Type III interferon-mediated effector functions of adaptive NK cells involved in control of HCMV infection

III型干扰素介导的适应性NK细胞的效应功能参与控制HCMV感染

• 批准号: 514891263
• 负责人: Professor Dr. Markus G. Uhrberg
• 金额: --
• 依托单位: Institut für Transplantationsdiagnostik und Zelltherapeutika (ITZ)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/514891263?language=en
• 关键词: Type; III; interferon; mediated; effector

Natural killer (NK) cells are part of the first line of defense against acute viral infections. Recently, a novel type of virus-specific NK cell was identified that expands during acute cytomegalovirus (CMV) infection and efficiently mediates antibody-dependent cellular cytotoxicity (ADCC). In contrast to conventional NK cells, adaptive NK cells can persist for many years and thus have the potential to contribute to long-term protection against reinfection or reactivation from latency. A hallmark of these adaptive (also known as memory) NK cells is the expression of the stimulatory receptor NKG2C, which binds to human leucocyte antigen E (HLA-E). Besides the well-defined HLA-E/NKG2C axis, it is presently unclear which other factors control the activation of adaptive NK cells during viral infections. In this regard, we have acquired preliminary data showing that adaptive NK cells are uniquely responsive to type III interferons, i.e. IFN lambda (IFNl) 1-4 due to specific up-regulation of the IFNl receptor (IFNlR). Lambda IFNs are a more recently described class of IFNs with homology to the classic type I IFNs (IFNalpha/beta) but with a more focused mode of action, including front-line immune responses against virus-infected epithelial cells. The responsiveness of adaptive NK cells to IFNl is particularly relevant given the well-described low sensitivity of adaptive NK cells to other key cytokines acting on conventional NK cells, such as IL-12 and IL-18. The results of additional transcriptomic analyses suggest that exposure to IFNl initiates a highly specific virus defense program in adaptive NK cells. In the present project, we would like to thoroughly characterize how type III interferons modulate the effector functions of adaptive NK cells. We would like to understand how IFNl-mediated stimulation synergizes with coactivation via the HLA-E/NKG2C axis and will use transporter associated with antigen processing (TAP)-deficient HLA-E transfectants enabling fine-tuning of HLA-E surface expression by loading defined peptides. Second, we will use transcriptomic, proteomic, and epigenetic analyses to characterize the changes in global expression programs in IFNl-treated primary adaptive NK cells. Third, we plan to analyze how IFNl modulates the function of adaptive NK cells in an in vitro infection model based on coculture of NK cells with human cytomegalovirus (HCMV)-infected mesenchymal stem cells. Finally, we will assess the clinical relevance of IFNl-mediated stimulation of adaptive NK cells by analyzing leukemia patients experiencing HCMV reactivation following chemotherapy and hematopoietic stem cell transplantation (HSCT). Together, the proposed work is expected to lead to a better understanding of type III IFN-mediated regulation of adaptive NK cells during virus infections, which we hope will help to unleash their high translational potential in cellular therapy in the setting of clinical reactivation of HCMV.

天然杀手（NK）细胞是针对急性病毒感染的第一道防线的一部分。最近，鉴定出一种新型的病毒特异性NK细胞，该细胞在急性巨细胞病毒（CMV）感染过程中扩展，并有效地介导了抗体依赖性细胞细胞毒性（ADCC）。与常规的NK细胞相反，自适应NK细胞可以持续多年，因此有可能有助于长期保护，以防止再感染或从潜伏期中重新激活。这些适应性（也称为记忆）NK细胞的标志是刺激受体NKG2C的表达，该表达与人白细胞抗原E（HLA-E）结合。除了定义明确的HLA-E/NKG2C轴外，目前尚不清楚其他因素在病毒感染过程中控制了哪些因素可以控制自适应NK细胞的激活。在这方面，我们获得了初步数据，表明自适应NK细胞对III型干扰素具有唯一的响应，即由于IFNL受体的特定上调（IFNLR），IFN lambda（IFNL）1-4。 Lambda IFN是最近描述的与经典I型IFN（IFNALPHA/BETA）同源的IFN类，但具有更为集中的作用方式，包括针对病毒感染的上皮细胞的前线免疫反应。鉴于适应性NK细胞对作用于常规NK细胞（例如IL-12和IL-18）的其他关键细胞因子（例如IL-12和IL-18），适应性NK细胞的反应性特别相关。其他转录组分析的结果表明，对IFNL的暴露会在自适应NK细胞中启动高度特异性的病毒防御计划。在本项目中，我们要彻底表征III型干扰素如何调节自适应NK细胞的效应函数。我们想了解IFNL介导的刺激如何通过HLA-E/NKG2C轴与共激活协同激活，并将使用与抗原加工（TAP） - 缺陷HLA-E转染剂相关的转运蛋白，从而通过加载定义的肽来实现HLA-E表面表达的微调。其次，我们将使用转录组，蛋白质组学和表观遗传分析来表征经过IFNL处理的原发性自适应NK细胞中全局表达程序的变化。第三，我们计划分析IFNL如何调节基于人类巨细胞病毒（HCMV）感染的间充质干细胞的NK细胞共培养的体外感染模型中自适应NK细胞的功能。最后，我们将通过分析化学疗法和造血干细胞移植后经历HCMV重新激活的白血病患者（HSCT）来评估IFNL介导的自适应NK细胞刺激的临床相关性。总之，预计拟议的工作将使对病毒感染期间的III型IFN介导的适应性NK细胞的调节有更好的了解，我们希望这将有助于在HCMV的临床重新激活中释放其在细胞治疗中的高转化潜力。