Cytolytic T Cell Activity In Response To Primary RSV Infection In Mice

呼吸道合胞病毒（RSV）是婴幼儿下呼吸道感染的主要原因。RSV感染小鼠的特征在于由CD8+细胞毒性T淋巴细胞（CTL）介导的显著免疫病理学。过去的研究表明，具有不同功能特性和特征的CD8+ T细胞可以在感染或免疫后被诱导，并且可能对病毒清除和RSV相关疾病具有不同的作用。我们已经描述了新生儿和成人之间的差异引起的RSV感染的CD8+ T细胞反应。CD8+ T细胞应答的克隆型、功能性亲合力和其他内在参数的差异可能有助于决定感染后建立的表位层次。我们现在已经确定了与成年期相比，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体的动态，并确定了感染后诱导RSV特异性适应性T细胞应答的肺树突状细胞群体。 发现这些树突状细胞以年龄依赖性方式诱导T细胞应答，并且我们已经将新生树突状细胞较低的共刺激分子表达作为这种差异的一种机制。 我们去年的工作得到了三种具有RSV特异性CD8+ T细胞的转基因小鼠品系的开发和表征的极大帮助。这项研究的继续工作将充分表征CD8+ T细胞对RSV的反应，阐明决定产生的CD8+ T细胞反应类型的重要因素，并帮助了解其他细胞类型如何以年龄依赖性方式调节CD8+ T细胞反应。

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. We have described differences between neonatal and adult CD8+ T cell responses elicited during RSV infection. Differences in clonotype, functional avidity, and other intrinsic parameters of the CD8+ T cell response may help dictate the epitope hierarchy established following infection. We 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 and have determined lung dendritic cell populations that induce RSV-specific adaptive T cell responses following infection. 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. Our work in the last year has been greatly aided by the development and characterization of three strains of transgenic mice with CD8+ T cells specific for RSV. Continued work on this study will fully characterize CD8+ T responses to RSV, elucidate important factors that dictate the type of CD8+ T cell response that is generated, and help understand how other cell types regulate the CD8+ T cell response in an age-dependent fashion.