Tissue-specific T cell migration in the intestine

肠道内组织特异性 T 细胞迁移

• 批准号: MR/N023625/1
• 负责人: Simon Milling
• 金额: $ 94.97万
• 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: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN023625%2F1
• 关键词: Tissue; specific; cell; migration; intestine

The intestine contains more immune cells than any other organ in the body. The small intestine and the large intestine (the colon), though connected, perform different functions. The small intestine digests and absorbs food, while the large intestine absorbs water. Both parts of the intestine are constantly exposed to harmless or beneficial microorganisms, and also to other microbes that can cause infections that can be unpleasant at best, and life threatening at worst. The immune cells in our intestine therefore face a formidable challenge. They have to recognise, attack and destroy potentially harmful infectious agents without damaging the tissue, but not mount similar attacks against food or the innocuous microorganisms that live in our intestine. These harmless materials are not just ignored. Deliberate and active processes are triggered to make sure that immune cells cannot respond to them. Most people have a healthy intestine but ineffective immune responses mean intestinal infections remain major causes of illness and death worldwide. On the other hand, inappropriate attacks on harmless foods or microorganisms can cause inflammatory bowel disease (IBD). Crohn's disease and ulcerative colitis, are the commonest types of IBD. They are life-changing conditions and currently affect over a quarter of a million people in the UK. IBD can also substantially increase the likelihood of developing bowel cancer. Currently there is no cure, and existing medicines are often ineffective at treating symptoms. Our recent work has generated results that will enable us to identify the molecules that direct the immune cells to the intestine. Identifying these molecules will be a major step towards developing new therapies to treat IBD and new ways of boosting responses to immunisation against intestinal infections.Immune responses in the intestine start within specialised tissues called the mesenteric lymph nodes (MLN). This is a chain of lymph nodes linked end-to-end and connected to the intestine by specialised vessels. These vessels convey information from the intestine that is used by the MLN to instruct immune cells, which can then travel to the intestine to perform specific tasks. We have shown that each individual lymph node in the MLN chain performs distinct functions and appears to be responsible for a specific region of the intestine - The immune cells in a particular lymph node travel to a particular part of the intestine. This is important, because it means that immune cells can be directed to the place where they are most likely to be useful, and can therefore protect us efficiently. While in the MLN, immune cells make particular molecules that allow them travel to the correct part of the intestine. Two molecules have already been identified that contribute to directing immune cells specifically to the small intestine. Drugs have been developed for the treatment of IBD that interfere with the function of one or other of these two molecules. Other as yet unidentified molecules are also involved in directing immune cells to the small intestine, and very little is known about the molecules that direct immune cells to the large intestine. Our new discoveries about the specialisation of lymph nodes in the MLN chain provide us with an opportunity to compare immune cells in each of the different nodes, determine where they travel to in the intestine, and identify novel molecules required to get them there. We will also be able to determine how immune cells in different lymph nodes acquire the unique sets of molecules they need to get back to the intestine. We will investigate this in healthy animals, and in animals with inflammation in different parts of their intestines. We anticipate that this work will identify new ways to control how immune cells travel in the body, and therefore new strategies to prevent them causing harm in patients with IBD or novel ways of boosting immunisations against intestinal infections.

