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：项目总结 树突状细胞(DC)是连接先天识别和获得性免疫的关键免疫哨兵。 病原体，从而启动T和B细胞反应。DC谱系包括两个主要的子集，类型I 干扰素产生的浆细胞样树突状细胞和抗原提呈的传统或经典树突状细胞 (疾控中心)。DC种群的确切子集组成和功能状态对于每一个都是特定的 器官/组织，反映独特的局部免疫环境。相关的DC函数的参数 对保护性反应和致病性反应的了解仍然很少。此外，地点和 DC群体在组织和淋巴器官中的功能尚未在整个 人体。在该项目的第一个周期中，我们发现人类pDC对游离病毒的反应不同 和病毒感染的细胞；与前者相比，后者的反应特征是持续的 产生I型和III型干扰素，减少炎性细胞因子的产生。这个 目前项目的总体目标是全面描述人类DC的组成和 功能，特别是与抗病毒疫苗的免疫反应有关的功能。我们假设这种类型的 PDC应答(干扰素和炎性细胞因子为主)是抗 可能与保护性T细胞和抗体相关和/或预测的病毒/抗疫苗免疫反应 回应。为了测试这一概念，在目标1中，我们将构建PDC激活和测试的通用参考地图 受试者体内PDCs启动干扰素聚焦和多功能反应的能力 接种流感疫苗或新冠肺炎。我们进一步假设DC功能可能由特定的 同一个体体内的组织环境。为了探索这一点，在目标2中，我们将使用高维 免疫组织化学鉴定DC亚群在组织和淋巴组织中的位置和细胞相互作用 并将结果与单细胞转录和细胞因子反应分析相结合。 总而言之，这些研究将产生关于成分、组织多样性和 人类DC隔间的功能。他们还将提供对角色和机制的见解 树突状细胞在对病毒感染的保护性免疫反应中的细胞因子反应。