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

摘要 浆细胞样树突状细胞(PDC)是一类独特的具有多种功能的天然免疫细胞 对抗病毒反应至关重要，包括I型干扰素的产生、抗原呈递和T细胞激活。 管理这些不同的PDC功能的机制仍然定义不清；然而，它们可能是 由不同的亚群进行调节。利用高维单细胞蛋白质组学和转录学 方法，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，我们称它们为过渡性DC或TDC。我们现在已经执行了一个集成的 多维比较，结果鉴定出人tdcs的小鼠同源物。这个 发现tDCs在人类和小鼠中都存在，这表明它们在进化过程中具有保守的作用 免疫反应。然而，TDC的功能从未被研究过。同样，人类的发展起源也是如此 还没有对tdcs进行分析。这代表了我们对细胞的理解上的一个根本差距。 介导针对病毒的先天免疫反应的组件，并对 治疗学的发展。基于我们在小鼠身上产生的初步数据，我们假设tdcs和 PDC形成一个独特的发育谱系，在病毒感染部位协同调节免疫。 回应。在三个具体目标中，我们建议查询贸发局的起源、功能以及与贸发局的关系。至 为了实现这些目标，我们将利用我们实验室中已经建立的高维方法， 体外和体内分化分析，以及新的谱系追踪和细胞特异性耗竭小鼠模型。我们 预计这项提案的发现将增强我们目前对先天细胞途径的理解 导致病毒感染的阳性结果。重要的是，我们的综合方法将结合以下分析 小鼠和人类的tdcs；因此，它有可能揭示先天免疫隔间的特征。 在物种之间是保守的。这一提议有可能影响未来的合理设计 治疗策略。

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.