Human dendritic cell localization and anti-viral function in tissue sites

人树突状细胞在组织部位的定位和抗病毒功能

• 批准号: 10419871
• 负责人: Boris Reizis
• 金额: $ 29.29万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419871
• 关键词: Anatomy; Animal Model; Antibody Response; Antigen Presentation; Antigens; B-Lymphocytes; Blood; Blood Circulation; COVID-19; Cell Compartmentation; Cell Count; Cell Lineage; Cell physiology; Cell surface; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Complement; Cross Presentation; Cytomegalovirus; Dendritic Cells; Elements; Environment; Flow Cytometry; Goals; Human; Human body; Immune; Immune response; Immunochemistry; Immunosuppressive Agents; Individual; Infection; Inflammation; Inflammatory; Influenza vaccination; Interferon Type I; Interferons; Link; Location; Maps; Organ; Organ Donor; Outcome; Pathogenicity; Patients; Phenotype; Population; Production; Resources; Role; Sampling; Sentinel; Shapes; Site; Spatial Distribution; T-Lymphocyte; TNF gene; Technology; Testing; Time; Tissue atlas; Tissues; Vaccination; Vaccines; Viral; Viral Physiology; Virus; Virus Diseases; adaptive immune response; adaptive immunity; cell type; cohort; cytokine; high dimensionality; human tissue; influenza infection; insight; lymphoid organ; monocyte; multiple sclerosis patient; pathogen; programs; response; single-cell RNA sequencing; transcriptomics; vaccine immunogenicity

PROJECT 2: PROJECT SUMMARY Dendritic cells (DCs) are key immune sentinels that link innate recognition to adaptive immunity against pathogens, thereby initiating T and B cell responses. The DC lineage comprises two major subsets, type I interferon-producing plasmacytoid DCs (pDCs) and antigen-presenting conventional or classical DCs (cDCs). The exact subset composition and functional state of DC populations is specific for each organ/tissue, reflecting unique local immune environments. The parameters of DC function that correlate with protective versus pathogenic responses are still poorly understood. Furthermore, the location and functionality of DC populations in tissues and lymphoid organs has not been interrogated within the entire human body. In the first cycle of the project, we found that human pDCs respond differently to free viruses and virus-infected cells; compared to the former, the response to the latter is characterized by sustained production of type I and type III interferons and diminished production of inflammatory cytokines. The overall goal of the current project is a comprehensive characterization of human DC composition and function, specifically as it relates to immune responses to antiviral vaccines. We hypothesize that the type of pDC response (interferon-focused vs inflammatory cytokine-focused) is an important parameter of anti- viral/anti-vaccine immune responses that may correlate with and/or predict protective T cell and antibody responses. To test this notion, in Aim 1 we will build a universal reference map of pDC activation and test the ability of pDCs to mount interferon-focused and polyfunctional responses in subjects undergoing vaccination against influenza or COVID-19. We further posit that DC functionality may be shaped by specific tissue environments within the same individual. To explore this, in Aim 2 we will use high-dimensional immunochemistry to identify the location and cellular interactions of DC subsets in tissues and lymphoid organs, and combine the results with single-cell transcriptomics and the analysis of cytokine responses. Collectively, these studies would yield a comprehensive view of the composition, tissue diversity and functionality of the human DC compartment. They would also provide insights into the role and mechanism of cytokine responses by DCs in protective immune responses to virus infections.

项目2：项目摘要 树突状细胞（DC）是关键的免疫哨兵，将天生识别与适应性免疫联系起来 病原体，从而启动T和B细胞反应。直流谱系包括两个主要子集，I型 产生干扰素的浆细胞类动物DC（PDC）和抗原呈递的常规或经典DC （CDC）。 DC种群的确切子集组成和功能状态是特定于每个的 器官/组织，反映独特的局部免疫环境。 DC函数的参数相关 保护性和致病反应仍然很少了解。此外，位置和 在整个组织和淋巴机构中DC种群的功能尚未在整个中审问 人体。在项目的第一个周期中，我们发现人PDC对自由病毒的反应不同 和病毒感染的细胞；与前者相比，对后者的响应的特征是持续 I型和III型干扰素的产生以及炎症细胞因子的产生减少。这 当前项目的总体目标是人类DC组成和 功能，特别是与抗病毒疫苗的免疫反应有关。我们假设 PDC反应（以干扰素为中心的炎症性细胞因子针对性）是抗 - 的重要参数 病毒/抗疫苗的免疫反应可能与和/或预测保护性T细胞和抗体相关 回答。为了测试这个概念，在AIM 1中，我们将构建PDC激活的通用参考图和测试 PDC在受试者中安装以干扰素为中心和多功能反应的能力 针对流感或Covid-19的疫苗接种。我们进一步认为，直流功能可能会由特定塑造 同一个人内的组织环境。为了探索这一点，在AIM 2中，我们将使用高维度 免疫化学以识别直流子集在组织和淋巴样中的位置和细胞相互作用 器官，并将结果与​​单细胞转录组学和细胞因子反应的分析相结合。 总的来说，这些研究将对组成，组织多样性和 人类直流室的功能。他们还将提供有关角色和机制的见解 DC在病毒感染的保护性免疫反应中的细胞因子反应。