Sampling the environment: Antigen presentation and T cell regulation by intestinal epithelial cells

人类的肠道是大量友好细菌的宿主，它们与我们生活在一个互惠互利的环境中——我们为它们提供了一个营养丰富的栖息地，它们产生一些维生素，帮助防止有害细菌的感染。这种和平共存的基础是我们的免疫系统学会容忍这些有益的细菌，同时保持对感染我们肠道的任何有害细菌的反应。然而，在一些个体中，这种耐受性被破坏，免疫系统攻击有益细菌，导致炎症性肠病（IBD）的发展，这是一种慢性的肠道衰弱疾病。IBD的病因尚不清楚，目前也没有治愈方法。相反，治疗包括长期服用免疫抑制药物，这些药物的副作用包括增加感染和癌症的风险。为了开发新的和改进的治疗方法，更好地了解IBD期间肠道免疫系统如何发生故障是必要的。排列在人体肠道内的细胞被称为肠上皮细胞，它们形成了一个关键的屏障，限制了我们的免疫系统接触肠道内的细菌。然而，这些上皮细胞如何与我们的免疫系统相互作用并促进肠道耐受性的维持尚不清楚。在这个项目中，我们将研究健康肠道和炎症期间肠上皮细胞的反应模式，特别关注上皮细胞和免疫系统之间的串扰，并研究在有害的炎症反应中，如IBD，这种串扰是如何改变的。辅助性T细胞是一种白细胞，是免疫系统的关键细胞之一。在IBD患者中，有害的炎症是由T辅助细胞引起的，T辅助细胞对有益的肠道细菌作出反应。然而，辅助性T细胞不能直接识别细菌，而是被其他类型的白细胞激活，这些白细胞吸收并消化细菌，然后在其表面呈现被称为抗原的细菌蛋白质片段。然而，已经发现肠上皮细胞也能够提呈抗原，但这是否会导致T辅助细胞的激活尚不清楚，有人提出这可能是诱导肠道有益细菌耐受的重要途径。本项目的主要目的是研究肠上皮细胞抗原呈递如何影响T辅助细胞。为了实现这一目标，我们将使用肠道上皮细胞缺乏呈递抗原能力的转基因小鼠。我们将分析这些动物肠道中的T辅助细胞反应，并检查这些反应是否在不同的肠道感染和炎症模型中发生变化。任何改变都将揭示肠上皮细胞抗原呈递如何影响免疫系统对肠道细菌的反应性。为了确定肠上皮细胞和T辅助细胞之间串扰的关键分子，我们将使用一种新的技术，使我们能够生长和培养肠上皮细胞。这种“体外”系统的巨大优势在于，所涉及的因子和细胞可以被选择性地操纵，关键途径可以被清楚地识别出来。此外，将从健康人或IBD患者身上培养肠上皮细胞，并测试其呈递抗原的能力。更好地了解肠上皮细胞如何促进肠道T辅助细胞反应的控制，可能会导致IBD新疗法的发展。

The human intestine hosts a huge number of friendly bacteria that live in a mutually beneficial arrangement with us - we provide a nutrient-rich habitat for them and they produce some vitamins and help prevent infection with harmful bacteria. The basis of this peaceful co-existence is that our immune system learns to tolerate these beneficial bacteria, while remaining poised to respond to any harmful bacteria that infect our intestine. However, in some individuals, this tolerance breaks down and the immune system attacks the beneficial bacteria, leading to the development of inflammatory bowel diseases (IBD), which are chronic, debilitating disorders of the intestine. The causes of IBD are not known and there is no current cure. Instead, treatment involves long-term administration of immune suppressive drugs, which have side effects that include an increased risk of infection and cancer. A better understanding on how the immune system malfunctions in the intestine during IBD is necessary in order to develop new and improved therapies. The cells that line the human gut are called intestinal epithelial cells, which form a key barrier that limits exposure of our immune system to the bacteria that live in our gut. However, how these epithelial cells interact with our immune system and contribute to the maintenance of tolerance in our intestine is not well understood. In this project we will investigate the response pattern of the intestinal epithelial cell in the healthy gut and during inflammation and specifically focus on the crosstalk between epithelial cells and the immune system and look at how this is altered during harmful inflammatory responses, like IBD. T helper cells, a type of white blood cells, represent one of the key cell types of the immune system. In IBD patients, the harmful inflammation is caused by T helper cells that respond to beneficial intestinal bacteria. However, T helper cells do not recognise the bacteria directly, but are activated by other types of white blood cells that take up and digest the bacteria and then present fragments of the bacterial proteins, termed antigens, on their surface. However, it has been found that intestinal epithelial cells are also capable of presenting antigens, but whether this leads to activation of T helper cells is unclear and it has been proposed that instead this may be an important way of inducing tolerance to beneficial bacteria in the intestine. The key aim of this project is to study how antigen presentation by intestinal epithelial cells influences T helper cells. To achieve this, we will use genetically modified mice in which the intestinal epithelial cells lack the ability to present antigens. We will analyze the T helper cell responses in the gut of those animals and examine if these change during different models of intestinal infection and inflammation. Any alterations will reveal how antigen presentation by intestinal epithelial cells impacts on the reactivity of the immune system towards intestinal bacteria. To identify key molecules involved in the crosstalk between intestinal epithelial cells and T helper cells, we will use a new technique that allows us to grow and culture the intestinal epithelial cells. The great advantage of this 'in vitro' system is that the factors and cells involved can be selectively manipulated and key pathways can be clearly identified. Furthermore, intestinal epithelial cells will be grown from healthy people or patients with IBD and tested for their ability to present antigen. A better understanding of how intestinal epithelial cells contribute towards the control of T helper cell responses in the gut may lead to the development of novel therapies for IBD.