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: 9331942
• 负责人: JORG J GORONZY
• 金额: $ 36.07万
• 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/9331942
• 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; Chronic; Cyclic AMP Receptors; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Development; 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; Purinergic P1 Receptors; Receptor Activation; Regulator Genes; Regulatory Pathway; Research; Role; Signal Transduction; Site; Surrogate Markers; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; TP53 gene; Testing; Time; Transcriptional Activation; Transcriptional Regulation; Vaccination; Vaccines; Variant; adaptive immune response; age related; base; cost effective; cytokine; demographics; design; effective intervention; 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.

项目摘要/摘要 老年人感染的发病率和死亡率都有所增加。疫苗接种有望成为 具有成本效益的干预措施；然而，老年人的疫苗反应普遍较差，充其量只能得到改善 疾病。因此，免疫老化研究的一个主要目标是识别适应性免疫中的缺陷。 损害免疫记忆生成的反应，并且可以成功地被靶向。之后 无论是接种疫苗还是感染，抗原特异性T细胞都遵循一个典型的事件序列。首先，它们呈指数级增长 扩增并分化为效应细胞，包括控制B细胞激活的滤泡辅助细胞 以及抗体的产生。虽然这些效应细胞中的大多数都经历了凋亡，但有一小部分 构成可分化为长寿记忆细胞的记忆T细胞前体。我们已经提供了 有证据表明，效应T细胞存活率降低会导致老年人记忆细胞生成缺陷 个人。我们已经证明，CD39识别不能分化为长期存活的效应CD4T细胞 老年人免疫反应中记忆T细胞和CD39+CD4T细胞生成增加 个人。CD39不仅是一种替代标记物，而且通过其自身的功能参与效应细胞的凋亡。 ATP/Dase活性，暗示嘌呤能信号调节T细胞记忆的产生。在此，我们建议 识别干扰CD39表达或靶向嘌呤能信号以促进T细胞生成的方法 存储单元。AIM 1将定义诱导CD39表达的基因调控网络 T细胞被激活后，将确定CD39在老年人中表达增加的分子基础。 目的2将研究是否可以针对嘌呤能信号来提高活化的CD4T细胞的存活率。 虽然目标1和目标2涉及体外实验，但目标3将检查CD39表达和嘌呤能 水痘带状疱疹疫苗接种后体内记忆T细胞生成的信号转导。