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

项目2：项目概要 树突状细胞（DC）是连接先天性识别和针对免疫缺陷病毒的适应性免疫的关键免疫哨兵。 病原体，从而启动T和B细胞应答。DC谱系包括两个主要亚群，I型 产生干扰素的浆细胞样DC（pDC）和抗原呈递的常规或经典DC （cDC）。DC群体的确切亚群组成和功能状态对于每一种都是特异性的。 器官/组织，反映了独特的局部免疫环境。DC函数的相关参数 保护性反应与致病性反应的关系仍然知之甚少。此外，位置和 组织和淋巴器官中DC群体的功能性尚未在整个研究中进行研究。 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，对后者的反应的特点是持续的 I型和III型干扰素的产生以及炎性细胞因子的产生减少。的 当前项目的总体目标是全面表征人类DC组成， 功能，特别是因为它涉及抗病毒疫苗的免疫反应。我们假设， pDC反应（干扰素聚焦vs炎性干扰素聚焦）是抗-CD 4 + T细胞的重要参数。 可能与保护性T细胞和抗体相关和/或预测保护性T细胞和抗体的病毒/抗疫苗免疫应答 应答为了测试这一概念，在目标1中，我们将构建pDC激活的通用参考图，并测试 pDC在接受干扰素治疗的受试者中产生干扰素聚焦和多功能应答的能力 接种流感或COVID-19疫苗。我们进一步指出，DC功能可能由特定的 在同一个人体内的组织环境。为了探索这一点，在目标2中，我们将使用高维 免疫化学以鉴定组织和淋巴细胞中DC亚群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应答分析结合联合收割机。 总的来说，这些研究将产生一个全面的看法，组成，组织多样性和 人体直流室的功能。他们还将提供关于作用和机制的见解， DCs对病毒感染的保护性免疫应答中细胞因子应答的变化。

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.