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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：
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
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/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

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