Modulation of Viral Antigen Presentation in the Lung

项目总结研究项目1 项目1将阐明人类肺中的抗原提呈细胞(APC)网络如何调节免疫。 呼吸道病毒。其目标也是解释微生物群驱动的肺部炎症或炎症是如何 与肿瘤过程有关会影响这种反应。项目1是建立在科学前提下的 识别免疫细胞对呼吸道病毒的原位反应的途径是识别 设计和开发改进疫苗的目标和战略。我们的总体假设是肺 环境定义了免疫状态，即免疫设定点，以及组织驻留的功能 树突状细胞(DC)。我们进一步假设，免疫设定点影响抗原的命运和质量，并 随之而来的粘膜T细胞免疫的大小。在这一假设中隐含的是当地微生物群的作用，它 我们预测，通过与免疫细胞的直接和间接串扰，我们对周围环境的贡献 随之而来的炎症反应。我们提出了三个目标：目标1将检验稳态细胞的假设 人类肺组织中的分子网络调节着对呼吸道病毒的早期反应。我们将定义 人体肺组织在一系列临床情况下的组成和功能状态：正常肺， 未受累的癌症患者肺和受累于癌症的肺组织。与上游的相关分析 环境调节者，如微生物组，将确定控制数量和质量的途径 随之而来的适应性免疫。目标2将检验抗病毒T细胞免疫的产生是 受肺上皮细胞(EC)-DC串扰的调制，这种串扰进一步受到共生的调制 细菌。我们将确定肺树突状细胞如何暴露于病毒感染的肺泡上皮细胞(AECs) 调节T细胞的分化；我们将在肺内皮细胞触发的DC中建立分子程序 这可以解释T细胞的表型；我们将确定从口腔和上半身培养的细菌是如何 呼吸道影响肺内皮细胞及其下游反应。目标3将检验这样一个假设，即肺 微环境调节肺内APC的交叉呈递能力，从而决定APC的命运 病毒抗原特异性CD8+T细胞。我们将在以下背景下评估病毒分布和交叉演示 由病毒抗性基因Rab15的表达定义的抗性和敏感细胞；以及 调理病毒在肺髓系细胞中的交叉呈递间隔。因此，这个项目将阐明关键 决定呼吸期间适应性免疫反应总体结果的先天免疫网络 病毒感染。与其他项目一样，我们提出的研究具有发现新目标的高潜力 这些分子最终将帮助我们设计针对呼吸道感染的改进疗法和疫苗。 最后，这里提出的工作将指导3D打印肺组织的开发和验证，这将 使基因实验成为可能，并可能在未来对人类组织免疫进行研究。

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.