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

基本信息

批准号：
10559630
负责人：
Juliana Idoyaga
金额：
$ 11.03万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-12 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10559630
关键词：
Antigen Presentation Antigen-Presenting Cells Antiviral Response Biological Biological Assay Cell Differentiation process Cell Maintenance Cell physiology Cells Characteristics Data Dendritic Cells Dependence Development Dimensions Future Genetic Genetic Transcription Goals Homologous Gene Human Immune Immune response In Vitro Infection Innate Immune Response Interferon Type I Lymphoid Mediating Modeling Mus Myelogenous Names Outcome Pathway interactions Phenotype Play Population Process Production Proteomics Research Resolution Role Site System T cell response T-Cell Activation T-Cell Proliferation T-Lymphocyte TCF7L2 gene Testing Therapeutic United States Viral Virus Virus Diseases adaptive immune response burden of illness cell type design experimental study high dimensionality immune function immunoregulation in vivo innate immune function mouse model novel novel strategies progenitor rational design response sensor therapeutic development transcription factor transcriptomics vaccination strategy

项目摘要

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.

抽象的浆细胞样树突状细胞 (pDC) 是具有多种功能的先天免疫细胞的独特子集对于抗病毒反应至关重要，包括 I 型干扰素产生、抗原呈递和 T 细胞激活。控制这些不同 pDC 功能的机制仍然不明确；然而，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我们和其他人最近发现了一种新的人类树突状细胞 (DC) 群体，该群体被捕获在传统的 pDC 定义中。这些细胞具有 pDC 和传统 DC 的表型特征子集（cDC）；因此，我们将它们称为过渡 DC 或 tDC。我们现在已经进行了综合多维比较导致鉴定出人类 tDC 的小鼠同源物。这人类和小鼠身上都存在 tDC 的发现表明，它们在进化过程中具有保守的作用。免疫反应。然而，tDC 功能从未被研究过。同样，发展的起源尚未对 tDC 进行分析。这代表了我们对细胞理解的根本差距介导针对病毒的先天免疫反应并构成障碍的成分治疗学的发展。根据我们在小鼠中生成的初步数据，我们假设 tDC 和 pDC 形成独特的发育谱系，在病毒感染部位协同调节免疫回应。在三个具体目标中，我们建议查询 tDC 的起源、功能以及与 pDC 的关系。到为了实现这些目标，我们将利用我们实验室已经建立的高维方法，体外和体内分化测定，以及新型谱系追踪和细胞特异性耗竭小鼠模型。我们预计该提案的发现将增强我们目前对先天细胞途径的理解导致病毒感染的积极结果。重要的是，我们的综合方法将纳入以下分析：小鼠和人类 tDC；因此，它有可能揭示先天免疫区室的特征物种间保守的。该提案有可能影响未来的合理设计治疗策略。