肠道含有比身体任何其他器官更多的免疫细胞。小肠和大肠（结肠）虽然相连，但功能不同。小肠吸收食物，而大肠吸收水分。肠道的这两个部分不断暴露于无害或有益的微生物，以及其他可能导致感染的微生物，这些感染最好的情况下可能是不愉快的，最坏的情况下可能危及生命。因此，我们肠道中的免疫细胞面临着巨大的挑战。它们必须识别、攻击和摧毁潜在有害的传染性病原体，而不损害组织，但不能对食物或生活在我们肠道中的无害微生物进行类似的攻击。这些无害的材料不仅被忽视。故意和主动的过程被触发，以确保免疫细胞不能对它们做出反应。大多数人都有健康的肠道，但无效的免疫反应意味着肠道感染仍然是全球疾病和死亡的主要原因。另一方面，对无害食物或微生物的不适当攻击可引起炎症性肠病（IBD）。克罗恩病和溃疡性结肠炎是IBD最常见的类型。它们是改变生活的条件，目前影响着英国超过25万人。IBD还可以大大增加患肠癌的可能性。目前还没有治愈的方法，现有的药物往往对治疗症状无效。我们最近的工作产生的结果将使我们能够识别将免疫细胞引导到肠道的分子。识别这些分子将是开发治疗IBD的新疗法和增强肠道感染免疫反应的新方法的重要一步。肠道中的免疫反应始于称为肠系膜淋巴结（MLN）的专门组织。这是一条淋巴结链，首尾相连，并通过专门的血管连接到肠道。这些血管从肠道传递信息，MLN使用这些信息来指导免疫细胞，然后免疫细胞可以前往肠道执行特定任务。我们已经表明，MLN链中的每个淋巴结都执行不同的功能，并且似乎负责肠道的特定区域-特定淋巴结中的免疫细胞移动到肠道的特定部分。这很重要，因为这意味着免疫细胞可以被引导到它们最有可能有用的地方，因此可以有效地保护我们。在MLN中，免疫细胞产生特定的分子，使它们能够到达肠道的正确部位。已经确定了两种分子，它们有助于将免疫细胞特异性地引导到小肠。已经开发了用于治疗IBD的药物，其干扰这两种分子中的一种或另一种的功能。其他尚未鉴定的分子也参与将免疫细胞引导到小肠，并且对将免疫细胞引导到大肠的分子知之甚少。我们关于MLN链中淋巴结特化的新发现为我们提供了一个机会，可以比较每个不同淋巴结中的免疫细胞，确定它们在肠道中的位置，并确定将它们带到那里所需的新分子。我们还将能够确定不同淋巴结中的免疫细胞如何获得它们返回肠道所需的独特分子组。我们将在健康动物和肠道不同部位有炎症的动物中研究这一点。我们预计，这项工作将确定控制免疫细胞在体内传播的新方法，从而确定防止免疫细胞对IBD患者造成伤害的新策略，或提高肠道感染免疫力的新方法。

项目成果

A guide to chemokines and their receptors.

• DOI: 10.1111/febs.14466
• 发表时间: 2018-08
• 期刊: The FEBS journal
• 作者: Hughes CE;Nibbs RJB
• 通讯作者: Nibbs RJB

Mass spectrometry imaging identifies palmitoylcarnitine as an immunological mediator during Salmonella Typhimurium infection.

• DOI: 10.1038/s41598-017-03100-5
• 发表时间: 2017-06-05
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Hulme HE;Meikle LM;Wessel H;Strittmatter N;Swales J;Thomson C;Nilsson A;Nibbs RJB;Milling S;Andren PE;Mackay CL;Dexter A;Bunch J;Goodwin RJA;Burchmore R;Wall DM
• 通讯作者: Wall DM

Regulatory T cells control the dynamic and site-specific polarization of total CD4 T cells following Salmonella infection.

• DOI: 10.1038/s41385-020-0299-1
• 发表时间: 2020-11
• 期刊: Mucosal immunology
• 影响因子: 8
• 作者: Clay SL;Bravo-Blas A;Wall DM;MacLeod MKL;Milling SWF
• 通讯作者: Milling SWF

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

Chemokine Transport Dynamics and Emerging Recognition of Their Role in Immune Function.

• DOI: 10.1016/j.cobme.2018.03.001
• 发表时间: 2018-03
• 期刊: Current opinion in biomedical engineering
• 影响因子: 3.9
• 作者: Moore JE Jr;Brook BS;Nibbs RJB
• 通讯作者: Nibbs RJB