Tissue distribution and antiviral response of primary human dendritic cells

树突状细胞（Dendritic cells，DC）是位于先天性免疫系统和适应性免疫系统界面的免疫细胞，作为哨兵发挥作用。它们是最有效的抗原呈递细胞，可启动幼稚T细胞。此外，它们可以通过第二信使引发各种其他反应。例如，它们可以在感染细胞周围的细胞中诱导抗病毒状态或召唤先天免疫系统的细胞。因此，它们处于多种免疫系统功能的起点，在对抗感染和癌症方面发挥着重要作用。免疫系统的持续工作反映在其与巨细胞病毒（CMV）的相互作用中。到成年时，CMV已经感染了一半以上的人口。在初次感染后，CMV以潜伏状态留在体内，伴随病毒复制的反复爆发。因此，CMV不断地挑战免疫系统，并且在免疫功能低下的个体中，例如胎儿和肾移植后的患者，CMV可以胜过免疫监视并导致严重的损伤甚至死亡。关于健康人体组织中DC的信息有限。Reizis实验室与合作伙伴一起，已经开始加深对健康状态下组织DC的了解，因为他们能够分析来自研究同意的人体器官供体的不同人体组织，使用未进入移植的组织（Granot等人。2017）。我在Reizis实验室的项目的总体目标是描述多样性，组织特异性和功能性的DC群体在全身规模，特别强调他们对CMV的反应。我们计划将联合收割机从健康个体（CMV阳性和阴性）的组织中分离的DC群体的独特来源与高维分析工具和功能测定相结合。为此，我们提出了两个子项目：在第一个，我们将分析DC亚型跨组织。在质谱细胞仪的帮助下，我们将评估各种表面活化标记物和信号分子，并考虑CMV组织潜伏期的影响。此外，我们将使用CODEX，一种新的荧光成像技术描述DC的微环境和组织生态位。在第二个子项目中，我们将测量从CMV血清阳性和CMV血清阴性个体的不同组织中分离的DC对细胞培养中的CMV和CMV感染的细胞的反应，通过这些实验，我们希望了解不同DC亚群的组织特异性特征以及它们如何与潜伏的CMV感染相互作用。在未来，这些结果可能会在疫苗策略和新的治疗方案中发挥作用。

Dendritic cells (DCs) are immune cells at the interface of the innate and adaptive immune system working as sentries. They are the most potent antigen-presenting cells priming naïve T cells. Moreover, they can trigger a variety of other reactions via second messengers. For example, they can induce an antiviral state in cells surrounding infected cells or summon cells of the innate immune system. Thus, they are at the starting point of a variety of immune system functions, giving them an important role in the fight against infections and cancer.The constant work of the immune system is mirrored in its interactions with cytomegalovirus (CMV). By adulthood CMV has infected more than half of the population. After the primary infection, CMV stays in the body in a latent state with recurring flares of viral replication. Thus CMV constantly challenges the immune system and in immunocompromised individuals, e.g. fetuses and patients after kidney transplantation, CMV can outwit the immune surveillance and lead to severe injury and even death.Most of our knowledge about DCs stem from studies in mice and from the peripheral blood of humans. Information on DC in the healthy human tissue is limited. The Reizis Lab, together with cooperation partners, has started to deepen the knowledge on tissue DCs in the healthy state, as they were able to analyze different human tissues from research-consented human organ donors, using tissues that were not going into transplant (Granot et al. 2017).The overall goal of my project in the Reizis Lab is to characterize the diversity, tissue specificity and functionality of DC populations on the whole-body scale, with particular emphasis on their response to CMV. We plan to combine the unique source of DC populations isolated from the tissues of healthy individuals (CMV-positive and -negative) with high-dimensional analysis tools and functional assays. To this end, we propose two subprojects: In the first one, we will analyze DC subtypes across tissues. With the help of mass cytometry, we will assess a variety of surface activation markers and signaling molecules, taking the influence of tissue latency of CMV in account. Additionally, we will describe the microenvironment and tissue niche of DCs using CODEX, a new fluorescence imaging technique. In the second subproject, we will measure the response of DCs isolated from different tissues from CMV-seropositive and CMV-seronegative individuals to CMV and CMV-infected cells in cell culture.Through these experiments we hope to understand tissue-specific features of the different DC subsets and how they interact with latent CMV infection. In the future, these results might play role in vaccine strategies and novel treatment options.