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

衰老过程中低亲和力病毒特异性T细胞的功能和迁移特征

基本信息

批准号：
BB/L005336/1
负责人：
Arne Akbar
金额：
$ 73.42万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FL005336%2F1
关键词：
functional migratory characteristics low avidity

项目摘要

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.

老年人容易受到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。感染源的持续挑战，尤其是终生在体内持续存在的病毒等感染源，可能会导致反应性白细胞衰竭。其次，免疫系统的主要属性之一是白细胞从血液迁移到组织并再返回的能力，这种现象称为免疫监视。在这个项目中，我们利用试剂来研究老年人 T 细胞的质量及其迁移能力，以确定这些基本功能中的一项或两项是否有缺陷。我们还将同时研究两组不同个体的血液、淋巴结、血液和骨髓中的白细胞。这是一个独特的机会，因为由于获取组织样本的困难，通常只研究人类血液中的白细胞。我们拥有能够进行这些研究的所有适当的伦理批准。该项目还将利用我们开发的其他新技术来测量端粒，相当于白细胞中对病毒做出反应的老化时钟。端粒较长的细胞有可能在体内持续存在，而端粒较短（衰老）的细胞则接近耗尽时间并会消失。此外，通过使用延时显微镜，我们可以可视化年老和年轻受试者的白细胞在实验室生长的血管细胞中迁移的能力。总的来说，这将告诉我们功能下降的衰老细胞是否在衰老过程中积累，以及这些细胞是否在免疫监视方面存在缺陷。众所周知，压力不利于免疫力，尤其是在衰老过程中。本提案正在寻求资助的科学家 Natalie Riddell 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。这包括要求志愿者向 3 人的小观众口头描述情况。值得注意的是，年轻受试者（<40 岁）的这种轻微压力能够诱导白细胞从组织动员到血液中，其程度与运动相同。因此，该方法是免疫监视能力的替代评估。我们现在要研究的是老年受试者（> 70岁）在这种应激反应期间动员白细胞的能力，并确定被动员的细胞的质量。这些研究将提供有关应激反应期间免疫质量变化的新信息。衰老以及老年人免疫系统对外部影响做出反应的能力。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。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging.

DOI：
10.1038/ni.3665
发表时间：
2017-03
期刊：
Nature immunology
影响因子：
30.5
作者：
Lanna A;Gomes DC;Muller-Durovic B;McDonnell T;Escors D;Gilroy DW;Lee JH;Karin M;Akbar AN
通讯作者：
Akbar AN

Multifunctional cytomegalovirus (CMV)-specific CD8(+) T cells are not restricted by telomere-related senescence in young or old adults.

DOI：
10.1111/imm.12409
发表时间：
2015-04
期刊：
Immunology
影响因子：
6.4
作者：
Riddell NE;Griffiths SJ;Rivino L;King DC;Teo GH;Henson SM;Cantisan S;Solana R;Kemeny DM;MacAry PA;Larbi A;Akbar AN
通讯作者：
Akbar AN

Convergence of Innate and Adaptive Immunity during Human Aging.