Cellular Immune Responses to RSV infection in Mice

小鼠对 RSV 感染的细胞免疫反应

• 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
• 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

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)是婴幼儿下呼吸道感染的主要原因。小鼠呼吸道合胞病毒感染以CD8+细胞毒性T淋巴细胞(CTL)介导的免疫病理为特征。过去的研究表明，感染或免疫后可以激发出具有不同功能属性和特征的CD8+T细胞，并且可能在病毒清除和RSV相关疾病中具有不同的作用。CD8+T细胞反应的克隆类型、功能亲和力和其他内在参数的这些差异可能决定了感染后建立的表位等级。在解剖小鼠的CD8+T细胞反应时，我们发现了新生儿和成人在RSV感染期间激发的CD8+T细胞反应的差异，并现在确定了与成年期相比，RSV感染小鼠早期生命中肺迁移树突状细胞种群在肺和肺引流淋巴结中的动态。这些树突状细胞被发现以一种年龄依赖的方式诱导T细胞反应，我们推测新生儿树突状细胞低共刺激分子表达是这种差异的机制之一。我们最近建立了一个小鼠成年骨髓和胎肝树突状细胞培养模型，以进一步表征重要的树突状细胞亚群的表型和功能。我们继续与莱顿化学研究所的一个小组合作，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，例如它们是可溶性蛋白质还是显示在纳米颗粒上，对运输到引流淋巴结和在引流淋巴结内的影响。最后，我们已经证明，经鼻接种持续表达RSV抗原的小鼠巨细胞病毒载体可促进组织驻留的记忆CD8+T细胞，以保护其免受RSV攻击。