Modulation of Viral Antigen Presentation in the Lung

研究项目1 项目1将阐明人类肺部的抗原呈递细胞（APC）网络如何调节免疫 呼吸道病毒。目的是解释微生物组驱动的肺部炎症或炎症是如何发生的， 与肿瘤过程有关的疾病会影响这种反应。项目1的科学前提是， 确定免疫细胞对呼吸道病毒原位应答的基础途径是确定 设计和开发改进疫苗的目标和战略。我们的总体假设是 环境定义免疫状态，即，“免疫设定点”和组织驻留功能 树突状细胞（DC）。我们进一步证实，免疫设定点影响抗原的命运和质量， 随后的粘膜T细胞免疫的大小。这一假设暗示了当地微生物组的作用， 我们预测通过与免疫细胞的直接和间接串扰对直接环境有贡献， 随之而来的炎症反应。我们提出了三个目标：目标1将测试的假设，稳态细胞 人肺组织中的分子网络调节对呼吸道病毒的早期反应。我们将定义 人肺组织在一系列临床情况下的组成和功能状态：正常肺， 未累及的癌症患者肺和癌症累及的肺组织。上游相关分析 微生物组等环境监管机构将确定控制数量和质量的途径， 获得性免疫的能力目的2将检验抗病毒T细胞免疫力的产生是由细胞免疫力的调节引起的这一假设。 通过肺上皮细胞（EC）-DC串扰调节，并且这种串扰通过肺上皮细胞（EC）-DC串扰进一步调节。 细菌我们将确定暴露于病毒感染的肺泡上皮细胞（AEC）的肺DCs 调节T细胞的分化;建立肺内皮细胞触发DC的分子程序 这可以解释T细胞的表型;我们将确定如何从口腔和上部培养细菌 呼吸道影响肺EC和下游反应。目标3将检验肺 微环境调节肺内APC的交叉呈递能力，从而决定了肺内APC的命运。 病毒抗原特异性CD 8 + T细胞。我们将评估病毒分布和交叉呈现的背景下， 通过表达病毒抗性基因Rab 15定义的抗性和易感细胞;以及 调理病毒在肺骨髓细胞中交叉呈递区室。因此，本项目将阐明 先天免疫网络，决定呼吸道疾病期间适应性免疫应答的总体结果， 病毒感染沿着其他项目，我们提出的研究具有很高的潜力，发现新的目标 这些分子最终将帮助我们设计出更好的呼吸道感染疗法和疫苗。 最后，本文提出的工作将指导3D打印肺组织的开发和验证， 使基因实验和未来可能的人体组织免疫研究成为可能。

PROJECT SUMMARY RESEARCH PROJECT 1 Project 1 will elucidate how the networks of antigen presenting cells (APCs) in the human lung regulate immunity to respiratory viruses. The goal is to also explain how microbiome-driven lung inflammation or inflammation that is linked with neoplastic processes affects such responses. Project 1 is founded on the scientific premise that identifying the pathways underpinning immune cell responses to respiratory viruses in situ is key to identifying targets and strategies for designing and developing improved vaccines. Our overall hypothesis is that the lung environment defines immunological status, i.e., the “immune set-point”, and the function of tissue-resident dendritic cells (DCs). We further posit that the immune set-point impacts the fate of antigen and the quality and magnitude of ensuing mucosal T-cell immunity. Implicit in this hypothesis is a role for the local microbiome, which we predict contributes to the immediate environment by direct and indirect crosstalk with immune cells and ensuing inflammatory responses. We propose three aims: Aim 1 will test the hypothesis that steady state cellular and molecular networks in human lung tissue regulate the early response to respiratory viruses. We will define the composition and functional status of human lung tissue across a range of clinical situations: normal lung, uninvolved cancer patient lung and cancer-involved lung tissue. Correlative analyses with upstream environmental regulators such as the microbiome will identify pathways that control the magnitude and quality of ensuing adaptive immunity. Aim 2 will test the hypothesis that the generation of anti-viral T-cell immunity is modulated by lung epithelial cell (EC)-DC crosstalk and that this crosstalk is further modulated by commensal bacteria. We will determine how lung DCs exposed to virally-infected lung alveolar epithelial cells (AECs) modulate the differentiation of T cells; we will establish the molecular programs in DCs triggered by lung ECs that can explain T-cell phenotypes; and we will determine how the bacteria cultured from the mouth and upper respiratory tract impacts lung ECs and downstream responses. Aim 3 will test the hypothesis that the lung microenvironment modulates the cross-presentation capacity of lung-resident APCs thereby dictating the fate of viral antigen-specific CD8+ T cells. We will assess viral distribution and cross-presentation in the context of resistant and susceptible cells defined by expression of a viral resistance gene, Rab15; and the access of opsonized virus to cross-presenting compartments in lung myeloid cells. Thus, this project will elucidate the key innate immune networks that determine the overall outcome of adaptive immune responses during respiratory viral infections. Along with other Projects, our proposed research has a high potential to discover novel target molecules that will eventually help us design improved therapeutics and vaccines for respiratory infections. Finally, the work proposed here will guide development and validation of 3D printed lung tissues, which will enable genetic experiments and possibly future studies on human tissue immunity.