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：
7991866
负责人：
Ann B Hill
金额：
$ 37.02万
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/7991866
关键词：
Acute Acyclovir Address Adoptive Transfer Affinity Age Antigen Presentation Antigens Appearance Attention Blood C57BL/6 Mouse CD28 gene 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 terminally differentiated effector memory (TEM) T cells 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) 是物种特异性 β 疱疹病毒，可在体内建立终生感染。大多数哺乳动物。这种终生居住会在体内激发非常大的 CD8 和 CD4 T 细胞反应。大多数宿主具有特征性的“效应记忆”（TEM）表型，并且倾向于增加数量随着年龄的增长而增加，有时在老年人中占主导地位的整个 CDST 细胞区室。两个悖论这个签名响应的基础。首先，大多数CDST细胞识别感染的能力很差细胞，由于 CMV 基因的功能会干扰抗原呈递。这些T细胞怎么样准备好了吗？其次，虽然受感染宿主体内存在潜伏病毒，但几乎没有病毒活动的证据。驱动反应的抗原从何而来？这些问题将通过 C57BL/6 CMV 感染小鼠模型。该提案的第一个具体目标是检验以下假设：交叉呈递负责引发大部分 CDST 细胞反应。为了实现这一目标，一套独特的工具正在组装中：25 个 CMV 表位之间的免疫优势层次结构将测量来自 C57BL/6 小鼠的 CDS T 细胞所识别的。突变病毒缺乏这两种能力损害抗原呈递和损害树突上共刺激分子表达的能力细胞正在生成，并且将使用交叉呈现受损的小鼠模型。有一个急性和慢性感染之间识别的主要抗原发生显着变化。第二个目标解决这种转变的原因。免疫系统影响不同细胞中病毒活性的能力类型，特别是内皮细胞，将被视为这种免疫优势改变的主要原因。最后，一个悖论是，巨大的、膨胀的 T 细胞反应是由低于病毒活性的病毒活性维持的。检测阈值将得到解决。将评估 CDST 细胞的 TEM 表型。是这些细胞相当于急性感染消退后观察到的短暂 TEM 细胞群，是由抗原不断再刺激引起的吗？或者他们代表的是静止的、长寿的人群，正如已提出的类似表型的人类 TEM？