no information is available regarding the roles of adhesion molecules in dictating the development of T cell exhaustion. Since continuous antigenic activation is required to develop and sustain exhaustion, it is plausible that adhesion molecule interactions amplify the strength of the antigen-dependent signals that the virus-specific CD8 T cell receives, driving the development of exhaustion. This concept, that ICAM-1 interactions influence the differentiation state of the responding T cells, is supported by our preliminary findings. Based upon these findings, as well as published studies of exhausted CD8 T cells, we have formulated the hypothesis that ICAM-1 interactions enhance antigenic signals, and potentiate the development and maintenance of CD8 T cell exhaustion. Testing this hypothesis will provide novel information regarding how T cell exhaustion is controlled and will also determine whether targeting adhesion molecule interactions is a viable therapeutic option during chronic infections. Our specific aims are: (1) Define the requirements for ICAM-1 and LFA-1 in the development of CD8 T cell exhaustion; and (2) Determine whether targeting ICAM-1 interactions is a viable therapeutic option. Completion of the aims of this exploratory proposal will provide novel mechanistic insights into the roles of adhesion molecules in driving and sustaining CD8 T cell exhaustion, and this information may broadly impact our understanding of how CD8 T cell differentiation is corrupted under conditions of chronic antigenic activation, as well as identify potential new therapeutic approaches.

描述（由申请人提供）：在慢性感染（例如由 HIV-1、丙型肝炎病毒和淋巴细胞性脉络膜脑膜炎病毒引起的感染）以及肿瘤生长过程中，抗原特异性 CD8 T 细胞通常会逐步丧失功能方式。这种功能丧失（称为 T 细胞耗竭）代表了一种极端的分化状态，其特征是无法发挥关键的抗病毒效应活性，在严重的情况下，最终导致 CD8 T 细胞的缺失。定义精疲力尽的方式和原因，以及确定维持这种状态的调节机制非常重要，因为这可能允许开发新的策略来增强对难以控制的感染的免疫力。这一探索性提议建立在急性感染研究初步数据的基础上，这些数据表明，如果 ICAM-1 不表达，则病毒特异性效应表型 CD8 T 细胞进入记忆期的保留会大大增强，即使感染已清除。这很重要，因为在慢性病毒感染期间保留这一群体可能会阻止衰竭的发展并有利于病毒控制。然而，实际上没有关于粘附分子在决定 T 细胞耗竭发展中的作用的信息。由于持续的抗原激活是产生和维持耗竭所必需的，因此粘附分子相互作用可能会放大病毒特异性 CD8 T 细胞接收的抗原依赖性信号的强度，从而推动耗竭的发展。我们的初步研究结果支持了 ICAM-1 相互作用影响响应 T 细胞的分化状态这一概念。基于这些发现以及已发表的耗竭 CD8 T 细胞研究，我们提出了以下假设：ICAM-1 相互作用增强抗原信号，并增强 CD8 T 细胞耗竭的发展和维持。测试这一假设将提供有关如何控制 T 细胞耗竭的新信息，并将确定靶向粘附分子相互作用是否是慢性感染期间可行的治疗选择。我们的具体目标是：（1）明确CD8 T细胞耗竭发展过程中ICAM-1和LFA-1的要求； (2) 确定靶向 ICAM-1 相互作用是否是一种可行的治疗选择。完成这一探索性提案的目标将为粘附分子在驱动和维持 CD8 T 细胞耗竭中的作用提供新的机制见解，并且该信息可能广泛影响我们对 CD8 T 细胞分化在慢性抗原激活条件下如何被破坏的理解，以及确定潜在的新治疗方法。