The Regulation of T Cell Exhaustion by Adhesion Molecules

描述（由申请人提供）：在慢性感染期间，如由HIV-1、丙型肝炎病毒和淋巴细胞性脉络丛脑膜炎病毒引起的感染，以及在肿瘤生长期间，抗原特异性CD 8 T细胞通常以逐步的方式逐渐丧失功能。这种功能能力的丧失，称为T细胞耗竭，代表了分化的极端状态，其特征在于不能产生关键的抗病毒效应物活性，并且在严重的情况下，最终导致CD 8 T细胞的缺失。定义如何和为什么耗尽发展，以及确定维持这种状态的调节机制，是重要的，因为这可能允许开发新的策略，以增强对难以控制的感染的免疫力。这个探索性的建议是建立在来自急性感染研究的初步数据的基础上的，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CD 8 T细胞也会大大增强保留到记忆阶段。这是重要的，因为在慢性病毒感染期间保留该群体可能会阻碍衰竭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细胞耗竭的发展中的作用的信息。由于持续的抗原活化是发展和维持衰竭所必需的，因此似乎粘附分子相互作用放大了病毒特异性CD 8 T细胞接收的抗原依赖性信号的强度，从而驱动衰竭的发展。ICAM-1相互作用影响应答性T细胞的分化状态这一概念得到了我们初步研究结果的支持。基于这些发现，以及已发表的耗尽的CD 8 T细胞的研究，我们已经制定了ICAM-1相互作用增强抗原信号，并加强发展和维持的CD 8 T细胞耗尽的假设。检验这一假设将提供关于如何控制T细胞耗竭的新信息，也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）确定在CD 8 T细胞耗竭的发展中对ICAM-1和LFA-1的要求;和（2）确定靶向ICAM-1相互作用是否是可行的治疗选择。完成这一探索性提案的目的将为粘附分子在驱动和维持CD 8 T细胞耗竭中的作用提供新的机制见解，这些信息可能会广泛影响我们对CD 8 T细胞分化在慢性抗原活化条件下如何被破坏的理解，以及确定潜在的新治疗方法。

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.