Amino acid availability acts as a critical environmental rheostat of mucosal ILC2 responses

我们的肠道不断地暴露在环境的各种刺激下，细菌--既有有益的，也有有害的--以及在食物消化过程中释放的代谢活性分子。免疫系统不断地保持肠道的健康和正常运作，并防止在喂养过程中因感染或化学物质进入身体而造成的任何损害。最近的研究表明，肠道中细菌和饮食衍生信号的平衡显著改变了免疫系统的反应方式，这种平衡的变化可能会导致对感染、炎症甚至肥胖或癌症进展的免疫力下降。然而，这些环境信号的确切性质和免疫细胞对它们的反应方式尚不清楚，这阻碍了旨在改变肠道中的环境信号或针对检测它们的免疫细胞传感器的新治疗方法的开发。在这个项目中，我们将建立在我们实验室新的和令人兴奋的早期工作的基础上，这些工作表明，居住在组织中的先天免疫细胞群体不断感知肠道环境，以寻找所谓的“基本”氨基酸家族的变化。这些氨基酸对保持我们的健康至关重要，但不能由人体细胞制造，必须从饮食中消化食物中摄取。这种特定的肠道免疫细胞群体不断地检查肠道是否存在潜在的危险，并对危险或感染做出快速反应，以启动保护性免疫并修复组织。这种反应的速度高度依赖于感知肠道环境变化的能力，以及细胞导入基本蛋白质构建块的能力--以氨基酸的形式--这种构建块起到了“补充”免疫功能的作用。我们表明，与其他免疫细胞相比，这些细胞具有更高的感知肠道氨基酸水平变化的能力，这使它们能够产生适当的快速和强大的免疫反应。在这项建议中，我们认为这些免疫细胞感知必需氨基酸的能力对于肠道免疫系统感知感染或潜在危险至关重要。我们建议使用令人兴奋的新实验工具和方法进一步探索这一假说，这将使我们能够准确地确定这些关键免疫细胞如何对肠道环境中氨基酸的变化做出反应。特别是，我们已经确定了两个编码氨基酸“转运体”的关键基因，这些转运体可以检测氨基酸并将其吸收到免疫细胞中。使用免疫细胞内这些基因被删除的模型，我们产生了早期的发现，表明免疫细胞内外的氨基酸水平决定了该细胞履行其组织保护功能并对肠道感染做出反应的程度。我们的中心目标是利用实验室中的新技术和实验工具来更好地了解免疫细胞如何感知他们的环境--特别是它们如何对重要营养物质和代谢物的变化做出反应，以确保适当的反应，从而保持我们的肠道健康。这些发现可能会对一系列肠道疾病产生重要影响，帮助我们了解饮食和感染等环境风险因素是如何改变免疫系统的功能并决定肠道健康的。

Our intestines are continually exposed to a wide range of stimuli from the environment in the form of bacteria - both beneficial and harmful - and metabolically active molecules released during the digestion of food. The immune system continually acts to keep the intestine healthy and functioning normally, and to prevent any damage caused by infections or chemicals entering the body during feeding. Recent advances have shown that the balance of bacterial and dietary-derived signals in the intestine dramatically alters the way the immune system responds, and changes in this balance can result in reduced immunity to infection, inflammation or even the progression of obesity or cancer. However, the precise nature of these environmental signals and the way immune cells respond to them remains unclear, blocking the development of new treatments aimed at modifying environmental signals in the gut, or targeting the immune cell sensors that detect them.In this project we will build upon new and exciting early work in our lab that suggest that a population of tissue-resident innate immune cells continually sense the intestinal environment for changes in a family of so-called "essential" amino acids. These amino acids are critical to keep us healthy but cannot be made by human cells and must be ingested from digestion of food in the diet. This particular population of gut-resident immune cells constantly surveys the intestine for potential danger, and responds quickly in response to danger or infections to launch protective immunity and to repair the tissue. The speed of this response is highly reliant on the ability to sense changes in the gut environment, as well as the cells ability to import basic building blocks of proteins - in the form of amino acids - that act to "fuel" immune function. We show these cells have a much higher ability to sense changes in intestinal amino acid levels compared to other immune cells, which allows them to generate an appropriate fast and powerful immune response. In this proposal we suggest that the ability of these immune cells to sense essential amino acids is critical for the intestinal immune system to sense infections or potential danger.We propose to further explore this hypothesis using exciting, new experimental tools and approaches which will allow us to determine exactly how these critical immune cells respond to changes in amino acids in the intestinal environment. In particular, we have identified two key genes that encode for amino acid "transporters" that detect and take up amino acids into immune cells. Using models in which these genes have been deleted within immune cells we have generated early findings which suggest the levels of amino acids both outside and inside an immune cell determine the degree to which that cell can perform it's tissue protective functions and respond to intestinal infection.Our central objectives are to utilize new technologies and experimental tools in the lab to better understand how immune cells sense their environment - particularly how they respond to changes in important nutrients and metabolites to ensure appropriate responses that subsequently keep our intestines healthy. These findings could have important consequences for a wide range of intestinal diseases by helping us to understand how environment risk factors such as diet and infections alter the function of the immune system and determine intestinal health.