Role of Dendritic Cells in Immunity to Pulmonary Influenza Virus Infections

描述(由申请人提供)：由于流行病和大流行性流感病毒(IAV)的新威胁，启动分析流感病毒感染的协调免疫反应的信息性研究越来越重要。虽然获得性免疫细胞在病毒清除和对后续感染的保护中发挥的重要作用已知很多，但对先天免疫，特别是树突状细胞(DC)的作用了解较少。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。我们的初步结果表明，肺内DC对IAV特异性CD8T细胞具有新的调节作用。这种调节依赖于细胞间的接触、MHC I、病毒抗原和 IL-15转压。如果没有这种相互作用，IAV特异的CD8 T细胞反应就会变钝，病毒滴度会增加，从而导致致命性。目前，肺内DC：T细胞相互作用的位置以及正确的肺CD8和CD4T细胞反应需要哪些额外的DC衍生因子和机制仍不清楚。此外，肺树突状细胞在鼻腔接种IAV疫苗的免疫中所起的作用尚不清楚。因此，在这项提案中，我们将利用我们在DC和肺免疫反应方面的专业知识以及我们的IAV和其他呼吸道病原体的小鼠模型来确定DC如何在以下特定目标中调节肺内病原体特异性T细胞反应：1)确定DC-T细胞相互作用的肺位置和动力学，以及对肺异位淋巴组织形成和维持中单个DC亚群的要求，2)确定在IAV感染期间RDC介导的抢救肺IAV特异性T细胞反应的要求，3)确定RDC在IAV疫苗免疫的诱导和外周调节中的作用，以及在T细胞对其他病毒和细菌呼吸道病原体的外周调节中的作用。从这项研究中获得的知识不仅与我们了解有效免疫反应和控制流感病毒感染所需的重要潜在事件有关，而且也与制定防治流行病和大流行性流感及其他呼吸道病毒感染的战略有关。

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.