Molecular mechanisms enabling cDC2s to control Th2 cell priming

使 cDC2 控制 Th2 细胞启动的分子机制

• 批准号: MR/T030879/1
• 负责人: Simon Milling
• 金额: $ 68.22万
• 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: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT030879%2F1
• 关键词: Molecular; mechanisms; enabling; cDC2s; control

The intestine is a continuous tube that starts from the mouth and ends at the anus. It is home to the largest number of immune cells in the body. The reason for this is that the intestine is constantly exposed both to billions of harmless and beneficial microorganisms, and also to microbes that can cause infections. The immune cells in the intestine therefore face a formidable challenge. They have to recognise, attack and destroy potentially harmful infectious agents without damaging the body, but they must not mount similar attacks against food, or harmless microorganisms. These harmless materials are not just ignored, active processes are triggered to make sure that immune cells cannot respond to them and cause unnecessary damage to the body. It is important to understand how these immune responses in the intestine are controlled, so that we can find better ways to both activate these responses (e.g. for vaccination, or to control infection), and to reduce their strength when they cause damage to the intestine (e.g. during inflammatory bowel disease). The two cell types that are most important for controlling immune responses in the intestine are "dendritic cells" and "T cells". These cells interact with each other, and the outcome of this interaction defines the type of immune responses that are generated. Dendritic cells are found in the wall of the intestine, where they are able to acquire samples of proteins from their local environment, from food and microbes. After acquiring these proteins, the dendritic cells leave the intestine and travel to lymph nodes, where the T cells are found. Depending on the source of the protein the dendritic cell has acquired, the dendritic cell will cause the T cell to respond in different ways. For instance, if the dendritic cell has taken up protein from food, the T cell will be de-activated, so that an immune response is not accidentally made against a harmless food protein. On the other hand, the dendritic cell has acquired proteins from a harmful microbe, the dendritic cell will be activated by signals it will have also received from the microbe. This activated dendritic cell will then cause the responding T cell to become activated. The activated T cell will then be able to make a response against the microbe, and kill it. Different types of T cell responses are required to kill different types of microbes, so T cells activated to help kill bacteria will produce different molecules to T cells activated to help kill viruses or large parasitic organisms.This response is difficult to study because very small numbers of dendritic cell : T cell interactions have very large effects on the type of response that then occurs. It has been very challenging to discover the details of how these small numbers of dendritic cells work. By studying immune responses to parasites, we have recently identified two molecules that appear to have important effects on dendritic cell functions. Our project has two objectives. The first is to investigate how these two molecules work, and therefore understand the details of how dendritic cells control this type of immune response. Our second objective is to use methods we have developed to identify new molecules that are important for controlling immune responses in the intestine. To achieve this second objective we will take advantage of new technology that is able to identify many of the molecules produced by very small numbers of cells within larger populations. Understanding the functions of dendritic cells in the way we propose should help us to manipulate the immune response in a wide range of important situations, perhaps by improving the efficiency of vaccines, or preventing the inappropriate and damaging immune responses that cause the symptoms of inflammatory bowel disease.

肠是一个连续的管道，从嘴开始，在肛门结束。它是体内免疫细胞数量最多的地方。这是因为肠道经常暴露于数十亿无害和有益的微生物，以及可能导致感染的微生物。因此，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，而不损害人体，但它们不得对食物或无害微生物进行类似的攻击。这些无害的物质不仅会被忽视，还会触发积极的过程，以确保免疫细胞不会对它们做出反应，对身体造成不必要的伤害。重要的是要了解肠道中的这些免疫反应是如何控制的，这样我们就可以找到更好的方法来激活这些反应（例如接种疫苗或控制感染），并在它们对肠道造成损害时（例如在炎症性肠病期间）降低它们的强度。对于控制肠道中的免疫应答最重要的两种细胞类型是“树突细胞”和“T细胞”。这些细胞彼此相互作用，这种相互作用的结果定义了产生的免疫反应的类型。树突状细胞存在于肠壁中，在那里它们能够从局部环境、食物和微生物中获取蛋白质样本。树突状细胞在获得这些蛋白质后，会离开肠道，前往淋巴结，在那里找到T细胞。根据树突状细胞获得的蛋白质来源，树突状细胞会以不同的方式引起T细胞的反应。例如，如果树突状细胞从食物中摄取了蛋白质，T细胞就会被灭活，这样免疫反应就不会意外地针对无害的食物蛋白质。另一方面，树突状细胞从有害微生物中获得蛋白质，树突状细胞将被它也从微生物中收到的信号激活。这种激活的树突状细胞然后将导致响应T细胞被激活。活化的T细胞将能够对微生物做出反应，并杀死它。不同类型的T细胞反应需要杀死不同类型的微生物，因此T细胞活化以帮助杀死细菌将产生不同的分子，以帮助杀死病毒或大型寄生生物体。这种反应很难研究，因为非常少量的树突状细胞：T细胞相互作用对随后发生的反应类型有非常大的影响。发现这些少量树突细胞如何工作的细节是非常具有挑战性的。通过研究对寄生虫的免疫反应，我们最近发现了两种似乎对树突状细胞功能有重要影响的分子。我们的项目有两个目标。首先是研究这两种分子是如何工作的，从而了解树突状细胞如何控制这种类型的免疫反应的细节。我们的第二个目标是使用我们开发的方法来识别对控制肠道免疫反应重要的新分子。为了实现第二个目标，我们将利用新技术，能够识别大量细胞中极少数细胞产生的许多分子。以我们提出的方式理解树突状细胞的功能应该有助于我们在广泛的重要情况下操纵免疫反应，也许是通过提高疫苗的效率，或者防止导致炎症性肠病症状的不适当和破坏性免疫反应。

项目成果

A specialist antigen storage compartment in dendritic cells to sustain cross-presentation.

树突状细胞中的专门抗原储存室，用于维持交叉呈递。

• DOI: 10.1111/imm.13422
• 发表时间: 2021
• 期刊: Immunology
• 影响因子: 6.4
• 作者: Cerovic V

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

Targeted Delivery of Narrow-Spectrum Protein Antibiotics to the Lower Gastrointestinal Tract in a Murine Model of Escherichia coli Colonization.

• DOI: 10.3389/fmicb.2021.670535
• 发表时间: 2021
• 期刊: Frontiers in microbiology
• 影响因子: 5.2
• 作者: Carpena N;Richards K;Bello Gonzalez TDJ;Bravo-Blas A;Housden NG;Gerasimidis K;Milling SWF;Douce G;Malik DJ;Walker D
• 通讯作者: Walker D

Monocytes mediate Salmonella Typhimurium-induced tumor growth inhibition in a mouse melanoma model.

• DOI: 10.1002/eji.202048913
• 发表时间: 2021-12
• 期刊: European journal of immunology
• 影响因子: 5.4

Mapping the Influence of the Gut Microbiota on Small Molecules across the Microbiome Gut Brain Axis.

• DOI: 10.1021/jasms.1c00298
• 发表时间: 2022-04-06
• 期刊: JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
• 影响因子: 3.2
• 作者: Hulme, Heather;Meikle, Lynsey M.;Strittmatter, Nicole;Swales, John;Hamm, Gregory;Brown, Sheila L.;Milling, Simon;MacDonald, Andrew S.;Goodwin, Richard J. A.;Burchmore, Richard;Wall, Daniel M.
• 通讯作者: Wall, Daniel M.