The Regulation of T Cell Exhaustion by Adhesion Molecules

描述(申请人提供)：在由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慢性感染期间，以及在肿瘤生长过程中，抗原特异性CD8 T细胞通常以循序渐进的方式逐渐丧失功能。这种功能能力的丧失被称为T细胞衰竭，代表着一种极端的分化状态，其特征是无法阐明关键的抗病毒效应活性，在严重的情况下，最终导致CD8T细胞的缺失。确定精疲力竭是如何和为什么发生的，以及确定维持这种状态的监管机制具有重要意义，因为这可能允许制定新的战略，以增强对难以控制的感染的免疫力。这一探索性建议是建立在急性感染研究的初步数据基础上的，这些数据表明，如果ICAM-1不表达，那么即使感染被清除，病毒特异性效应表型CD8 T细胞的记忆期也会大大增强。这一点意义重大，因为在慢性病毒感染期间保留这一群体可能会阻碍精疲力竭的发展，并有利于病毒控制。然而，几乎没有关于黏附分子在T细胞耗竭发展中的作用的信息。由于持续的抗原激活是发生和维持疲劳所必需的，因此黏附分子的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信号的强度，从而推动疲劳的发展。这一概念，即ICAM-1相互作用影响反应T细胞的分化状态，得到了我们初步发现的支持。基于这些发现，以及已发表的CD8T细胞耗竭研究，我们提出了ICAM-1相互作用增强抗原信号，并加强CD8T细胞耗竭的发展和维持的假说。验证这一假说将提供关于如何控制T细胞耗竭的新信息，并将确定靶向黏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细胞衰竭发展过程中对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方案。这一探索性建议的目的的完成将为黏附分子在驱动和维持CD8T细胞耗竭中的作用提供新的机制见解，这些信息可能广泛地影响我们对CD8T细胞在慢性抗原激活条件下的分化是如何破坏的理解，以及确定潜在的新的治疗方法。 公共卫生相关性：全球有超过5亿公民患有慢性艾滋病毒、丙型肝炎或乙肝病毒感染。这项建议的目的是提供新的信息，说明为什么宿主的防御系统无法清除这些类型的感染，并研究一种可能的新的治疗方案，以恢复保护不良的反应。

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. PUBLIC HEALTH RELEVANCE: Globally there are over 500 million citizens living with chronic HIV, hepatitis C, or hepatitis B virus infections. The purpose of this proposal is to provide new information regarding why the hosts' defense system is unable to clear these types of infections and investigate a possible new therapeutic option for rejuvenating poorly protective responses.