T Cells and Aging

T 细胞与衰老

基本信息

批准号：
7261907
负责人：
JORG J GORONZY
金额：
$ 29.01万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-08-15 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7261907
关键词：
Address Adoptive Transfer Affect Age Aging Antigen-Presenting Cells Antigens Apoptosis B-Lymphocytes Biological Assay Biological Markers CD28 Antigens CD28 gene CD4 Antigens CD4 Positive T Lymphocytes CD8B1 gene Cell Aging Cell Cycle Kinetics Cell Differentiation process Cell physiology Cells Characteristics Chimera organism Chromosomes, Human, Pair 19 Chronic Clinical Clinical Research Complex Condition Cytomegalovirus DNA Binding Defect Dendritic Cells Dependency Development Elderly Epstein-Barr Virus Infections Flow Cytometry Frequencies Funding Gene Expression Genes Genetic Transcription Granzyme HLA-A2 Antigen HLA-B7 Antigen HLA-B8 Antigen HLA-C Antigens Herpes zoster disease Herpesviridae Heterogeneity Heterogeneous-Nuclear Ribonucleoproteins Human Human Herpesvirus 4 Immune Immune system Immunity Immunocompetence In Vitro Incidence Individual Infection Lead Leukocytes Lymphoproliferative Disorders MHC Class I Genes Memory Modeling Molecular Monitor Morbidity - disease rate Mus Natural Killer Cells Nuclear Extract Numbers Organism Pathway interactions Patients Pattern Peptide/MHC Complex Peptides Peripheral Blood Lymphocyte Phenotype Polymerase Chain Reaction Population Production Proteins Reagent Receptor Gene Regulatory Element Reporter Genes Repression Research Personnel Resistance Risk Role SCID Mice Sampling Signal Transduction Stimulus Stress Syndrome System T memory cell T-Lymphocyte T-Lymphocyte Subsets TNFSF5 gene Telomere Shortening Testing Transcriptional Regulation Vaccination Viral Antigens Virus Virus Diseases age related aged autoreactivity cell age clinically relevant concept cytokine cytotoxicity fitness functional restoration granulocyte immune function immunosenescence in vivo killer immunoglobulin-like receptor monocyte colony stimulating factor novel nucleolin older patient perforin pleiotropism prognostic programs promoter receptor receptor expression receptor function research study response senescence size theories tumor young adult

项目摘要

DESCRIPTION(provided by applicant): Aging of the immune system has significant impact on morbidity and survival. In the elderly, the incidence of severe infection increases and the protective factor of vaccination wanes. In this proposal, we hypothesize that cellular senescence of CD4+ and CD8+ memory T cells contributes to the decline of protective immunity in the aging individual and is in part responsible for the reactivation of chronic viral infections. Memory T cells are under high replicative stress from both antigen-specific and homeostatic proliferation. Progressive telomere shortening, changes in cell cycle kinetics, and resistance to apoptosis-inducing stimuli are all consistent with the model that memory cells undergo cellular senescence. Cellular senescence is associated with changes in gene expression. The most widely appreciated change is the loss of the costimulatory molecule, CD28. However, the senescence program also causes aberrant expression of genes, including the killer immunoglobulin-like receptors (KIRs) and other functionally related genes encoded in the leukocyte receptor complex. Many of these genes encode for inhibitory regulatory molecules that may dampen T-cell responses to antigen and may synergize with the loss of CD28. We hypothesize that immune function in the elderly is compromised by this gain in gene expression. This model is consistent with the evolutionary theory of antagonistic pleiotropy, which implies that genes selected to enhance the fitness of young organisms have unselected deleterious effects in the aging organism. We will test this hypothesis in models of chronic herpes virus infection. In Specific Aim #1, we propose to analyze the age-dependency of the expression of inhibitory KIRs in CMV- and EBV-specific CD8+ T cells. The functional relevance of KIR expression on antigen-specific CD8 + T-cell responses will be tested in vitro and in the in vivo system of the EBV-associated lymphoproliferative disorder in Specific Aim #2. Parallel studies will be performed with antigen-specific CD4+ T cells in Specific Aim #3. In Specific Aim #4, the effect of CD4 + and CD8 + senescent T cells on dendritic cell function will be analyzed to test the hypothesis that gene expression in senescent T cells also has a direct effect on the microenvironment of antigen-presenting cells. The clinical relevance of these hypotheses will be tested in Specific Aim #5. Biomarkers indicative of T cell senescence, including the expression of inhibitory KIRs, will be analyzed for their prognostic value to identify healthy elderly patients who are at risk of herpes zoster reactivation. Finally, in Specific Aim #6, we will examine the transcriptional control of KIR expression to test the hypothesis that expression in senescent T cells is a default to a developmental pathway characteristic of natural killer cells. This proposal takes a novel view on the phenomenon of immunosenescence. Instead of considering immunosenescence as an acquired immune defect, we propose that active immune mechanisms and immune defects act in concert. The promise of this concept is that targeting these active mechanisms can, in part, restore immunocompetence.

描述（由申请人提供）：免疫系统的老化对发病率和生存率有显着影响。在老年人中，严重感染的发生率增加，疫苗接种的保护因素减弱。在此提议中，我们假设 CD4+ 和 CD8+ 记忆 T 细胞的细胞衰老导致衰老个体的保护性免疫力下降，并在一定程度上导致慢性病毒感染的重新激活。记忆 T 细胞面临着来自抗原特异性和稳态增殖的高复制压力。端粒进行性缩短、细胞周期动力学的变化以及对诱导凋亡的刺激的抵抗都与记忆细胞经历细胞衰老的模型一致。细胞衰老与基因表达的变化有关。最广泛认可的变化是共刺激分子 CD28 的丢失。然而，衰老程序也会导致基因的异常表达，包括杀伤性免疫球蛋白样受体（KIR）和白细胞受体复合物中编码的其他功能相关基因。其中许多基因编码抑制性调节分子，这些分子可能会抑制 T 细胞对抗原的反应，并可能与 CD28 的缺失产生协同作用。我们假设老年人的免疫功能因基因表达的增加而受到损害。该模型与拮抗多效性的进化理论相一致，这意味着选择增强年轻生物体适应性的基因会对衰老生物体产生未经选择的有害影响。我们将在慢性疱疹病毒感染模型中检验这一假设。在具体目标#1 中，我们建议分析 CMV 和 EBV 特异性 CD8+ T 细胞中抑制性 KIR 表达的年龄依赖性。 KIR 表达对抗原特异性 CD8 + T 细胞反应的功能相关性将在具体目标 #2 中的 EBV 相关淋巴增殖性疾病的体外和体内系统中进行测试。将在特定目标#3 中使用抗原特异性 CD4+ T 细胞进行平行研究。在具体目标#4中，将分析CD4+和CD8+衰老T细胞对树突状细胞功能的影响，以检验衰老T细胞中的基因表达也对抗原呈递细胞的微环境有直接影响的假设。这些假设的临床相关性将在具体目标#5 中进行测试。将分析指示 T 细胞衰老的生物标志物（包括抑制性 KIR 的表达）的预后价值，以识别有带状疱疹再激活风险的健康老年患者。最后，在具体目标#6中，我们将检查 KIR 表达的转录控制，以检验衰老 T 细胞中的表达是自然杀伤细胞发育途径特征的默认值的假设。该提案对免疫衰老现象提出了新的观点。我们不认为免疫衰老是一种获得性免疫缺陷，而是认为主动免疫机制和免疫缺陷协同作用。这一概念的前景是，针对这些活性机制可以部分恢复免疫能力。