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

目的研究人类免疫细胞(T细胞)与一种可能在抗结核(TB)感染中起关键作用的特定蛋白(CD1c)之间的相互作用。这项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。肺结核是一种肺部感染，通过咳嗽传播。它继续在世界范围内引发疾病，每天导致4000多人死亡，并对治疗它的抗生素产生越来越强的抗药性。由于40多年来标准疫苗接种、诊断和治疗基本保持不变，迫切需要新的方法来控制这种疾病。一种名为CD1c的人类蛋白质结合了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，然后这些T细胞可以保护我们免受感染。CD1c还可以结合引起结核病的细菌的物质，然后将它们展示给T细胞来激活它们。然而，许多识别与细菌成分(如结核病)结合的CD1c的T细胞似乎也识别与来自我们自身细胞的脂肪物质结合的CD1c。目前，还不清楚这些对我们自己的细胞和细菌表现出双重识别的T细胞是如何在人类结核病感染的背景下工作的。我建议CD1c及其T细胞调节引起结核病的细菌和其人类宿主之间的接口，并将使用一系列尖端科学方法来研究这一点。为了全面了解CD1c和反应性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CD1c与其受体结合进行沟通的基本过程入手，然后转移到对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CD1c是如何通过包括结构、突变、计算和细胞方法在内的技术组合来结合并向T细胞受体呈现脂肪成分的，这将有助于剖析T细胞与CD1c结合的基本基础。然后，我将研究CD1c反应T细胞如何识别人类和细菌细胞壁共享的脂肪成分。为此，我将从人类血液和组织中分离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能力。最后，我将通过采用新开发的结核感染细胞培养模型来研究CD1c及其T细胞在人类结核病感染中的作用。该模型使用微小的三维球体，其中人类细胞感染结核细菌。这个模型更接近于结核病感染的人肺中发生的事情。我将通过调节CD1c的表达并通过操纵控制细胞中脂肪成分水平的途径来研究CD1c的作用。我还将用CD1c反应T细胞来增强受感染的球体，以充分了解它们在人类结核病感染中的功能影响。应用效益本研究将首次深入研究CD1c及其T细胞在人类结核病中的作用。我的发现将带来新的发现，可能带来新的治疗机会，以帮助应对结核病大流行，而基本的科学发现也将与治疗癌症和炎症性疾病相关。这将有助于保持英国在研究领域的领先地位，更重要的是，将帮助全球许多受结核病影响的人。

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.