CD4 T cell control of cytomegalovirus

CD4 T 细胞对巨细胞病毒的控制

基本信息

批准号：
10091391
负责人：
CHRISTOPHER A BENEDICT
金额：
$ 61.51万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-07 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10091391
关键词：
Acute Adult Antiviral Agents Bacterial Artificial Chromosomes CD28 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Compartmentation Cell physiology Cell surface Cells Cellular immunotherapy Cercopithecine Herpesvirus 1 Chronic Clinical Cytolysis Cytomegalovirus Cytomegalovirus Infections Cytomegalovirus Vaccines Data Disease Environment Epitopes Equilibrium Event GZMA gene Gene Expression Profile Granzyme Herpesviridae Homeostasis Human Image Immune Immune System Diseases Immune system Immunity Infection Interleukin-10 Interleukin-2 Life Malignant Neoplasms Mediating Memory Messenger RNA Murid herpesvirus 1 Mus Patients Periodicity Phase Phenotype Population Protein Family Proteins Recombinants Reporter Reporting Resolution Role Salivary Glands Site Specificity T cell response T memory cell T-Lymphocyte T-cell receptor repertoire TNF gene Testing Time Tissues Vaccinated Vaccination Vaccines Viral Virus Virus Diseases Virus Replication Virus Shedding antigen processing autoinflammatory base chronic infection combat memory CD4 T lymphocyte response senescence tool transcriptome transcriptome sequencing transcriptomics vaccine development vaccine immunotherapy

项目摘要

Summary Cytomegalovirus (CMV, a b-herpesvirus) establishes a persistent infection that is endemic in humans and mice. CMV causes acute clinical disease only if immunity is naïve or compromised, exemplifying how coevolution with its host over millennia has resulted in a largely non-pathogenic détente. However, this `percolating' infection imposes a huge footprint on the immune system, especially the T cell memory pool, and growing evidence suggests this may ultimately be detrimental. Mounting a rapid CD4 T cell response correlates with protection from CMV-associated disease and reduced viral shedding. Our lab identified the first mouse CMV (MCMV) epitope-specific CD4 T cells. Of these, one response against the viral M09 protein expands long after systemic viral infection is controlled, and is critical for resolving the persistent-phase of CMV replication. Our new data show these `late-rising' M09 cells are unique with regards to their phenotype, effector function and transcriptome when compared to conventional CD4 T cells that expand early during infection. Additionally, vaccine-induced late-rising CD4 T cells provide potent protection against CMV challenge. Our overarching hypothesis is that distinct immune environments during the acute and persistent phases of CMV infection promote the expansion/differentiation of these late-rising cells that ultimately resolve persistence and promote latency establishment. We will determine why these cells show such delayed expansion, determine whether they use unique mechanisms of cytolysis to kill infected cells and resolve persistence and initiate studies to determine whether similar CD4 T cells exist in CMV infected people. Together this proposal represents a comprehensive plan using unique viral tools and omics-based approaches to elucidate how newly identified late-rising CD4 T cells function to resolve persistent CMV replication, a question that has remained largely unaddressed to date.

概括巨细胞病毒（CMV，A B- HERPESVIRUS）建立了一种持续的感染，该感染在人类和小鼠中是内在的。 CMV仅在免疫学是幼稚或妥协的情况下才会引起急性临床疾病，这表明如何与它的几千年中的宿主在很大程度上导致了非病原性détente。但是，这种“渗透”感染在免疫系统，尤其是T细胞内存库上施加巨大的足迹，并越来越多的证据建议最终可以确定这一点。安装快速CD4 T细胞响应与保护相关来自CMV相关的疾病和病毒脱落的降低。我们的实验室确定了第一个鼠标CMV（MCMV）表位特异性CD4 T细胞。其中，针对病毒M09蛋白的一种反应在全身后很长一段时间扩展病毒感染受到控制，对于解决CMV复制的持续性阶段至关重要。我们的新数据在其表型，效应子功能和转录组方面，显示这些“后期升高” M09细胞是独一无二的与传统的CD4 T细胞相比，这些细胞在感染期间早期扩展。另外，疫苗引起的晚期升高的CD4 T细胞为CMV挑战提供了潜在的保护。我们的总体假设是在CMV感染的急性和持续阶段，不同的免疫环境促进了这些后期升高的细胞的扩展/分化最终解决持久性并促进潜伏期建立。我们将确定为什么这些细胞显示出如此延迟的扩展，确定它们是否使用杀死感染细胞并解决持久性并启动研究以确定的细胞解析的独特机制 CMV感染的人是否存在类似的CD4 T细胞。该提议共同代表了一个全面的计划使用独特的病毒工具和基于OMICS的方法来阐明新近识别的晚期CD4 T的方式细胞的功能可以解决持续的CMV复制，这个问题在很大程度上尚未得到解决。