Cellular Immune Responses to RSV infection in Mice

小鼠对 RSV 感染的细胞免疫反应

基本信息

批准号：
10273005
负责人：
Barney Graham
金额：
$ 65.4万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10273005
关键词：
Adult Affect Antigens Antiviral Agents Avidity Bone Marrow CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Culture Techniques Cell Maturation Cell physiology Cells Characteristics Chemicals Chemistry Child Dendritic Cells Development Disease Epitopes Exposure to Fetal Liver Flow Cytometry Glycoproteins Goals Immune response Immunity Immunization Immunologics Infant Infection Institutes Interleukin-4 Label Life Lower Respiratory Tract Infection Lung Mediating Memory Methods Modeling Murid herpesvirus 1 Mus Neonatal Outcome Pathogenesis Phenotype Population Property Proteins Respiratory Syncytial Virus Infections Respiratory Syncytial Virus Vaccines Respiratory syncytial virus Role Stromal Cells T cell response T-Lymphocyte Tissues Vaccination Vaccines Viral Viral Antigens Virus Virus Diseases age related cytotoxic CD8 T cells defined contribution draining lymph node immunopathology lymph nodes nanoparticle response trafficking vector

项目摘要

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and small children. RSV infection in mice is characterized by significant immunopathology which is mediated by CD8+ cytotoxic T lymphocytes (CTL). Past studies have suggested that CD8+ T cells with different functional properties and characteristics can be elicited following infection or immunization, and may have differential effects on viral clearance and RSV-associated illness. These differences in clonotype, functional avidity, and other intrinsic parameters of the CD8+ T cell response may dictate the epitope hierarchy established following infection. In dissecting the CD8+ T cell responses in mice, we have discovered differences between neonatal and adult CD8+ T cell responses elicited during RSV infection and have now defined the dynamics of lung-migratory dendritic cell populations in the lung and lung-draining lymph nodes of RSV-infected mice during early life as compared to adulthood. These dendritic cells were found to induce T cell responses in an age-dependent manner, and we have implicated lower costimulatory molecule expression by neonatal dendritic cells as one mechanism for this difference. We have recently developed a murine adult bone-marrow and fetal liver dendritic cell culture model to further characterize the phenotype and function of important dendritic cell subset. We continue to collaborate with a group at Leiden Institute of Chemistry to investigate mechanisms of controlling CD8+ T cell recognition using chemical methods. We have now begun to assess how the composition of vaccines, e.g. whether they are soluble protein or displayed on nanoparticles affects trafficking to and within the draining lymph nodes. Finally, we have demonstrated that intranasal vaccination with murine cytomegalovirus vectors that persistently expressing RSV antigens promotes tissue-resident memory CD8+ T cells which protect against RSV challenge.

呼吸道合胞病毒（RSV）是婴儿和小儿童下呼吸道感染的主要原因。小鼠的RSV感染的特征是显着的免疫病理学，由CD8+细胞毒性T淋巴细胞（CTL）介导。过去的研究表明，在感染或免疫后，可以引起具有不同功能特性和特征的CD8+ T细胞，并且可能对病毒清除率和与RSV相关的疾病具有不同的影响。 CD8+ T细胞响应的克隆型，功能亲和力和其他内在参数的这些差异可能决定感染后建立的表位层次结构。在剖析小鼠的CD8+ T细胞反应时，我们发现了在RSV感染期间引起的新生儿和成人CD8+ T细胞反应之间的差异，现在已经确定了与早在RSV感染的小鼠相比，与Adulthood相比，肺和肺淋巴结淋巴结的肺迁移树突状细胞群体的动态。发现这些树突状细胞以年龄依赖性的方式诱导T细胞反应，并且我们暗示了新生儿树突状细胞的较低的共刺激分子表达是这种差异的一种机制。我们最近开发了一种鼠成人骨row和胎儿肝脏树突状细胞培养模型，以进一步表征重要的树突状细胞子群的表型和功能。我们继续与莱顿化学研究所的一个小组合作，以研究使用化学方法控制CD8+ T细胞识别的机制。我们现在已经开始评估疫苗的组成，例如无论它们是可溶性蛋白，还是在纳米颗粒上显示的都会影响流量到排水淋巴结的运输。最后，我们已经证明，持续表达RSV抗原的鼠内鼻内疫苗接种，可促进组织居住的记忆CD8+ T细胞，以防止RSV挑战。