ADAMs going viral: novel regulators of dendritic cell function during viral infection

树突状细胞（DC）是针对病毒的有效免疫反应的关键启动器。在感染后，DC成熟为有效的抗原呈递细胞，具有启动naïve T细胞和启动适应性免疫反应的能力，但DC也激活先天免疫细胞，如自然杀伤细胞。尽管基因转录和炎症蛋白翻译的重要性已被广泛研究，但许多分子线索，特别是细胞表面分子的翻译后修饰在控制DC功能中的作用基本上是未知的。崩解素和金属蛋白酶（ADAM）家族成员ADAM10和ADAM17在细胞膜相关底物的脱落中起关键作用。这种所谓的外畴脱落导致多种细胞因子和粘附分子的脱落，从而调节许多不同细胞类型的活性、定位和相互作用。然而，ADAM10和ADAM17在DC中的确切功能以及由此产生的免疫仍不清楚。引人注目的是，我的初步数据表明，ADAM10和ADAM17的翻译后脱落是一种新的未被探索的控制DC功能的机制，因为ADAM10-和ADAM17缺陷DC的小鼠的病毒感染导致更强的促炎反应以及更好的抗病毒T细胞反应，控制病毒在体内的复制。因此，我假设ADAM10-和adam17介导的DC上的外结构域脱落作为翻译后的分子开关，控制DC生物学的关键方面，因此，在诱导和调节抗病毒免疫反应中起着至关重要的作用。利用独特的cd11c特异性ADAM10和ADAM17敲除小鼠，结合创新的分泌组和转录组分析，我将确定ADAM10和ADAM17参与DC免疫调节的新底物。此外，利用体内感染模型的最新分析，从分子上定义了ADAM10-和adam17介导的DC上的外结结构域脱落如何参与诱导和调节抗病毒免疫反应。这项研究计划将揭示ADAMs的翻译后修饰作为启动和控制免疫的一个新的关键途径的重要性，因此将开辟一个全新的DC生物学研究领域。从长远来看，这将有助于改进基于dc的治疗方法的发展。

Dendritic cells (DC) are crucial initiators of effective immune responses against viruses. Upon infection, DC mature into potent antigen-presenting cells with the ability to prime naïve T cells and initiate adaptive immune responses, but DC also activate innate immune cells such as natural killer cells. Although the importance of gene transcription and translation of inflammatory proteins has been extensively studied, many molecular cues, in particular, the role of post-translational modification of cell-surface molecules in controlling DC function are essentially unknown. A disintegrin and metalloproteinase (ADAM) family members ADAM10 and ADAM17 play a crucial role in the shedding of cell membrane-associated substrates. This so called ectodomain shedding results in the shedding of a diversity of cytokines and adhesion molecules and thereby regulates the activity, localization and interaction of many different cell types. However, the exact function of ADAM10 and ADAM17 in DC and resulting immunity remain elusive.Strikingly, my preliminary data demonstrate that post-translational shedding by ADAM10 and ADAM17 is a novel unexplored mechanism controlling DC function, as viral infection of mice with ADAM10- and ADAM17-deficient DC led to stronger pro-inflammatory responses as well as superior anti-viral T cell responses controlling viral replication in vivo. Therefore, I hypothesize that ADAM10- and ADAM17-mediated ectodomain shedding on DC acts as a post-translational molecular switch that governs critical aspects of DC biology, and as such, plays a crucial role in the induction and regulation of anti-viral immune responses. Taking advantage of unique CD11c-specific ADAM10 and ADAM17 knockout mice, in combination with innovative secretome and transcriptome analysis, I will identify novel substrates of ADAM10 and ADAM17 that are involved in DC immune regulation. Moreover, using state-of-the-art analysis of in vivo infection models molecularly define how ADAM10- and ADAM17-mediated ectodomain-shedding on DC is involved in the induction and regulation of anti-viral immune responses. This research proposal will uncover the importance of post-translational modification by ADAMs as a novel crucial pathway to initiate and control immunity, and as such will open a completely new field of research in DC biology. In the long term, this will enable the development of improved DC-based therapy approaches.