The CD8 T cell response to murine cytomegalovirus

CD8 T 细胞对鼠巨细胞病毒的反应

• 批准号: 7540954
• 负责人: Ann B Hill
• 金额: $ 37.77万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 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/7540954
• 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 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

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）是种特异性β疱疹病毒，其在人类中建立终身感染。 大多数哺乳动物这种终身居住在体内引起非常大的CD8和CD4 T细胞应答。 大多数宿主，具有特征性的"效应记忆"（TEM）表型，并倾向于增加 随着年龄的增长，有时在老年人中占主导地位的整个CDST细胞室。两个悖论 这一标志性的回应。首先，大多数CDST细胞识别感染者的能力很差， 细胞，由于CMV基因的功能干扰抗原呈递。这些T细胞 准备好了吗第二，虽然潜伏病毒存在于受感染的宿主中，但几乎没有病毒活性的证据。 驱动免疫反应的抗原从何而来？这些问题将使用 CMV感染的C57BL/6小鼠模型。本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多数CDST细胞应答。为了实现这一目标，A 一套独特的工具正在组装：25个CMV表位之间的免疫优势等级 将测量由来自C57BL/6小鼠的CD8 T细胞识别的细胞因子。突变病毒既没有能力 损害抗原呈递和损害树突状细胞上共刺激分子表达的能力 正在产生细胞，并将使用交叉呈递受损的小鼠模型。有一个 急性和慢性感染之间主要抗原的显著改变。第二个目的 解决了这种转变的原因。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，将被视为这种改变的免疫显性的主要原因。 最后，悖论是，大的、膨胀的T细胞反应是由低于正常水平的病毒活性维持的。 检测阈值将得到解决。将评价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群体， 是由抗原持续刺激引起的吗或者他们代表了一个安静的长寿的群体， 正如已经提出的人类TEM相似的表型？