Memory T cell development and survival in T cell responses of older individuals

老年人 T 细胞反应中记忆 T 细胞的发育和存活

• 批准号: 9904524
• 负责人: JORG J GORONZY
• 金额: $ 35.17万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904524
• 关键词: ADORA2A gene; Adenosine; Adult; Age; Aging; Antibodies; Antigens; Apoptosis; Apyrase; B-Cell Activation; Binding; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Differentiation process; Cell Survival; Cell physiology; Cells; Chickenpox; Chromatin; Cyclic AMP Receptors; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Disease; Effector Cell; Elderly; Enhancers; Event; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic Transcription; Health; Helper-Inducer T-Lymphocyte; Herpes zoster disease; Human; Immune; Immune response; Immune system; Immunologic Memory; Impairment; In Vitro; Individual; Infection; Infectious Agent; Influenza; Lead; Mediating; Memory; Metabolic Activation; Metabolic stress; Modeling; Molecular; Morbidity - disease rate; Nucleoside Transporter; P2X-receptor; Pathway interactions; Phenotype; Population; Predictive Factor; Promoter Regions; Purinergic P1 Receptors; Receptor Activation; Regulator Genes; Regulatory Pathway; Research; Role; Signal Transduction; Site; Surrogate Markers; T cell differentiation; T cell response; T memory cell; T-Cell Activation; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; TP53 gene; Testing; Time; Transcriptional Activation; Transcriptional Regulation; Vaccination; Vaccines; Variant; adaptive immune response; age related; antigen-specific T cells; base; chronic infection; cost effective; cytokine; demographics; design; effective intervention; effector T cell; experimental study; improved; in vivo; memory process; mortality; prevent; promoter; receptor; response; transcription factor; uptake; vaccine response

PROJECT SUMMARY / ABSTRACT Older individuals have increased morbidity and mortality from infections. Vaccination holds the promise of a cost-effective intervention; however, vaccine responses are generally poor in the elderly and at best ameliorate disease. One major objective of immune aging research therefore is to identify defects in adaptive immune responses that impair the generation of immune memory and that can be successfully targeted. After vaccination or infection, antigen-specific T cells follow a typical sequence of events. First, they exponentially expand and differentiate into effector cells including follicular helper cells that control the activation of B cells and the generation of antibodies. While most of these effector cells undergo apoptosis, a small subset constitutes memory T cell precursors that differentiate into long-lived memory cells. We have provided evidence that reduced survival of effector T cells contributes to defective memory cell generation in older individuals. We have shown that CD39 identifies effector CD4 T cells that cannot differentiate into long-lived memory T cells and that generation of CD39+ CD4 T cells is increased in immune responses of older individuals. CD39 is not only a surrogate marker, but actively contributes to effector cell apoptosis through its ATP/Dase activity, implicating purinergic signaling in regulating T cell memory generation. Here, we propose to identify means to interfere with CD39 expression or to target purinergic signaling to improve generation of T memory cells. Aim 1 will define the gene-regulatory networks that induce CD39 expression in a subset of CD4 T cells after activation and will identify the molecular basis of increased CD39 expression in older individuals. Aim 2 will examine whether purinergic signaling can be targeted to improve survival of activated CD4 T cell. While Aims 1 and 2 involve in vitro experiments, Aim 3 will examine the role of CD39 expression and purinergic signaling on memory T cell generation in vivo in individuals after varicella zoster vaccination.

项目总结/摘要 老年人感染的发病率和死亡率增加。接种疫苗有望 具有成本效益的干预措施;然而，老年人的疫苗反应通常很差，最好的情况是改善 疾病因此，免疫衰老研究的一个主要目标是识别适应性免疫系统中的缺陷。 这些免疫应答损害免疫记忆的产生，并且可以被成功地靶向。后 疫苗接种或感染后，抗原特异性T细胞遵循典型的事件顺序。首先，他们以指数方式 扩增并分化为效应细胞，包括控制B细胞活化的滤泡辅助细胞 和抗体的产生。虽然这些效应细胞中的大多数经历凋亡，但小的亚群 构成记忆T细胞前体，其分化为长寿命记忆细胞。我们提供了 有证据表明，效应T细胞的存活减少有助于老年人记忆细胞的产生缺陷， 个体我们已经表明，CD 39识别不能分化为长寿命T细胞的效应CD 4 T细胞。 在老年人的免疫应答中，记忆T细胞和CD 39 + CD 4 T细胞的产生增加， 个体CD 39不仅是一种替代标志物，而且通过其自身的作用积极促进效应细胞凋亡。 ATP/Dase活性，涉及调节T细胞记忆产生的嘌呤能信号传导。在此，我们建议 鉴定干扰CD 39表达或靶向嘌呤能信号传导以改善T细胞生成方法 记忆细胞目的1将定义诱导CD 4亚群中CD 39表达的基因调控网络。 T细胞活化后，并将确定在老年人中增加的CD 39表达的分子基础。 目的二是探讨是否可以靶向嘌呤能信号通路来提高活化的CD 4 T细胞的存活率。 虽然目标1和2涉及体外实验，但目标3将研究CD 39表达和嘌呤能的作用。 水痘带状疱疹疫苗接种后个体体内记忆T细胞生成的信号传导。