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

• 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

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.

年长的人容易感染和恶性肿瘤，表明其免疫系统效果降低。传染剂的持续挑战，尤其是那些一生中持续存在的病毒，可能会将反应性的白细胞驱动到疲惫中。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，然后又返回，这是一种称为免疫监视的现象。在这个项目中，我们利用使我们能够研究T细胞质量及其在老年人中迁移的能力的试剂，以确定其中一个或两个基本功能是否有缺陷。我们还将同时研究血液中的白细胞，淋巴结和血液和骨髓中的白细胞。这是一个独特的机会，因为由于难以获得组织样本，通常只有在人类中研究血液中的白细胞。我们拥有所有适当的道德认可，以便能够进行这些研究。该项目还将利用我们开发的其他新技术来测量端粒，相当于对病毒反应的白细胞中衰老时钟。端粒较长的细胞有可能持续体内，而端粒短（衰老）的细胞几乎没有时间耗尽，并且会丢失。此外，通过使用延时显微镜，我们可以可视化白细胞从老年和年轻受试者迁移到实验室生长的血管细胞的能力。总体而言，这将告诉我们有关在衰老期间功能降低的衰老细胞以及这些细胞是否在毫米露天监视中有缺陷。在该提案中寻求资金的科学家，娜塔莉·里德尔（Natalie Riddell）博士在博士学位研究期间使用了一种技术来在人类中产生轻度压力。这涉及要求志愿者对3人的少数听众进行口头说明。值得注意的是，年轻受试者的轻度应激（<40岁）能够诱导白细胞从组织进入血液的动员，其程度与练习程度相同。因此，该方法是对免疫监视能力的替代评估。我们现在将研究的是，在这种压力反应期间，老年受试者（> 70年）动员白细胞的能力并确定动员的细胞质量。这些研究将提供有关衰老期间免疫质量的新信息，以及衰老能力的变化以及老年人中免疫系统对外部影响的反应。这是跨学科的工作，利用多种技术来了解衰老对人免疫的影响。

项目成果

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.

• DOI: 10.3389/fimmu.2016.00445
• 发表时间: 2016
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Pereira BI;Akbar AN
• 通讯作者: Akbar AN

Killer Cell Lectin-like Receptor G1 Inhibits NK Cell Function through Activation of Adenosine 5'-Monophosphate-Activated Protein Kinase.

• DOI: 10.4049/jimmunol.1600590
• 发表时间: 2016-10-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Müller-Durovic B;Lanna A;Covre LP;Mills RS;Henson SM;Akbar AN
• 通讯作者: Akbar AN

A breakdown in communication? Understanding the effects of aging on the human small intestine epithelium.

• DOI: 10.1042/cs20150364
• 发表时间: 2015-10
• 期刊: Clinical science (London, England : 1979)
• 作者: Mabbott NA