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.

项目摘要 /摘要老年人因感染而增加了发病率和死亡率。疫苗接种持有具有成本效益的干预；但是，老年人的疫苗反应通常很差，最多可以改善疾病。因此，免疫衰老研究的主要目标是确定适应性免疫的缺陷损害免疫记忆产生并可以成功针对的反应。后疫苗接种或感染，抗原特异性T细胞遵循典型的事件序列。首先，他们成倍地扩展并分化为效应细胞，包括控制B细胞激活的卵泡辅助细胞以及抗体的产生。这些效应细胞中的大多数都经历了凋亡，但小子集构成了分化为长寿命的存储单元的内存T细胞前体。我们提供了效应T细胞生存降低的证据导致记忆细胞中的记忆细胞产生有缺陷个人。我们已经表明，CD39识别无法区分长寿命的效应子CD4 T细胞记忆T细胞和CD39+ CD4 T细胞的产生在较老的免疫反应中增加个人。 CD39不仅是替代标记，而且通过其通过其积极促进效应细胞凋亡 ATP/DASE活性，将嘌呤能信号传导在调节T细胞记忆产生中。在这里，我们建议确定干扰CD39表达或靶向嘌呤能信号以改善t的产生的手段记忆单元。 AIM 1将定义在CD4子集中诱导CD39表达的基因调节网络激活后T细胞，并将确定老年人中CD39表达增加的分子基础。 AIM 2将检查是否可以针对嘌呤能信号传导来提高活化的CD4 T细胞的存活。虽然目标1和2涉及体外实验，但AIM 3将检查CD39表达和嘌呤能的作用在水痘带状疱疹疫苗接种后的个体中，对记忆T细胞产生的记忆T细胞产生。