Role of Notch signaling in the Differentiation and Function of Inflammatory DCs

描述(申请人提供)：树突状细胞(DC)是专业的抗原提呈细胞，在适应性免疫反应中起核心作用。它们专门负责抗原的摄取、加工和呈递给T细胞。通过保护粘膜屏障和将抗原输送到淋巴器官，它们至关重要地控制着保护性免疫和免疫耐受之间的平衡。病原体诱导的炎症反应导致感染部位和引流淋巴结出现树突状细胞。一个重要的问题是，什么信号调节炎症灶中DC的发育和功能。最近的研究表明，炎性单核细胞在感染过程中作为新生DC形成的主要前体发挥着中心作用。这个R21的应用展示了我们的计划，以了解Notch信号在单核细胞来源的DC(Mo-DC)在慢性炎症中的分化和功能中的作用。正如我们的研究方法所概述的那样，我们最近发现了一种独特的Mo-DC群体，它们具有增强的细胞-细胞融合能力，这是慢性炎症的标志。这些细胞在稳定状态的淋巴器官中不存在，但在炎症条件下存在。我们已经在骨髓中鉴定了这些炎性树突状细胞的前体，并表明体外分化是Notch依赖的。在这个提案中，我们将讨论这些依赖Notch的Mo-DC的功能意义以及Notch信号在这些细胞的分化和功能中的作用。我们假设这些细胞被赋予启动效应和/或调节T细胞反应的能力，并且Notch信号对这些细胞的分化和功能都起着关键的推动作用。总而言之，这些研究不仅应该导致对慢性炎症性疾病的更好的理解，而且还将确定治疗的新治疗策略。 公共卫生相关性：这一建议与传染病、自身免疫性疾病和其他炎症反应中的炎性免疫反应直接相关。我们将讨论一类新的Notch依赖的炎性DC的分化和功能。我们的研究将有助于更好地理解炎症性疾病，并将确定新的治疗策略。

DESCRIPTION (provided by applicant): Dendritic cells (DCs) are professional antigen-presenting cells with a central role in adaptive immune responses. They are specialized for the uptake, processing and presentation of antigen to T-cells. By guarding mucosal barriers and transporting antigens to lymphoid organs, they critically control the balance between protective immunity and immune tolerance. Pathogen- induced inflammatory responses lead to the emergence of DCs at the infection site and draining lymph nodes. A significant question is what signals regulate the development and function of DCs at inflammatory foci. Recent research suggests a central role for inflammatory monocytes as major precursors for de novo DC formation during infection. This R21 application presents our plan to understand the role of Notch signaling in the differentiation and function of monocyte-derived DCs (Mo-DC) in chronic inflammation. As outlined in our research approach, we recently identified a unique population of Mo-DCs that have an enhanced ability to undergo cell-cell fusion, a hallmark of chronic inflammation. These cells are absent in steady-state lymphoid organs, however, they are present under inflammatory conditions. We have identified the precursors of these inflammatory DCs in the bone marrow and shown that differentiation in vitro is Notch-dependent. In this proposal, we will address the functional significance of these Notch-dependent Mo-DCs and the role of Notch signaling in the differentiation and function of these cells. We hypothesize that these cells are endowed with the ability to prime effector and/or regulatory T-cell responses and that Notch signaling critically drives both the differentiation and function of these cells. Togethr, these studies should not only lead to an improved understanding of chronic inflammatory disorders but will also identify novel therapeutic strategies for treatment. PUBLIC HEALTH RELEVANCE: This proposal is directly relevant to the inflammatory immune response in infectious disease, autoimmune diseases and other inflammatory responses. We will address the differentiation and function of a novel class of Notch-dependent inflammatory DCs. Our studies will lead to an improved understanding of inflammatory disorders and will identify novel treatment strategies.