Influence of Age on CD4 T Memory Cells

描述（由申请人提供）：老化的免疫系统产生适应性免疫反应的能力降低，降低了疫苗接种的效力，增加了感染的发病率。对外源性或内源性威胁的适应性免疫应答依赖于抗原特异性T细胞群的快速扩增和效应功能的获得。在研究年龄对CD4 T记忆细胞功能的影响时，我们发现了一个由双特异性磷酸酶DUSP4介导的负反馈循环，该循环在老年人中过度活跃。DUSP4是核磷酸酶；其活性在T细胞活化后2 - 4天达到峰值，并通过控制核ERK和JNK活性影响T细胞分化。在目前的提案中，我们研究了这样的假设，即不适当的激活该反馈回路会损害T细胞分化和效应功能，并且可以通过识别和纠正DUSP4表达的机制或直接抑制DUSP4活性来改善老年人的T细胞反应。为了验证这一假设，设计了三个具体目标。在Aim 1中，我们将描述dusp4介导的反馈回路对CD4记忆T细胞核ERK和JNK活性动力学的影响。在第二步中，我们将确定年龄相关的核MAPK活性衰减是否普遍存在于T细胞中，或者是否仅限于特定的T细胞亚群，这取决于它们的分化和复制历史。在Aim 2中，我们将探索DUSP4在老年人T细胞中表达增加的机制，并确定DUSP4的表观遗传或转录控制是否随着年龄的变化而变化。特别有趣的是，随着年龄增长而增加的AMPK激活会改变tcr诱导的信号级联，从而有利于DUSP4的转录。在Aim 3中，我们将研究DUSP4表达增加的功能后果，并探索如何靶向DUSP4以恢复效应细胞功能。

DESCRIPTION (provided by applicant): The reduced ability of the aging immune system to mount adaptive immune responses compromises the efficacy of vaccinations and increases the morbidity from infections. Adaptive immune responses to exogenous or endogenous threats rely on the rapid expansion of an antigen-specific T cell population and acquisition of effector functions. In studying the effect of age on CD4 T memory cell function, we have identified a negative feedback loop mediated by the dual-specific phosphatase DUSP4 which is overactive in the elderly. DUSP4 is a nuclear phosphatase; its activity peaks two to four days after T cell activation and influences T cell differentiation by controlling nuclear ERK and JNK activity. In th current proposal we examine the hypothesis that the inappropriate activation of this feedback loop impairs T cell differentiation and effector function and that T cell responses in the elderly can be improved by identifying and correcting the mechanism of DUSP4 expression or by directly inhibiting DUSP4 activity. Three specific aims have been designed to test this hypothesis. In Aim 1, we will delineate the effect of DUSP4-mediated feedback loop on the kinetics of nuclear ERK and JNK activity in CD4 memory T cells. In a second step, we will then determine whether the age-associated attenuation of nuclear MAPK activities is universal for T cells or whether it is limited to selected T cell subpopulation depending on their differentiation and their replicative history. In Aim 2, we will explore the mechanisms of increased DUSP4 expression in T cells from the elderly and determine whether the epigenetic or transcriptional control of DUSP4 changes with age. Of particular interest is the hypothesis that increased AMPK activation with age modifies the TCR-induced signaling cascade to favor DUSP4 transcription. In Aim 3, we will examine the functional consequences of increased DUSP4 expression and explore how DUSP4 can be targeted to restore effector cell function.