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）：衰老的免疫系统产生适应性免疫反应的能力降低，损害了疫苗接种的功效并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反应依赖于抗原特异性 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，我们发现了由双特异性磷酸酶 DUSP4 介导的负反馈回路，该酶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 活性影响 T 细胞分化。在当前的提案中，我们检验了这样的假设：该反馈环路的不适当激活会损害 T 细胞分化和效应器功能，并且可以通过识别和纠正 DUSP4 表达机制或直接抑制 DUSP4 活性来改善老年人的 T 细胞反应。设计了三个具体目标来检验这一假设。在目标 1 中，我们将描述 DUSP4 介导的反馈环路对 CD4 记忆 T 细胞中核 ERK 和 JNK 活性动力学的影响。第二步，我们将确定与年龄相关的核 MAPK 活性减弱对于 T 细胞来说是否是普遍的，或者是否仅限于选定的 T 细胞亚群，具体取决于它们的分化和复制历史。在目标 2 中，我们将探索老年人 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年龄而变化。特别令人感兴趣的是这样的假设：随着年龄的增长，AMPK 激活的增加会改变 TCR 诱导的信号级联，从而有利于 DUSP4 转录。在目标 3 中，我们将检查 DUSP4 表达增加的功能后果，并探索如何靶向 DUSP4 来恢复效应细胞功能。