Probing the effect of dendritic cell co-stimulatory ligand lateral mobility on T cell mediated immunity and tolerance

探讨树突状细胞共刺激配体横向移动对T细胞介导的免疫和耐受的影响

• 批准号: BB/X015408/1
• 负责人: Michael Dustin
• 金额: $ 74.67万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX015408%2F1
• 关键词: Probing; effect; dendritic; cell; co

The immune system protects us from outside pathogens like viruses and bacteria, but also from internal treats like cancerous cells. Central to the function of the immune system is its capability to discriminate these treats from the vast number of harmless cells of our own bodies. Two distinct cell types of the immune system, termed dendritic cells (DCs) and T cells, are crucial to this process. DCs act as sentinels and messengers. They constantly take samples of their surroundings, harmless cells and pathogens alike, digest them and present these digested parts on their surface to identify potential threats. During this process, cues and signals from their environment lead DCs to become either mature or tolerogenic. Both, mature and tolerogenic DCs, communicate with T cells that recognise the identifier on the DC's surface by forming a close cell-cell contact, termed an immunological synapse. T cells that interact with mature DCs will become activated, start to multiply and finally attack and eliminate the treat, a process termed immunity. In contrast, tolerogenic DCs instruct T cells to become non-responsive, leading our immune system to ignore the source of the identified entity, which is deemed harmless, in a process termed tolerance. Importantly, many diseases in humans are caused by a mis-regulation of immunity and tolerance. Cancers for example, are able to instruct DCs to become tolerogenic, leading to escape from our immune system and metastasis. Conversely, the accidental identification of a healthy cell as a threat by mature DCs, leading to an immune response, is the cause for many autoimmune diseases where the immune system attacks our own body. Therefore, a comprehensive understanding of how the different properties of mature DCs and tolerogenic DCs lead to T cell responses or non-responses is an important topic in developing effective vaccines, immunotherapies and cures for autoimmune diseases. The different properties of mature and tolerogenic DCs are in part explained by the particular set of protein types that they carry on their surface to communicate and instruct T cells. Each of these proteins is recognised by its counterpart on T cells, triggering internal signals in the T cell that either contribute to immunity or tolerance. However, previous research suggests that it is not only the mere presence or absence of particular proteins that matters in this process. DCs also seem to be able to control the movement of these proteins on their surface, either allowing them to move freely or fixing them to certain positions. This in turn, changes how individual types of proteins are recognised by their counterparts on T cells and influences their signals. Consequently, the aim of this project is to study how protein mobility on DCs influences the decision between immunity and tolerance in a detailed, comprehensive and comparative manner. To this end we will employ a novel, artificial substrate that we developed to specifically control the mobility of different types of proteins i.e. some will be mobile while others will be immobile. This will allow us to emulate the surface of DCs in a fully controlled manner and to study the effect of mobility of a broad selection of specific types of proteins. In addition, we will measure protein mobility on the surface of mature and tolerogenic DCs and characterize their immunological synapses with T cells in a three-dimensional setup that mimics the complexity of human tissue. Additionally, and to complement our results from the artificial substrates, we will alter the mobility of specific types of proteins in mature and tolerogenic DCs by genetic engineering and measure how this affects the interaction and instruction of T cells. Together, this will give us an extensive understanding of the role of protein mobility in the decision between immunity and tolerance, potentially opening up new avenues for therapeutic interventions.

免疫系统保护我们免受病毒和细菌等外部病原体的侵害，也保护我们免受癌细胞等内部治疗。免疫系统功能的核心是它能够将这些治疗与我们自己身体的大量无害细胞区分开来。免疫系统的两种不同类型的细胞，称为树突状细胞（DC）和T细胞，对这一过程至关重要。DC充当哨兵和信使。它们不断地从周围环境、无害细胞和病原体中取样，消化它们，并将这些消化的部分呈现在它们的表面，以识别潜在的威胁。在此过程中，来自其环境的提示和信号导致DC变得成熟或致耐受性。成熟和致耐受性DC两者都通过形成称为免疫突触的紧密细胞-细胞接触与识别DC表面上的标识符的T细胞通信。与成熟DC相互作用的T细胞将被激活，开始繁殖并最终攻击和消除治疗，这一过程称为免疫。相比之下，致耐受性DC指示T细胞变得无应答，导致我们的免疫系统在称为耐受的过程中忽略被认为无害的已鉴定实体的来源。重要的是，人类的许多疾病是由免疫和耐受性的错误调节引起的。例如，癌症能够指示DC成为致耐受性的，导致从我们的免疫系统逃逸和转移。相反，成熟DC意外识别健康细胞作为威胁，导致免疫反应，是许多自身免疫性疾病的原因，其中免疫系统攻击我们自己的身体。因此，全面了解成熟DC和致耐受性DC的不同性质如何导致T细胞应答或无应答是开发有效的疫苗、免疫疗法和自身免疫性疾病治疗的重要课题。成熟DC和致耐受性DC的不同性质部分地由它们在其表面上携带的用于通信和指导T细胞的特定蛋白质类型的集合来解释。这些蛋白质中的每一种都被T细胞上的对应物识别，触发T细胞中有助于免疫或耐受的内部信号。然而，以前的研究表明，在这个过程中，不仅仅是特定蛋白质的存在或不存在。DC似乎也能够控制这些蛋白质在其表面上的运动，要么允许它们自由移动，要么将它们固定在某些位置。这反过来又改变了T细胞上对应物识别各种类型蛋白质的方式，并影响它们的信号。因此，本项目的目的是以详细、全面和比较的方式研究DC上的蛋白质流动性如何影响免疫和耐受之间的决定。为此，我们将采用一种新的人工底物，我们开发了这种底物来特异性地控制不同类型蛋白质的移动性，即一些蛋白质是移动的，而另一些蛋白质是不移动的。这将使我们能够以完全受控的方式模拟DC表面，并研究广泛选择的特定类型蛋白质的迁移率的影响。此外，我们将测量成熟和致耐受性DC表面上的蛋白质流动性，并在模拟人体组织复杂性的三维设置中表征其与T细胞的免疫突触。此外，为了补充我们从人工基质中获得的结果，我们将通过基因工程改变成熟和致耐受性DC中特定类型蛋白质的流动性，并测量这如何影响T细胞的相互作用和指令。总之，这将使我们广泛了解蛋白质流动性在免疫和耐受之间的决定中的作用，可能为治疗干预开辟新的途径。