Influence of Age on CD4 T Memory Cells

年龄对 CD4 T 记忆细胞的影响

• 批准号: 9113469
• 负责人: JORG J GORONZY
• 金额: $ 38.04万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9113469
• 关键词: 3' 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; Knockout Mice; MAP Kinase Gene; MAPK8 gene; Mediating; Memory; Methylation; MicroRNAs; Morbidity - disease rate; 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

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)：老化的免疫系统启动适应性免疫反应的能力降低，损害了疫苗接种的效果，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细胞群体的快速扩张和效应器功能的获得。在研究年龄对CD4T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介导的负反馈环，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2-4天达到高峰，通过调控核ERK和JNK活性来影响T细胞的分化。在目前的建议中，我们检验了这样一种假设，即这种反馈环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表达的机制或通过直接抑制DUSP4活性来改善老年人的T细胞反应。已经设计了三个具体的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，我们将根据T细胞的分化和复制历史，确定与年龄相关的核MAPK活性减弱是否在T细胞中普遍存在，或者是否仅限于选定的T细胞亚群。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变化。特别令人感兴趣的假设是，随着年龄的增加，AMPK的激活改变了TCR诱导的信号级联，有利于DUSP4的转录。在目标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来恢复效应细胞功能。