The CD8 T cell response to murine cytomegalovirus

CD8 T 细胞对鼠巨细胞病毒的反应

基本信息

批准号：
7738501
负责人：
Ann B Hill
金额：
$ 37.39万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-15 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7738501
关键词：
Acute Acyclovir Address Adoptive Transfer Affinity Age Antigen Presentation Antigens Appearance Attention Blood C57BL/6 Mouse CD4 Positive T Lymphocytes CD80 gene CD8B1 gene Cell surface Cells Characteristics Chronic Chronic Disease Chronic Phase Confounding Factors (Epidemiology)Contracts Cross Presentation Crowding Cytomegalovirus Cytomegalovirus Infections Cytoplasmic Tail Dendritic Cells Dependence Detection Disease Economic Inflation Elderly Employee Strikes Endothelial Cells Epitopes Fetus Funding Genes Goals Health Herpesviridae Human Immune Immune response Immune system Immunity Immunobiology Immunocompetent Individual Infection Latent Virus Lead Life Literature Longevity Lymphocyte Homing Receptors Mammals Maps Measures Memory Modeling Murid herpesvirus 1 Mus Mutant Strains Mice Mutation Obsession PTPRC gene Peripheral Phenotype Population Protein Isoforms Research Personnel Resistance Resolution SELL gene Salivary Glands Simplexvirus Specificity Splenocyte Staging Subgroup System T cell response T memory cell T-Lymphocyte T-Lymphocyte Epitopes TK Gene Testing Time Tissues Vaccination Vascular Diseases Viral Viral Antigens Viral Genes Viral Genome Viral Interference Viral Physiology Virus Virus Diseases Virus Replication Virus Shedding base cell type immunopathology immunosuppressed macrophage member mouse model mutant peripheral blood prevent programs protein expression receptor recombinant virus research study residence response suicide virus tool young adult

项目摘要

Cytomegaloviruses (CMVs) are species specific beta herpesviruses that establish life long infection in the majority of mammals. This lifelong residence is provokes very large CD8 and CD4 T cell responses in the majority of hosts, that have a characteristic "effector memory" (TEM) phenotype and tend to increase in numbers with age, sometimes dominating the entire CDST cell compartment in the elderly. Two paradoxes underlie this signature response. First, the majority of CDST cells have a poor ability to recognize infected cells, due to the function of CMVs genes that interfere with antigen presentation. How are these T cells primed? Second, although latent virus is present in infected hosts, there is little evidence of virus activity. Where does the antigen come from that drives the response? These questions will be addressed using the C57BL/6 mouse model of CMV infection. The first specific aim of this proposal is to test the hypothesis that cross-presentation is responsible for priming that majority of the CDST cell response. To address this aim, a unique set of tools is being assembled: the immunodominance hierarchy amongst 25 CMV epitopes recognized by CDS T cells from C57BL/6 mice will be measured. Mutant viruses lacking both the ability to impair antigen presentation and the ability to impair the expression of co-stimulatory molecules on dendritic cells are being generated, and a mouse model of impaired cross presentation will be used. There is a marked alteration in the main antigens recognized between acute and chronic infection. The second aim addresses the cause of that shift. The ability of the immune system to impact viral activity in different cell types, particularly endothelial cells, will be addressed as a primary cause of this altered immunodominant. Finally, the paradox that the large, inflating T cell response is maintained by viral activity that is below the threshold of detection will be addressed. The TEM phenotype of the CDST cells will be evaluated. Are these cells equivalent to the transitory TEM population observed following resolution of acute infection, resulting from constant restimulation with antigen? Or do they represent a quiescent, long-lived population, as has been proposed for human TEM of a similar phenotype?

巨细胞病毒（CMV）是特定物种的β疱疹病毒，可在大多数哺乳动物。这个终生的住所是在很大的CD8和CD4 T细胞反应中引起的大多数主机，具有特征性的“效应器记忆”（TEM）表型，并且倾向于增加随着年龄的增长，有时会在老年人中占主导地位。两个悖论这是这种签名响应的基础。首先，大多数CDST细胞识别感染的能力较差细胞，由于CMVS基因的功能，干扰了抗原表现。这些T细胞如何底漆？其次，尽管受感染宿主存在潜在病毒，但几乎没有病毒活性的证据。抗原来自哪里可以推动反应？这些问题将使用 C57BL/6 CMV感染的小鼠模型。该提议的第一个具体目的是检验以下假设。交叉呈递负责启动大多数CDST细胞反应。为了解决这个目标，组装了独特的工具集：25 cmv表位之间的免疫力层次结构将测量来自C57BL/6小鼠的CDS T细胞识别。突变病毒既缺乏能力损害抗原表现及其在树突状上损害共刺激分子表达的能力正在生成细胞，并将使用跨表现受损的小鼠模型。有一个急性和慢性感染之间识别的主要抗原的明显改变。第二个目标解决了这种转变的原因。免疫系统影响不同细胞病毒活性的能力类型，尤其是内皮细胞，将作为这种改变的免疫主导作用的主要原因。最后，大型膨胀T细胞反应的悖论是由病毒活性维持的，该病毒活性低于检测阈值将被解决。将评估CDST细胞的TEM表型。是这些细胞等于急性感染后观察到的暂时性TEM种群由抗原持续重新刺激而产生？还是它们代表静止，长寿的人口，正如针对类似表型的人类TEM提出的那样？