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：
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
项目类别：
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

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

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项目摘要

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）感染的特征在于巨大的效应子/记忆T细胞反应，这些反应保持在高水平的生命水平上 - 一种称为记忆膨胀的现象。我们已经报道说，“通货膨胀记忆”细胞实际上是短暂的生命效应细胞与感染早期产生的真实记忆细胞不断区分的细胞。真实的记忆细胞不容易从感染宿主的脾脏转移到受感染的受体，我们建议它们驻留在基质的小众中。我们还表明，一个单个循环CMV无法在首先进入人体时传播到其感染的细胞之外的单个循环CMV，使记忆膨胀出人意料。这两个发现定义了我们寻求在该项目中揭示的悖论：如何占据抗原以保持免疫系统的不断激活而不会受到免疫消除而不断激活的抗原？我们首先询问是否通过直接或交叉呈现病毒抗原传播有关病毒存在的信息。这将通过产生表达KB的病毒来实现，以将抗原呈现限制为直接感染的细胞。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以及对T细胞抗原呈现抗原的细胞。作为另一种方法，我们将生成病毒，该病毒可用于感染CRE小鼠以将抗原表达限制为特定组织或细胞类型。最后，我们将表征受到潜在感染的细胞相对于其免疫学表型，病毒基因表达以及与记忆CD8和CD4 T细胞共同辅助转移后的记忆膨胀的足够。了解驱动记忆通货膨胀的病毒计划将使我们能够聪明工程师CMV向量作为疫苗，以产生有效的免疫反应。它还将帮助我们了解CMV在某些慢性疾病中的作用及其与免疫衰老的推定关联。