CD8 T Cell Response to Murine Cytomegalovirus

CD8 T 细胞对鼠巨细胞病毒的反应

• 批准号: 8698704
• 负责人: Ann B Hill
• 金额: $ 38.5万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698704
• 关键词: Adoptive Transfer; Age; Antigen Presentation; Antigen-Presenting Cells; Antigens; Automobile Driving; Biological Assay; Bone Marrow; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Vaccines; Cell Count; Cell Separation; Cells; Chronic; Chronic Disease; Chronic Phase; Clinical Pathology; Competence; Cross Presentation; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; DNA biosynthesis; Dendritic Cells; Detection; Digestion; Disease; Economic Inflation; Effector Cell; Elderly; Engineering; Environment; Funding; Gene Expression; Genomic DNA; Goals; Grant; HIV; Human Virus; Hybridomas; ITGAX gene; Immune; Immune response; Immune system; Individual; Infection; Inflammatory; Knowledge; Life; Location; Longevity; Memory; Murid herpesvirus 1; Mus; Organ; Phenotype; Play; Population; Process; Property; Reporting; Resources; Role; Spleen; T cell response; T-Lymphocyte; Time; Tissues; Transplant Recipients; Vaccines; Vascular Diseases; Viral; Viral Antigens; Viral Genes; Viral Genome; Virus; Work; base; cell type; cytokine; immunosenescence; programs; recombinase; response; vector; vector vaccine

DESCRIPTION (provided by applicant): Cytomegalovirus (CMV) infection is characterized by enormous effector/memory T cell responses that are maintained at high levels for life- a phenomenon known as memory inflation. We have reported that "inflationary memory" cells are in fact short lived effector cells continuously differentiating from true memory cells generated early during infection. The true memory cells are not readily transferred from the spleen of an infected host to an infected recipient, and we suggest that they reside in a stromal niche. We have also shown that a single cycle CMV which is unable to spread beyond the cells it infects upon first entering the body drives surprisingly robust memory inflation. These two findings define the paradox that we seek to unravel in this project: how can a tiny number of infected cells present antigen to keep the immune system constantly activated without being subject to immune eradication? We first ask whether the information about viral presence is transmitted to T cells through direct or cross presentation of viral antigen. This will be accomplished by generating a virus expressing Kb in order to limit antigen presentation to directly infected cells. We will next use an iterative process of organ digestion, cell sorting and bioassays to identify the cells that carry the viral genome and the cells that present antigen to T cells. As an alternative approach, we will generate virus which can be used to infect cre mice to limit antigen expression to particular tissues or cell types. Finally, we will characterize the latently infected cells with respect to their immunological phenotype, their viral gene expression, and their sufficiency for driving memory inflation upon co-adoptive transfer with memory CD8 and CD4 T cells. Understanding the viral program that drives memory inflation will enable us to intelligently engineer CMV-vectors as vaccines to generate potent immune responses. It will also help us to understand CMV's role in certain chronic diseases, and its putative association with immunosenescence.

描述（由申请人提供）：巨细胞病毒（CMV）感染的特征是巨大的效应/记忆T细胞应答，终生维持在高水平-一种称为记忆膨胀的现象。我们已经报道，“膨胀记忆”细胞实际上是短寿命的效应细胞，不断从感染早期产生的真正的记忆细胞分化。真正的记忆细胞不容易从受感染宿主的脾脏转移到受感染的受体，我们认为它们存在于基质龛中。我们还表明，一个单周期的CMV在第一次进入人体时无法传播到它感染的细胞之外，这会驱动令人惊讶的强大记忆膨胀。这两个发现定义了我们在这个项目中试图解开的悖论：少量受感染的细胞如何呈递抗原以保持免疫系统持续激活而不被免疫根除？我们首先要问的是，关于病毒存在的信息是否通过病毒抗原的直接或交叉呈递传递给T细胞。这将通过产生表达Kb的病毒以限制抗原呈递至直接感染的细胞来实现。 接下来，我们将使用器官消化、细胞分选和生物测定的迭代过程来鉴定携带病毒基因组的细胞和将抗原呈递给T细胞的细胞。作为一种替代方法，我们将产生病毒，该病毒可用于感染cre小鼠，以将抗原表达限制在特定组织或细胞类型。最后，我们将描述潜伏感染者的特征， 细胞的免疫表型、病毒基因表达以及在与记忆性CD 8和CD 4 T细胞共过继转移后驱动记忆膨胀的充分性。了解驱动记忆膨胀的病毒程序将使我们能够智能地 工程化CMV载体作为疫苗以产生有效的免疫应答。它也将帮助我们了解CMV在某些慢性疾病中的作用，以及它与免疫衰老的假定联系。