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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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要老年人感染的发病率和死亡率增加。疫苗接种有望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，最多只能改善疾病。因此，免疫衰老研究的一个主要目标是识别适应性免疫的缺陷损害免疫记忆生成并且可以成功靶向的反应。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，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和抗体的产生。虽然大多数效应细胞会发生凋亡，但一小部分细胞会发生凋亡构成记忆 T 细胞前体，可分化为长寿命记忆细胞。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产生缺陷个人。我们已经证明 CD39 可以识别不能分化为长寿命的效应 CD4 T 细胞记忆 T 细胞和 CD39+ CD4 T 细胞的产生在老年人的免疫反应中增加个人。 CD39 不仅是一种替代标记物，而且还通过其自身作用积极促进效应细胞凋亡 ATP/Dase 活性，表明嘌呤能信号传导调节 T 细胞记忆生成。在此，我们建议确定干扰 CD39 表达或靶向嘌呤能信号传导以改善 T 生成的方法记忆细胞。目标 1 将定义在 CD4 子集中诱导 CD39 表达的基因调控网络 T 细胞激活后将识别老年人 CD39 表达增加的分子基础。目标 2 将检查嘌呤能信号传导是否可以靶向提高活化 CD4 T 细胞的存活率。目标 1 和 2 涉及体外实验，目标 3 将检查 CD39 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。