Dynamics of human T cell memory in blood and secondary lymphoid tissue in shaping vaccine induced immunity in ageing

疫苗通过训练免疫系统保留感染的记忆来保护。它由不同种类的细胞组成，这些细胞可以保存信息，就像计算机软件系统中的比特一样。这就是所谓的免疫记忆。正是这一特征使我们在接种疫苗后，如果我们遇到感染，可以得到保护。我们并不完全理解所涉及的过程。一种非常重要的T细胞与B细胞相互作用，帮助它们产生抗体。这些相互作用发生在称为淋巴结的专门组织中。这些是小的肾形器官，在某些区域（如腋下）聚集在一起。正是在这里，T细胞和B细胞与疫苗或疫苗的一部分相遇，结果，细胞做出反应，发生变化并繁殖。在老年人中，我们知道免疫启动、维持免疫记忆和回忆的过程可能都不同，可能更慢，但我们不知道确切的原因。一种可能性是T细胞在老年人中的反应不同。老年人的疫苗通常需要高剂量或额外的激活成分。虽然淋巴结很重要，但它们在人类中尚未得到很好的研究。这是因为采集淋巴结样本需要与采血不同的技能，而这些技能以前没有投入。需要一名熟练掌握超声引导下穿刺活检的临床医生。这意味着我们在了解疫苗如何工作以及如何在不同情况下更好地设计疫苗方面缺少关键信息;例如，对于老年人，或者应对艾滋病毒，流感和SARS-CoV-2等快速变化的高度复杂感染。本奖学金旨在改变这一点。不仅是为了这个项目的持续时间，也是为了疫苗科学的未来。首先，我将进行床边成像，以确定哪些淋巴结对疫苗有反应，哪些没有。目前，这有时可以使用灰度超声，但结果并不总是可靠的，或者使用PET/CT，但这涉及辐射剂量。我相信我们可以更频繁地使用无害的超声波在更多的人身上这样做。志愿者将接种流感疫苗，并在接种疫苗前后多天参加成像预约。每次他们参加，他们将有一个扫描，看看大小和血液流动的淋巴结附近的疫苗接种部位。这将决定使用这些类型的疫苗进行采样的最佳地点和最佳日期。其次，我将使用超声引导细针穿刺（USFNA）活检，在接种流感疫苗前后采集淋巴结样本。我也会要求志愿者同时提供血液样本。可从同侧和对侧（对照）淋巴结中采集样本。这些细胞将被染色，并使用一种称为流式细胞仪的机器进行测量，这样我就可以确定哪些是T细胞，什么类型的T细胞，它们对什么有反应，以及它们的数量是否在增长（在细胞周期中）。我将在血液和淋巴结中进行比较。第三，我将通过检测单个T细胞产生的核糖核酸（RNA）来测量它们对疫苗接种的反应。这将详细说明不同类型的T细胞对疫苗的反应。为了了解年龄如何影响免疫反应，我将邀请不同年龄的人参加。我的愿景是生成一幅T细胞如何对淋巴结中的疫苗做出反应的图片，并展示这种反应如何以及为什么会随着年龄而变化。这将为疫苗设计的未来提供新的见解。

Vaccines protect by training the immune system to retain memory of an infection. This is made up of different kinds of cells which can retain information, like bits in a computer software system. This is called immune memory. It is this feature which allows us to be protected after vaccination if we encounter an infection. We do not fully understand the processes involved. One very important type of T cell interacts with B cells to help them make antibodies. These interactions happen in specialised tissues called lymph nodes. These are small kidney-shaped organs found together in clusters in certain areas such as the underarm. It is here that T cells and B cells meet the vaccine or parts of the vaccine and as a result, the cells respond, change and multiply. In older people, we know that the processes of immune priming, maintaining immune memory and recalling it may all happen differently, perhaps more slowly, but we don't know precisely why. One possibility is that T cells respond differently in older people. Vaccines for older people often need a high dose or an extra activating component. Although lymph nodes are important, they have not been well studied in humans. This is because taking a lymph node sample requires different skills from taking blood and these have not previously been invested in. A clinician who is skilled in ultrasound-guided needle biopsy, is needed. This means that we are missing key information in understanding how vaccines work, and how we might design them better in different circumstances; for older people for example, or to tackle highly complex infections that rapidly change such as HIV, flu and SARS-CoV-2. This Fellowship aims to change that. Not just for the duration of this project but for the future of vaccine science. Firstly, I will develop bedside imaging to determine which lymph nodes are responding to the vaccine and which are not. At present this is sometimes possible with greyscale ultrasound but the results are not always reliable, or with PET/CT but this involves a dose of radiation. I believe we can do this more frequently and in more people using harmless ultrasound. Volunteers will be vaccinated with a vaccine against influenza and attend for an imaging appointment on multiple days before and after vaccination. Each time they attend they will have a scan to see the size and blood flow in the lymph nodes near to the site of vaccination. This will determine the best site and best day on which to take a sample using these types of vaccines. Secondly, I will use the ultrasound to guide a fine needle aspiration (USFNA) biopsy to take a sample of the lymph node before and after vaccination with influenza vaccine. I will also ask volunteers to give a sample of the blood at the same time. Samples from lymph nodes on the same side and opposite (control) side can be taken. The cells will be stained and measured using a machine called a flow cytometer so that I can determine which are T cells, what type of T cells, what they are responding to and whether they are growing in number (in cell cycle). I will compare this in the blood and in the lymph node. Thirdly, I will measure how individual T cells are responding to vaccination by testing the ribonucleic acid (RNA) that they are producing. This will indicate in detail how different types of T cells respond to the vaccine. To understand how age might affect the immune response, I will ask people of different ages to participate. My vision is to generate a picture of how T cells respond to vaccines in lymph nodes, and to demonstrate how, and why, this changes with age. This will provide new insight for the future of vaccine design.