Molecular basis of defective CD8 T cells during chronic viral infection

描述(由申请人提供)：CD8 T细胞在清除许多病毒感染和提供针对再次感染的保护性免疫方面发挥着重要作用。在评估CD8 T细胞反应的有效性时，大多数研究都集中在反应的大小与其提供的保护水平之间的相关性。然而，最近的研究表明，有效控制病毒感染不仅取决于抗原特异性CD8T细胞的数量，而且取决于其质量。以小鼠感染淋巴细胞性脉络膜脑膜炎病毒(LCMV)为模型，我们发现在没有CD4T细胞帮助的情况下产生的记忆CD8T细胞的质量很差。这些“无助”的记忆CD8 T细胞的持续能力下降，在重新刺激后产生低水平的效应细胞因子，最重要的是，不能提供足够的保护来抵御二次挑战。在慢性LCMV感染期间也会观察到CD8T细胞功能的丧失，这被认为是宿主未能清除感染的原因之一。我们最近的研究集中在阐明为什么“无帮助”的CD8 T细胞不能正常发挥作用的机制。我们已经证明，“无助”记忆CD8T细胞的缺陷不是由于TCR谱系的异常，也不是由于功能亲和力成熟的损害。相反，我们的结果表明，缺陷存在于TCR信号的下游，是由于这些细胞未能在几个对效应器功能至关重要的位置进行特定的表观遗传修饰。我们将检验这一假设，即CD8T细胞未能进行必要的表观遗传修饰，导致它们在慢性LCMV感染期间无法正常发挥功能。更具体地说，在目标1中，我们将确定表观遗传重塑的差异是否导致抗原特异性CD8T细胞在慢性感染期间无法正常发挥功能。在目标2中，我们将检查在慢性感染期间出现的有缺陷的CD8 T细胞是否可以通过表观遗传修饰重新编程以获得完整的功能。这些研究的结果可能有助于我们开发新的策略，改善CD8T细胞的功能，从而增强对病毒感染的免疫控制。许多病毒感染的公共卫生相关性清除严重依赖于CD8T细胞的功能。最近的研究结果表明，CD8T细胞在缺乏CD4T细胞帮助的情况下会出现功能缺陷。在慢性病毒感染期间，也会观察到CD8T细胞功能的丧失，这被认为是宿主未能清除感染的原因之一。在这项研究中，我们的目的是了解为什么CD8T细胞在慢性病毒感染期间变得有缺陷，并在缺乏CD4T细胞的情况下有所帮助。在此过程中，我们希望开发新的策略，以增强CD8 T细胞的功能，从而对病毒感染进行免疫控制。

DESCRIPTION (provided by applicant): CD8 T cells play an important role in the clearance of many viral infections and in providing protective immunity against re-infection. In assessing the effectiveness of the CD8 T cell response, most studies have focused on correlating the magnitudes of the response with the level of protection it provides. However, recent studies have shown that effective control of viral infection is dependent on not only the quantity but also the quality of antigen-specific CD8 T cells. Using infection of mice with lymphocytic choriomeningitis virus (LCMV) as a model, we have discovered that memory CD8 T cells generated in the absence of CD4 T cell help are of poor quality. These "unhelped" memory CD8 T cells have a decreased ability to persist, produce low levels of effector cytokines following restimulation, and most significantly, do not provide adequate protection against secondary challenge. This loss of functionality in CD8 T cells is also observed during chronic LCMV infection and is thought to contribute to the failure of the host to clear the infection. Our recent studies have been focused on elucidating the mechanisms behind why "unhelped" CD8 T cells are unable to function properly. We have shown that defects in "unhelped" memory CD8 T cells are not due to aberrations in the TCR repertoire nor to impairment in functional avidity maturation. Instead, our results show that the defect lies downstream of TCR signaling and is due to a failure of these cells to undergo specific epigenetic modifications at several loci critical for effector functions. We will test the hypothesis that a failure of CD8 T cells to undergo requisite epigenetic modifications contributes to their inability to function properly during chronic LCMV infection. More specifically, in Aim 1 we will determine if differences in epigenetic remodeling contribute to the inability of antigen-specific CD8 T cells to function properly during chronic infection. In Aim 2, we will examine if the defective CD8 T cells that arise during chronic infection can be reprogrammed through epigenetic modification to gain full functionality. The results of these studies may help us develop new strategies that will improve the functionality of CD8 T cells and thus enhance immune control of viral infection. PUBLIC HEALTH RELEVANCE Clearance of many viral infections is critically dependent on the function of CD8 T cells. Recent results have shown that CD8 T cells become functionally defective when CD4 T cell help is absent. This loss of functionality in CD8 T cells is also observed during chronic viral infection and is thought to contribute to the failure of the host to clear the infection. In this study, we aim to understand why CD8 T cells become defective during chronic viral infection and in the absence of CD4 T cells help. In doing so, we hope to develop new strategies that will enhance the functionality of CD8 T cells and thus immune control of viral infection.