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）：在慢性感染期间，例如由HIV-1，乙型肝炎病毒和淋巴细胞绒毛膜炎病毒以及在肿瘤生长期间，抗原特异性CD8 T细胞经常以逐步稳定的方式逐渐逐步失去功能。这种功能能力的丧失称为T细胞耗尽，代表了一种极端的分化状态，其特征是无法详细阐述关键的抗病毒效应激活物，并且在严重的情况下，在CD8 T细胞的缺失方面达到了顶点。定义疲惫的发展以及为什么确定维持这种状态的监管机制，这很重要，因为这可能会允许制定新的策略，以增强难以控制的感染免疫力。该探索性建议建立在急性感染研究的初步数据的基础上，表明如果未表达ICAM-1，那么即使感染已清除，也可以很好地增强病毒特异性效应表型CD8 T细胞的保留良好。这很重要，因为在慢性病毒感染过程中保留该人群可能会阻碍疲惫的发展并有利于病毒控制。然而，几乎没有关于粘附分子在决定T细胞耗尽发展的作用的信息。由于需要连续的抗原激活才能发展和维持衰竭，因此粘附分子相互作用放大了病毒特异性CD8 T细胞所接受的抗原依赖性信号的强度，从而促进了精疲力尽的发展。我们的初步发现支持了这个概念，即ICAM-1相互作用会影响响应T细胞的分化状态。基于这些发现以及对耗尽的CD8 T细胞的发表研究，我们提出了以下假设：ICAM-1相互作用增强了抗原信号，并增强了CD8 T细胞耗尽的发展和维持。检验该假设将提供有关如何控制T细胞耗尽的新信息，还将确定靶向粘附分子相互作用是否是慢性感染过程中可行的治疗选择。我们的具体目的是：（1）定义ICAM-1和LFA-1在CD8 T细胞耗尽过程中的要求； （2）确定靶向ICAM-1相互作用是否是可行的治疗选择。该探索性提案的目的的完成将提供对粘附分子在驾驶和维持CD8 T细胞疲劳中作用的新型机械见解，并且该信息可能会广泛影响我们对CD8 T细胞分化如何在慢性抗原激活条件下损坏的理解，以及确定潜在的新治疗方法。