Dendritic cell subsets in the maintenance of gut health and response to bioactives

为了保持人体健康，至关重要的是，进入人体的有害病原体（如细菌和病毒）被免疫系统迅速消除。然而，必须仔细控制免疫反应，以便它们仅在适当的时间被激活。如果这种严格的调节被破坏，免疫系统可能会攻击和损害身体的器官和组织，导致所谓的“自身免疫性疾病”。同样，如果免疫系统对通常无害的物质（如珠宝中的金属或食物物质）作出反应而被激活，则可能导致过敏。人体免疫调节的一个特别关键的区域是肠道。肠道内有数万亿的细菌，这些细菌对维持正常健康很重要，但可能引发免疫反应，导致炎症性肠病。同样，当食物物质通过肠道时，它们也可能在缺乏严格控制的情况下触发免疫激活，导致食物过敏。因此，了解控制免疫系统激活的细胞和分子是至关重要的，如果我们要了解我们的免疫系统如何发挥作用，以维持正常的健康。在食品工业中，人们对设计能够积极促进人类健康（所谓的“生物活性物质”），特别是肠道健康的食品非常感兴趣。例如，许多乳制品和饮料含有所谓的“益生菌”，这是旨在增强肠道健康的活细菌。然而，生物活性物质增强肠道健康的机制尚不明确，公众往往不信任制造商声称其产品将改善健康的说法。因此，了解生物活性物质如何影响肠道生物学以促进健康，提供可用于科学评估现有和新型生物活性物质的重要读数至关重要。增强肠道健康的唯一方法是增加我们对维持和促进正常肠道健康的细胞和分子的基本了解。由于免疫调节对于维持健康的肠道至关重要，因此了解肠道中的免疫反应如何调节对于确定生物活性物质的潜在有益作用至关重要。参与调节所有免疫应答的重要细胞类型是树突状细胞（DC）。我们的实验室最近使用小鼠模型表明，肠道中存在的重要DC亚群对维持肠道健康至关重要。这些DC亚群的特征在于其表面上不同蛋白质的表达，称为CD 103和整合素α v β 8，以及它们产生重要分子TGF-β和视黄酸的能力。DC通过诱导称为“调节性T细胞”的免疫细胞类型来促进免疫调节，所述调节性T细胞是防止有害免疫反应的重要细胞。为了建立在我们的小鼠研究基础上，现在至关重要的是确定这些专门的DC在人类肠道健康中的作用。我们的提案将根据它们表达的蛋白质标记物和分子以及它们在健康人体中的功能来鉴定这些专门的DC。我们将继续确定已知的生物活性物质如何影响这些DC亚群的生物学。因此，这项工作将确定对维持肠道健康至关重要的重要细胞和途径，提供有关已知生物活性物质如何工作的新数据，并确定可以科学评估新型生物活性食品物质对肠道的潜在有益影响的读数。

In order to maintain human health, it is vital that harmful pathogens that enter the body (such as bacteria and viruses) are quickly eliminated by the immune system. However, immune responses must be carefully controlled so that they are only activated at an appropriate time. If this tight regulation is disrupted, the immune system can potentially attack and damage the organs and tissue of the body, resulting in so-called 'autoimmune disease'. Similarly, allergies can result if the immune system is activated in response to normally harmless substances, such as metal in jewellery or food substances. A particularly critical area of the body for immune regulation is the intestine. The intestine is lined with trillions of bacteria which are important in maintaining normal health, but could potentially trigger an immune response causing inflammatory bowel disease. Similarly, as food substances pass through the intestine, they could also potentially trigger immune activation in the absence of tight control, resulting in food allergy. Therefore, understanding the cells and molecules that control activation of the immune system is paramount if we are going to understand how our immune system functions to maintain normal health. In the food industry, there is great interest in the design of foodstuffs that can actively promote human health (so called 'bioactives'), especially in the gut. For example, many dairy products and drinks contain so-called 'probiotics', which are live bacteria intended to enhance gut health. However, the mechanisms by which bioactives enhance gut health are ill defined, and often there is mistrust from the public in manufacturer's claims that their products will improve health. Therefore, it is essential to understand how bioactives affect the biology of the gut to promote health, to provide important read-outs that can be used to scientifically assess existing and novel bioactives. The only way that enhancement of gut health will be achieved is by increasing our basic understanding of the cells and molecules that maintain and promote normal gut health. As immune regulation is critical in maintaining a healthy gut, understanding how immune responses in the intestine are regulated will be critical in identifying potentially beneficial effects of bioactives. An important cell type involved in regulating all immune responses is the dendritic cell (DC). Our laboratories have recently shown, using mouse models, that important subsets of DC present in the intestine are critical in maintenance of gut health. These DC subsets are characterised by the expression of different proteins on their surface, called CD103 and integrin alphav beta8, and by their ability to produce important molecules called TGF-beta and retinoic acid. The DC promote immune regulation by inducing an immune cell type called 'regulatory T-cells', which are important cells in preventing harmful immune reactions. To build on our mouse studies, it is now critical to identify the role of these specialised DCs in human gut health. Our proposal will characterise these specialised DCs, in terms of the protein markers and molecules they express and how they function in healthy humans. We will go on to identify how known bioactives affect the biology of these DC subsets. This work will therefore identify important cells and pathways that are central to the maintenance of gut health, provide novel data on the how known bioactives work, and identify read-outs by which novel bioactive food substances can be scientifically evaluated for potential beneficial effects on the gut.