Influence of Age on CD4 T Memory Cells

年龄对 CD4 T 记忆细胞的影响

基本信息

批准号：
9074540
负责人：
JORG J GORONZY
金额：
$ 8.32万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9074540
关键词：
3&apos Untranslated Regions ATM activation Accounting Adoptive Transfer Adult Age Aging Antigens B-Lymphocytes Biological Assay CD4 Positive T Lymphocytes CREB1 gene CaM kinase I activator Cell Differentiation process Cell physiology Chronic Data E2F1 gene Effector Cell Elderly Epigenetic Process Feedback Fluorescent Probes Gene Activation Gene Expression Gene Expression Regulation Genetic Engineering Genetic Transcription Health Herpes zoster disease Heterogeneous-Nuclear Ribonucleoprotein K Immune Immune system Immunization In Vitro Infection Infectious Agent Influenza Intervention JUN gene Kinetics MAP Kinase Gene MAPK8 gene Mediating Memory Methylation MicroRNAs Morbidity - disease rate Mus Mutate Nuclear Oxygen Pathway interactions Phosphoric Monoester Hydrolases Phosphorylation Population Predisposition Recording of previous events Regulation Reporter Genes Repression Role STK11 gene Signal Pathway Signal Transduction T Cell Receptor Signaling Pathway T cell differentiation T cell response T-Cell Activation T-Cell Proliferation T-Lymphocyte T-Lymphocyte Subsets Testing Transcript Transcriptional Regulation Vaccination adaptive immunity age effect age related aged attenuation base chromatin immunoprecipitation demographics design enzyme activity frailty improved in vivo inhibitor/antagonist interest memory CD4 T lymphocyte mortality overexpression promoter research study response transcription factor vaccine response

项目摘要

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.

描述（由申请人提供）：衰老免疫系统安装适应性免疫反应的能力降低了疫苗接种的疗效并增加了感染的发病率。对外源或内源性威胁的自适应免疫反应取决于抗原特异性T细胞群体的快速扩张和效应功能的获取。在研究年龄对CD4 T记忆细胞功能的影响时，我们已经确定了由双特异性磷酸酶DUSP4介导的负反馈回路，该循环在老年人中过度活跃。 DUSP4是一种核磷酸酶；其活性在T细胞激活后两到四天达到峰值，并通过控制核ERK和JNK活性来影响T细胞分化。在当前的建议中，我们研究了以下假设：这种反馈回路的不适当激活会损害T细胞分化和效应子功能，并且可以通过识别和纠正DUSP4表达的机制或直接抑制DUSP4活性来改善老年人中的T细胞反应。已经设计了三个特定目标来检验这一假设。在AIM 1中，我们将描述DUSP4介导的反馈回路对CD4记忆T细胞中核ERK和JNK活性动力学的影响。在第二步中，我们将确定核MAPK活性的年龄相关的衰减是T细胞的普遍性，还是仅限于选定的T细胞亚群，具体取决于其分化和复制史。在AIM 2中，我们将探讨老年人T细胞中DUSP4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增长而变化。特别令人感兴趣的是，随着年龄的增长，AMPK激活增加的假设会改变TCR诱导的信号级联反应以有利于DUSP4转录。在AIM 3中，我们将研究增加DUSP4表达的功能后果，并探讨如何将DUSP4靶向以恢复效应细胞功能。