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

迁移树突状细胞群如何控制肠道的免疫反应？

• 批准号: MR/K021095/1
• 负责人: Simon Milling
• 金额: $ 68.5万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK021095%2F1
• 关键词: How; do; Migratory; Dendritic; Cell

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.

肠道的表面积比皮肤大近一百倍，并且暴露于许多潜在危险的微生物。它需要有效的免疫反应来保护肠道免受感染，并且必须做出正确类型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，免疫反应不能针对大量无害的细菌和丰富的食物蛋白质，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）。许多树突状细胞存在于肠道中，在那里它们积极收集有关其局部环境的信息，包括是否有任何微生物设法穿过将食物和“友好细菌”与身体组织分开的细胞屏障。在肠中停留约20天后，DC在淋巴中迁移，携带关于肠的信息到达局部（肠系膜）淋巴结（MLN）中的免疫细胞。在到达MLN时，DC与T细胞（关键的免疫效应细胞）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口服疫苗的设计或预防炎症性肠病非常重要。然而，迁移性DC的研究一直很困难，因为它们不能容易地在MLN和肠中的其他细胞中分离或鉴定。收集肯定是迁移的DC的细胞的最佳方法是通过手术，其用于直接收集含有DC的淋巴液。以前，这种手术主要在大型动物身上进行。我们开发了人性化的手术技术来从小鼠中收集迁移的DC，因此现在可以使用各种免疫学技术来分析DC的功能。在我们之前的工作中，我们使用这些技术来识别四种不同类型的迁移性肠道DC，每种DC在与T细胞相互作用后都会产生不同的免疫反应。在我们进行这些研究之前，人们认为其中两种类型的DC不能从肠道中迁移，通过这项应用，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-无论是提高口服疫苗的效率，还是帮助预防或控制肠道炎症疾病。具体来说，我们将研究如何控制三种不同类型的T细胞免疫反应在肠道中，使用这些免疫反应的小鼠模型。我们将研究在每个模型中发生的DC的变化，以及特定的DC类型是否是诱导这些反应所必需或足够的。最后，我们将使用这些数据来开发用于治疗性调节肠道免疫应答的方法。总之：我们已经开发了一系列独特的技术来分析迁移性肠道DC的功能，并使用这些技术来发现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，以发现这些DC如何控制肠道中T细胞反应的发展，并使用这些数据来开发操纵肠道免疫反应的策略。

项目成果

Increased S-nitrosylation and proteasomal degradation of caspase-3 during infection contribute to the persistence of adherent invasive Escherichia coli (AIEC) in immune cells.

• DOI: 10.1371/journal.pone.0068386
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Dunne KA;Allam A;McIntosh A;Houston SA;Cerovic V;Goodyear CS;Roe AJ;Beatson SA;Milling SW;Walker D;Wall DM
• 通讯作者: Wall DM

The lymph nodes draining the small intestine and colon are anatomically separate and immunologically distinct

• DOI: 10.1038/mi.2015.77
• 发表时间: 2016-03-01
• 期刊: MUCOSAL IMMUNOLOGY
• 影响因子: 8
• 作者: Houston, S. A.;Cerovic, V.;Milling, S.
• 通讯作者: Milling, S.

Salmonella enterica Serovar Typhimurium Travels to Mesenteric Lymph Nodes Both with Host Cells and Autonomously.

• DOI: 10.4049/jimmunol.1701254
• 发表时间: 2019-01-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Bravo-Blas A;Utriainen L;Clay SL;Kästele V;Cerovic V;Cunningham AF;Henderson IR;Wall DM;Milling SWF
• 通讯作者: Milling SWF

CCR7-dependent trafficking of RORγ⁺ ILCs creates a unique microenvironment within mucosal draining lymph nodes.

• DOI: 10.1038/ncomms6862
• 发表时间: 2015-01-09
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Mackley, Emma C.;Houston, Stephanie;Marriott, Clare L.;Halford, Emily E.;Lucas, Beth;Cerovic, Vuk;Filbey, Kara J.;Maizels, Rick M.;Hepworth, Matthew R.;Sonnenberg, Gregory F.;Milling, Simon;Withers, David R.
• 通讯作者: Withers, David R.

Mucosal CD8 T Cell Responses Are Shaped by Batf3-DC After Foodborne Listeria monocytogenes Infection.

• DOI: 10.3389/fimmu.2020.575967
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Imperato JN;Xu D;Romagnoli PA;Qiu Z;Perez P;Khairallah C;Pham QM;Andrusaite A;Bravo-Blas A;Milling SWF;Lefrancois L;Khanna KM;Puddington L;Sheridan BS
• 通讯作者: Sheridan BS