How do Migratory Dendritic Cell Populations Control Immune Responses in the Intestine?

肠道的表面积几乎是皮肤的100倍，并且暴露在许多潜在危险的微生物中。它需要有效的免疫反应来保护肠道免受感染，并且必须做出正确的免疫反应来控制可能遇到的不同类型的病原体。另一方面，免疫反应不能对抗大量无害细菌和大量食物蛋白质，它们也存在于肠道中。当不适当的反应发生时，可能会产生严重的后果，导致炎症性肠病或食物过敏。控制免疫反应的关键细胞是树突状细胞（DC）。许多dc在肠道中被发现，它们在肠道中积极收集有关当地环境的信息，包括是否有微生物成功地穿过了将食物和“友好细菌”与身体组织分开的薄薄的细胞屏障。在肠道中停留约20天后，dc在淋巴中迁移，将肠道的信息传递给局部（肠系膜）淋巴结（MLN）的免疫细胞。在到达MLN后，树突状细胞与关键的免疫效应细胞T细胞相互作用。这种相互作用不仅控制是否会发生免疫反应，而且还决定将产生哪种类型的反应。了解dc如何控制这些过程对于设计口服疫苗或预防炎症性肠病非常重要。然而，迁移dc的研究一直很困难，因为它们不容易在mln和肠中的其他细胞中分离或鉴定。收集肯定是迁移的树突细胞的最佳方法是通过手术，直接收集含有树突细胞的淋巴。以前，这种手术大多在大型动物身上进行。我们开发了人性化的手术技术来收集小鼠迁移的dc，因此现在可以使用各种各样的免疫学技术来分析dc的功能。在我们之前的工作中，我们已经使用这些技术鉴定了四种不同类型的迁移肠DC，每种DC在与T细胞相互作用后产生不同的免疫反应。在我们进行这些研究之前，人们认为其中两种DC类型无法从肠道迁移。通过这一应用，我们的目标是继续研究这些不同类型的迁移dc，并发现如何操纵它们的特性来控制肠道中的免疫反应——要么提高口服疫苗的效率，要么帮助预防或控制肠道炎症性疾病。具体来说，我们将研究dc如何控制肠道中三种不同类型的T细胞免疫反应，使用这些免疫反应的小鼠模型。我们将检查每个模型中DC的变化，以及特定DC类型是否必要或足以引起这些响应。最后，我们将利用这些数据来开发肠道免疫反应的治疗性调节方法。总之：我们已经开发了一套独特的技术来分析迁移肠dc的功能，并利用这些技术发现了具有特定免疫功能的令人兴奋的新细胞群。我们将建立在这个坚实的基础上，发现这些dc如何控制肠道中T细胞反应的发展，并利用这些数据来制定操纵肠道免疫反应的策略。

The intestine has a surface area nearly one hundred times greater than the skin, and is exposed to many potentially dangerous micro-organisms. It requires effective immune responses to protect the intestine from infections, and the correct type of immune response must be made to control the different types of pathogen that may be encountered. On the other hand, immune responses must not be made against the large numbers of harmless bacteria and abundant food proteins that are also present in the intestine. When an inappropriate response occurs it can have serious consequences, leading to inflammatory bowel diseases or food allergy. A critical cell for controlling immune responses is the dendritic cell (DC). Many DCs are found in the intestine, where they actively gather information about their local environment, including about whether any micro-organisms have managed to cross the thin barrier of cells that separates food and "friendly bacteria" from the tissues of the body. Following a period of residence in the intestine of approximately 20 days, DCs migrate, in lymph, carrying information about the intestine to the immune cells in the local (mesenteric) lymph nodes (MLN). On reaching the MLN, DCs interact with T cells, key immune effector cells. This interaction not only controls whether an immune response will occur, but also determines which type of response will be generated. Understanding how DCs control these processes is important for the design of oral vaccines or prevention of inflammatory bowel diseases. However, the study of migrating DCs has been difficult because they cannot easily be separated or identified among the other cells in the MLNs and intestine. The best way to collect cells that are certain to be migrating DCs is by surgery, which is used to directly collect the DC-containing lymph. Previously this surgery has mostly been performed in large animals. We developed humane surgical techniques to collect migrating DCs from mice, and can therefore now use a wide variety of immunological techniques to analyse the DCs' functions. In our previous work, we have used these techniques to identify four different types of migrating intestinal DC, each of which generates different immune responses after interacting with T cells. Before we carried out these studies, it was thought that two of these DC types were unable to migrate from the intestine.With this application, we aim to continue our investigations into these different types of migrating DCs, and discover how their properties may be manipulated to control immune responses in the intestine- either to improve the efficiency of oral vaccines, or to help prevent or control intestinal inflammatory disease. Specifically, we will investigate how DCs control three different types of T cell immune responses in the intestine, using mouse models of these immune responses. We will examine the changes in the DCs that occur in each of the models, and also whether particular DC types are necessary or sufficient for inducing each of these responses. Finally, we will use these data to develop approaches for therapeutic modulation of intestinal immune responses.In summary: we have developed a unique array of techniques for the analysis of the functions of migrating intestinal DCs, and have used these to discover exciting new populations of cells with specific immunological functions. We will built on this strong foundation to discover how these DCs control the development of T cell responses in the intestine, and use these data to develop strategies for manipulating the intestinal immune response.