The functional and migratory characteristics of low avidity virus-specific T cells during ageing

老年人易受感染和恶性肿瘤的影响，这表明他们的免疫系统变得不那么有效。感染因子的持续挑战，特别是那些在体内持续存在的病毒，可能会驱使反应性白色细胞趋于衰竭。其次，免疫系统的主要属性之一是白色细胞从血液迁移到组织并再次返回的能力，这种现象称为免疫监视。在这个项目中，我们使用的试剂使我们能够研究T细胞的质量以及它们在老年人中的迁移能力，以确定这些基本功能中的一种或两种是否存在缺陷。我们还将同时研究两组不同个体的血液和淋巴结以及血液和骨髓中的白色细胞。这是一个独特的机会，因为由于难以获得组织样本，通常只研究人类血液中的白细胞。我们有所有适当的伦理批准，能够进行这些研究。该项目还将利用我们开发的其他新技术来测量端粒，相当于白色细胞中对病毒反应的老化时钟。具有长端粒的细胞有可能在体内持续存在，而具有短端粒的细胞（衰老）接近耗尽时间并将丢失。此外，通过使用延时显微镜，我们可以可视化来自老年和年轻受试者的白色细胞迁移穿过实验室中生长的血管细胞的能力。总的来说，这将告诉我们衰老细胞是否在衰老过程中积累，这些细胞的功能是否下降，以及这些细胞是否在免疫监视中有缺陷。在这项提案中寻求资助的科学家娜塔莉里德尔博士在她的博士研究期间使用了一种在人类中产生轻微压力的技术。这包括要求志愿者对3个人的小听众口头描述一种情况。值得注意的是，年轻受试者（<40岁）的这种轻度应激能够诱导白色细胞从组织动员到血液中，其程度与运动相同。因此，该方法是免疫监测能力的替代评估。我们现在要研究的是老年受试者（>70岁）在应激反应中动员白色细胞的能力，并确定动员的细胞的质量。这些研究将为衰老过程中免疫质量的变化以及老年人免疫系统对外部影响的反应能力提供新的信息。这是一项跨学科的工作，利用多种技术来了解衰老对人体免疫力的影响。

Older humans are susceptible to infections and malignancy indicating that their immune systems become less effective. The continuous challenge by infectious agents, especially those such as viruses that persist in the body throughout life, may drive the reactive white cells towards exhaustion. Secondly, one of the main attributes of the immune system is the capacity of white cells to migrate from the blood to the tissues and back again, a phenomenon known as immunosurveillance. In this project we make use of reagents that enable us to investigate the quality of T cells as well as their capacity for migration in older humans, to determine if one or both of these essential functions are defective. We will also investigate the white cells in the blood and in the lymph nodes and in the blood and bone marrow in two different groups of individuals simultaneously. This is a unique opportunity as normally only the leukocytes in blood are studied in humans due to the difficulty of obtaining tissue samples. We have all the appropriate ethical approval to be able to perform these studies. This project will also utilize additional novel technology that we developed, to measure the telomeres, the equivalent of an ageing clock in white cells that react to viruses. The cells with long telomere have the potential to persist in the body while those with short telomeres (senescent) are close to running out of time and will be lost. Furthermore, by using time-lapse microscopy, we can visualize the capacity of white cells from old and young subjects to migrate across blood vessel cells that are grown in the laboratory. Collectively this will tell us about whether senescent cells, that have decreased function accumulate during ageing and whether these cells are defective in imunosurveillance.Stress is known to be bad for immunity, especially during ageing. The scientist for whom funding is being sought in this proposal, Dr. Natalie Riddell used a technique for generating mild stress in humans during her PhD studies. This involved asking volunteers to give a verbal account of a situation to a small audience of 3 people. Significantly, this mild stress in young subjects (<40 yrs) was able to induce the mobilization of white cells from tissues into the blood to the same extent as excercise. This method is therefore a surrogate assessment of capacity for immunosurveillance. What we will now investigate is the capacity of older subjects (>70 yrs) to mobilize white cells during this stress response and to determine the quality of the cells that are mobilized.These studies will provide new information on changes in the quality of immunity during ageing and also the ability of the immune system in older humans to respond to external influences. This is cross-disciplinary work that utilizes multiple technologies to understand the impact of ageing on human immunity.