Role of Dendritic Cells in Immunity to Pulmonary Influenza Virus Infections

描述（由申请人提供）：由于流行性和大流行性流感病毒（IAV）的新威胁，开展分析流感病毒感染的协调免疫反应的信息性研究变得越来越重要。适应性免疫细胞在病毒清除和后续感染保护中发挥的重要作用已广为人知，但对先天免疫，特别是树突状细胞（DC）的作用了解甚少。因此，我们的长期目标是确定DC如何调节粘膜免疫反应并控制呼吸道感染的范围和结果。我们的初步结果显示肺内DC对iav特异性CD8 T细胞的一种新的调节。这种调节依赖于细胞间接触，MHC I，病毒抗原和

DESCRIPTION (provided by applicant): Due to the emerging threat of epidemic and pandemic influenza virus (IAV), it is increasingly important to initiate informative studies that dissect the coordinated immune response to influenza virus infections. While much is known about the important role adaptive immune cells play in viral clearance and protection to subsequent infections, much less is understood about innate immunity and in particular, the contributions of dendritic cells (DC). Therefore our long-term goal is to determine how DC regulate mucosal immune responses and control the scope and outcome of respiratory infections. Our preliminary results show a novel regulation of IAV-specific CD8 T cells by DC within the lungs. This regulation is dependent upon cell-to-cell contact, MHC I, viral antigen, and IL-15 transpresentation. Without this interaction the IAV-specific CD8 T cell response is blunted and viral titers are increased leading to lethality. At this time the location of the DC:T cell interactions within the lungs and what additional DC derived factors and mechanisms are required for proper pulmonary CD8 and CD4 T cell responses remain unknown. Further, what role pulmonary DC play in immunity to intranasal IAV vaccines is unknown. Therefore in this proposal we will use our expertise in DC and pulmonary immune responses as well as our mouse model of IAV and other respiratory pathogens to determine how DC regulate pathogen specific T cell responses within the lungs in the following Specific Aims: 1) Determine the pulmonary location and kinetics of DC-T cell interactions and the requirements for individual DC subsets in pulmonary ectopic lymphoid tissue formation and maintenance, 2) Determine the requirements for rDC-mediated rescue of pulmonary IAV-specific T cell responses during IAV infections, 3) Determine the contribution of rDC to the induction and peripheral regulation of immunity to IAV vaccinations as well as during the peripheral regulation of T cell responses to other viral and bacterial respiratory pathogens. The knowledge gained from this study will not only be relevant to our understanding of the important underlying events required for effective immune responses and control of influenza-virus infections but also in the design of strategies to combat epidemic and pandemic influenza and other respiratory virus infections.