Cellular Immune Responses to RSV infection in Mice

呼吸道合胞病毒（RSV）是婴儿和幼儿下呼吸道感染的主要原因。小鼠 RSV 感染的特征是由 CD8 细胞毒性 T 淋巴细胞 (CTL) 介导的显着免疫病理学。过去的研究表明，感染或免疫后可以引发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和 RSV 相关疾病产生不同的影响。 CD8 T 细胞反应的克隆型、功能亲和力和其他内在参数的这些差异可能决定了感染后建立的表位层次结构。在剖析小鼠 CD8 T 细胞反应时，我们发现了 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，并且现在已经定义了与成年期相比，RSV 感染小鼠早期肺和肺引流淋巴结中肺迁移树突状细胞群的动态。人们发现这些树突状细胞以年龄依赖性方式诱导 T 细胞反应，并且我们认为新生儿树突状细胞的共刺激分子表达较低是造成这种差异的机制之一。我们最近开发了一种小鼠成年骨髓和胎儿肝脏树突状细胞培养模型，以进一步表征重要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成分，例如疫苗的成分如何。无论它们是可溶性蛋白质还是纳米颗粒上的展示都会影响到引流淋巴结以及在引流淋巴结内的运输。最后，我们证明，持续表达 RSV 抗原的鼠巨细胞病毒载体鼻内疫苗接种可促进组织驻留记忆 CD8 T 细胞，从而防止 RSV 攻击。

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.