The T cell ecosystem: How do T cells co-exist and co-regulate each other during an immune response?

大多数实体，如人类、动物或植物，生活在群体、社会或生态系统中并从中受益。例如，当蜜蜂找到食物来源时，它们会相互通知，并将它们单独找到的所有食物保留在蜂箱中，这对整个蜂群都有好处。这一建议是基于一种假设，即一些被称为CD8 T细胞的白细胞在健康反应期间也会将自己组织成一个生态系统，这对整体结果是有利的。每个CD8T细胞克隆都是独一无二的，因为它表达一种特定的T细胞受体，该受体识别不同组具有不同亲和力的抗原。有人提出，这种多样性是对病毒的长期免疫所必需的。尽管一些CD8 T细胞具有竞争优势并足以控制感染，但多样性仍然存在，这表明招募到反应中的CD8 T细胞克隆的广度受到积极调节。不同的T细胞克隆如何共存和沟通，以实现它们提供长期保护的共识目标，目前尚不清楚。我们认为这类似于一个基于集体行为的生态系统，目的是建立不同的CD8T细胞克隆在启动免疫反应时共存的机制。具体地说，我们将：1)定义T细胞之间的相互联系和共同影响。我们将讨论不同的CD8 T细胞克隆单独存在或相互共存时的命运。2)定义培育CD8 T细胞多样性的环境。我们将定义这个环境在空间和时间上的细胞组成，以及这个环境是否可能对招募的T细胞进行分类。3)定义T细胞生态系统与异型免疫结果的相关性。总之，我们预计这些结果将提高我们对健康CD8 T细胞反应的理解，并最终带来操纵这些反应的新概念。接种疫苗是成功操纵免疫系统的最好例子，然而，控制某些病原体，如流感。CD8 T细胞在疫苗接种期间通常不会被触发，尽管它们对根除病毒很重要。该项目将全面描述产生T细胞生态系统所需的机制和环境，以及免疫反应的益处。

Most entities, such as humans, animals or plants, are living in and benefit from being in a group, society or ecosystem. For example, bees inform each other when they find a food source, and keep all the food they individually find into the beehive, which benefits the whole colony. This proposal is based on the hypothesis some white blood cells called CD8 T cells also organise themselves as an ecosystem during healthy responses, and that this is beneficial for the overall outcome. Each CD8 T cell clone is unique, as it expresses a specific T cell receptor that recognises different sets of antigens with different affinities. It has been proposed that this diversity was required for long-term immunity towards viruses. Diversity happens despite the fact that some CD8 T cells have a competitive advantage and are sufficient to control infections, suggesting that the breadth of CD8 T cell clones recruited to a response is actively regulated. How different T cell clones co-exist and communicate to achieve their consensus goal to provide long-term protection, is unknown. We propose that this resembles an ecosystem based on collective behaviour, and aim to establish by which mechanism the diverse CD8 T cell clones coexist at the initiation of an immune response. In particular, we will: 1) Define T cell inter-communication and co-influence. We will address the fate of diverse CD8 T cell clones when they are by themselves, or when they cohabit with each other.2) Define the environment that fosters CD8 T cell diversity. We will define the cellular composition in space and time of this environment, and whether this environment might triage recruited T cells.3) Define the relevance of a T cell ecosystem for the outcome of heterosubtypic immunity. Altogether, we expect the outcomes will improve our understanding of healthy CD8 T cell responses and ultimately bring new concepts to manipulate those responses. Vaccination is the best example of successful manipulation of the immune system, however, the control of some pathogens, like influenza. CD8 T cells are usually not triggered during vaccination, despite their importance for virus eradication. This project will provide a comprehensive characterisation of the mechanisms and environment necessary for the generation of a T cell ecosystem, and the benefits for immune responses.