MICA Investigating CD1c lipid-antigen presentation and its role in tuberculosis

研究背景我的目的是研究人类免疫细胞（T细胞）和一种特异性蛋白（CD 1c）之间的相互作用，这种蛋白可能在对抗结核病（TB）感染时发挥关键作用。该研究项目创造的知识将有助于指导未来更成功的结核病治疗。肺结核是一种通过咳嗽传播的肺部感染。它继续在全世界引起疾病，每天造成4 000多人死亡，并且对用于治疗它的抗生素的耐药性越来越强，迫切需要新的方法来控制这种疾病，因为标准的疫苗接种、诊断和治疗40多年来基本上没有变化。一种名为CD 1c的人类蛋白质结合细胞表面的脂肪物质，以便人类免疫细胞（称为T细胞）识别它们，这些T细胞可以保护我们免受感染。CD 1c还可以结合导致结核病的细菌的物质，然后将它们显示给T细胞以激活它们。然而，许多识别与细菌成分（如TB）结合的CD 1c的T细胞似乎也识别与来自我们自己细胞的脂肪物质结合的CD 1c。目前，还不清楚这些T细胞如何表现出我们自己的细胞和细菌的双重识别，在人类结核病感染的背景下工作，我建议，CD 1c和它的T细胞调节结核病致病细菌和它的人类宿主之间的界面，并将使用一系列尖端的科学方法来研究这一点。目的为了充分了解CD 1c和应答性T细胞在人类结核病感染中的作用，我将从了解细胞如何通过CD 1c与其受体结合进行通信的基本过程开始，然后转移到患者和感染细胞的研究。我将在分子水平上进行详细的研究，以了解CD 1c如何结合并通过结构，突变，计算和细胞方法等技术的组合将脂肪脂质成分呈递给T细胞受体，这将有助于剖析T细胞与CD 1c结合的基本基础。然后，我将研究CD 1c反应性T细胞如何识别人类和细菌细胞壁共享的脂肪脂质成分。为此，我将从人体血液和组织中分离T细胞，并研究它们对人类和细菌细胞共有的脂肪成分的反应性。最后，我将研究CD 1c及其T细胞在人类结核感染中的作用，通过采用新开发的结核感染细胞培养模型，该模型使用微小的三维球体，其中人类细胞被结核细菌感染。该模型更接近于结核病感染的人肺中发生的情况。我将研究CD 1c的作用，通过调节其表达，并通过操纵的途径，控制在细胞中产生的脂肪成分的水平。我还将增加感染球与CD 1c-反应性T细胞，以充分了解其功能的影响，在人类TB infection.Application benefits的影响这项研究将进行第一次在深入调查的作用，CD 1c和它的T细胞在人类TB。我的发现将带来新的发现，可以提供新的治疗机会，以帮助应对结核病的流行，基础科学发现也将与治疗癌症和炎症性疾病有关。这将有助于使英国保持在研究领域的前沿，更重要的是，这将有助于世界各地受结核病影响的许多人。

BackgroundI aim to research the interaction between human immune cells (T-cells) and a specific protein (CD1c) which may play a key role when fighting tuberculosis (TB) infection. The knowledge created by this research project will help to direct future, more successful treatments for TB. TB is a lung infection that spreads by people coughing. It continues to cause disease worldwide, killing over 4,000 people every day, and is becoming progressively more resistant to the antibiotics used to treat it. New approaches to control the disease are urgently needed as standard vaccination, diagnosis and treatment have remained largely unchanged for over 40 years. A human protein called CD1c binds fatty substances on the cell surface in order for human immune cells (called T-cells) to recognise them, these T cells can then protect us from infection. CD1c can also bind substances from the bacteria that causes TB and then show them to T-cells to activate them. However, many T-cells that recognise CD1c bound to bacterial components (such as TB) also seem to recognise CD1c bound to fatty substances derived from our own cells. Currently, it is not understood how these T-cells that exhibit dual recognition of our own cells and bacteria, work within the context of human tuberculosis infection.I propose that CD1c and its T-cells regulate the interface between the TB causing bacteria and its human host and will investigate this using a range of cutting edge scientific approaches. AimsTo fully understand CD1c and the role of responsive T-cells in human TB infection, I will proceed from understanding the fundamental process of how cells communicate through the binding of CD1c to its receptor and then move to studies in patients and infected cells. I will perform detailed studies at the molecular level to understand how CD1c binds and presents fatty lipid components to T-cell receptors through a combination of techniques including structural, mutational, computational, and cellular methods that will help to dissect the fundamental basis for binding of T-cells to CD1c. I will then investigate how CD1c responsive T-cells recognise fatty lipid components that are shared by human and bacterial cell walls. For this I will isolate T-cells from human blood and tissues, and investigate their reactivity to fatty components that are shared by human and bacterial cells. Finally, I will investigate the role of CD1c and its T-cells in human TB infection through employing a newly developed TB infection cell culture model using tiny 3 dimensional spheres within which human cells are infected with TB bacteria. This model is a closer representation of what happens in TB infected human lung. I will investigate the role of CD1c by modulating its expression and through manipulating the pathways that control the levels of fatty components that are produced in cells. I will also augment the infected spheres with CD1c-responsive T-cells in order to fully understand their functional impact in human TB infection.Application benefitsThis study will perform the first in depth investigation of the role of CD1c and its T-cells in human TB. My findings will result in new discoveries that could deliver new treatment opportunities to help tackle the TB pandemic and the basic scientific findings will also be relevant to treating cancer and inflammatory disease. This will help to keep the UK at the forefront of the research area and more importantly will help the many people affected by TB worldwide.