Transitional dendritic cells: identifying the origin and role of a novel innate immune population during viral infection

移行树突状细胞：确定病毒感染过程中新型先天免疫群体的起源和作用

• 批准号: 10185957
• 负责人: Juliana Idoyaga
• 金额: $ 57.7万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-12 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10185957
• 关键词: Antigen Presentation; Antigen-Presenting Cells; Antigens; Antiviral Agents; Antiviral Response; Biological; Biological Assay; Cell Differentiation process; Cell physiology; Cells; Characteristics; Data; Dendritic Cells; Dependence; Development; Future; Genetic; Genetic Transcription; Goals; Homologous Gene; Human; Immune; Immune response; In Vitro; Infection; Innate Immune Response; Interferon Type I; Interferons; Lymphoid; Maintenance; Mediating; Modeling; Mus; Myelogenous; Names; Outcome; Pathway interactions; Phenotype; Play; Population; Process; Production; Proteomics; Research; Resolution; Role; Site; System; T cell factor 4; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; United States; Virus; Virus Diseases; adaptive immune response; base; burden of illness; cell type; design; experimental study; high dimensionality; immune function; in vivo; innate immune function; mouse model; novel; novel strategies; progenitor; response; sensor; therapeutic development; transcription factor; transcriptomics; vaccination strategy

ABSTRACT Plasmacytoid dendritic cells (pDCs) are a unique subset of innate immune cells capable of multiple functions essential for antiviral responses, including type I interferon production, antigen-presentation and T cell activation. The mechanisms that govern these distinct pDC functions remain poorly defined; however, they could be mediated by distinct subpopulations. Using high-dimensional single-cell proteomic and transcriptomic approaches, we and others recently discovered a novel human dendritic cell (DC) population that is captured within traditional pDC definitions. These cells harbor phenotypic features of both pDCs and conventional DC subsets (cDCs); thus, we called them transitional DCs or tDCs. We have now performed an integrated multidimensional comparison that resulted in the identification of the mouse homolog of human tDCs. The discovery that tDCs occur in both human and mouse suggests they have an evolutionarily conserved role during immune responses. However, tDC function has never been investigated. Similarly, the developmental origin of tDCs has not yet been analyzed. This represents a fundamental gap in our understanding of the cellular components that mediate innate immune responses against viruses and poses an impediment to the development of therapeutics. Based on our preliminary data generated in mouse, we hypothesize that tDCs and pDCs form a distinct developmental lineage that cooperates at the site of viral infection to modulate immune responses. In three specific aims, we propose to query tDC origin, function and relationship with pDCs. To achieve these aims, we will take advantage of high-dimensional approaches already established in our lab, in vitro and in vivo differentiation assays, and novel lineage tracing and cell-specific depletion mouse models. We anticipate that findings from this proposal will enhance our current understanding of innate cellular pathways that result in the positive outcome of viral infection. Importantly, our integrated approach will incorporate analyses of both mouse and human tDCs; thus, it has the potential to reveal features of the innate immune compartment that are conserved between species. This proposal has the potential to impact the rational design of future therapeutic strategies.

抽象的 静脉细胞树突状细胞（PDC）是能够多种功能的先天免疫细胞的独特子集 对于抗病毒反应所必需的，包括I型干扰素产生，抗原呈递和T细胞激活。 控制这些独特的PDC功能的机制仍然很差。但是，他们可能是 由不同的亚群介导。使用高维单细胞蛋白质组学和转录组学 方法是，我们和其他人最近发现了一个新型的人类树突细胞（DC）种群 在传统的PDC定义中。这些细胞具有PDC和常规DC的表型特征 子集（CDC）;因此，我们称它们为过渡DCS或TDC。我们现在已经进行了集成 多维比较导致鉴定人类TDC的小鼠同源物。这 发现TDC出现在人和小鼠中的发现表明它们在 免疫反应。但是，从未研究过TDC功能。同样， 尚未分析TDC。这代表了我们对细胞的理解的根本差距 介导对病毒的先天免疫反应并构成障碍的成分 治疗学的发展。基于我们在鼠标中生成的初步数据，我们假设TDC和 PDC形成了一个独特的发育谱系，该谱系在病毒感染部位合作以调节免疫 回答。在三个特定目标中，我们建议查询TDC来源，功能以及与PDC的关系。到 实现这些目标，我们将利用我们实验室中已经建立的高维度 体外和体内分化测定法，以及新型的谱系追踪和细胞特异性耗尽小鼠模型。我们 预计该提案的发现将增强我们当前对先天蜂窝路径的理解 导致病毒感染的阳性结果。重要的是，我们的集成方法将结合 小鼠和人类TDC；因此，它有可能揭示先天免疫室的特征 物种之间的保守。该建议有可能影响未来的理性设计 治疗策略。