The integration of human T cell senescence and function at the molecular level

人类T细胞衰老与功能在分子水平上的整合

• 批准号: MR/P00184X/1
• 负责人: Arne Akbar
• 金额: $ 74.37万
• 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: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP00184X%2F1
• 关键词: integration; human; cell; senescence; function

Immunity decreases during ageing, resulting in the increased susceptibility of older individuals to both infections and cancer. The powerhouse of immunity is the T lymphocyte, that recognizes and combats malignant and infected cells. However these cells have to expand in number, akin to the mobilization of an army, to combat the infectious or cancerous challenge. This mobilization takes time and during this lag period, protection is offered by another population of leukocytes in the front line known as natural killer (NK) cells, that are less specialized in the recognition of the invaders but highly efficient in killing them. Efficient immunity therefore, requires that the 'beserker' NK cells that are involved in the first line of defense and the specialized T cells that are mobilized later fulfill their role at different phases of the war. In earlier studies we showed that T cells get older progressively as a result of repeated immune challenges and in older humans, immune protection is mediated by the equivalent of "Dad's Army" soldiers that do not function as well as younger leukocytes. The changes in old T lymphocyte population includes the decrease in their ability to proliferate and increase in numbers after immune activation, this expansion is essential for increasing the number of T cells that can seek and destroy the invaders. We showed that the decreased activity in old T cells was due to an active signaling process mediated by p38 MAPkinase and that by blocking the activity of this molecule, we could enhance proliferative activity. p38 is one of a family of distinct MAP kinases, others include JNK. Our preliminary results indicate that the T cells in old individuals also express JNK spontaneously, without the requirement of any additional activation and that these molecules may also regulate the function of T cells. Thus while we showed that p38 was a brake on lymphocyte function, our recent preliminary observations show that JNK is an additional brake, that may be engaged simultaneously. Both brakes work to inhibit different processes. Furthermore, both brakes are engaged by the energy sensor molecule AMPK that is activated by low nutrient availability or the process of ageing in the cells. We will investigate whether blocking JNK, using novel reagents that we have developed in the laboratory can restore additional functions to those that are regulated by p38 in these old T cells. Furthermore, we will determine whether either or both p38 and/or JNK MAP kinases regulate the NK-like function of old T cells. Another novel part of this investigation is the use of a human experimental system where we induce and antigen specific response by injecting chickenpox virus proteins into the skin to induce a memory immune response that we can harvest cells from. This is a totally unique model that has been developed and refined in the Akbar lab over 18 years. All the appropriate safety and ethical approvals are in place to do this. This will enable the study of how quickly leukocytes age in the skin during an immune response and the role of AMPK and the MAP kinases in this process. We will also be able to determine when T cells start to develop NK characteristics in real life, after immune stimulation in vivo.These studies will identify changes that occur in the early and late phases of the immune response and how ageing affects this. More importantly, we will determine whether it is possible to enhance the activity of old T cells by removing the MAP kinase brakes that will provide proof of principle of whether we can enhance the activity of these cells during ageing.

免疫力在衰老过程中下降，导致老年人对感染和癌症的易感性增加。免疫力的发电站是T淋巴细胞，它识别并对抗恶性细胞和感染细胞。然而，这些细胞必须在数量上扩大，类似于动员军队，以对抗传染病或癌症的挑战。这种动员需要时间，在这一滞后期，保护是由另一个群体的白细胞在前线被称为自然杀伤（NK）细胞，这是不太专业的识别入侵者，但高效地杀死他们。因此，有效的免疫需要参与第一道防线的“beserker”NK细胞和随后动员的特化T细胞在战争的不同阶段发挥作用。在早期的研究中，我们发现T细胞由于反复的免疫挑战而逐渐老化，在老年人中，免疫保护是由相当于“爸爸的军队”士兵介导的，这些士兵的功能不如年轻的白细胞。老年T淋巴细胞群的变化包括它们增殖能力的降低和免疫激活后数量的增加，这种扩增对于增加能够寻找和摧毁入侵者的T细胞数量是必不可少的。我们发现，老年T细胞活性的降低是由于p38 MAPK激酶介导的活性信号传导过程，通过阻断该分子的活性，我们可以增强增殖活性。p38是一个独特的MAP激酶家族之一，其他包括JNK。我们的初步结果表明，老年人的T细胞也自发表达JNK，而不需要任何额外的激活，这些分子也可以调节T细胞的功能。因此，虽然我们表明p38是淋巴细胞功能的制动器，但我们最近的初步观察表明JNK是一个额外的制动器，可能同时参与。两个制动器都能抑制不同的过程。此外，这两个制动器都由能量传感器分子AMPK接合，AMPK由低营养可用性或细胞老化过程激活。我们将研究使用我们在实验室开发的新试剂阻断JNK是否可以恢复这些旧T细胞中由p38调节的额外功能。此外，我们将确定是否p38和/或JNK MAP激酶调节老T细胞的NK样功能。这项研究的另一个新部分是使用人类实验系统，我们通过将水痘病毒蛋白注射到皮肤中来诱导抗原特异性反应，以诱导记忆免疫反应，我们可以从中收获细胞。这是一个完全独特的模型，已经在Akbar实验室开发和完善了18年。所有适当的安全和道德批准都已到位。这将使研究白细胞在免疫应答期间在皮肤中老化的速度以及AMPK和MAP激酶在此过程中的作用成为可能。我们还将能够确定在体内免疫刺激后，T细胞在真实的生活中何时开始发展NK特征。这些研究将确定免疫应答早期和晚期发生的变化以及衰老如何影响这一点。更重要的是，我们将确定是否有可能通过去除MAP激酶制动器来增强老年T细胞的活性，这将为我们是否可以在衰老过程中增强这些细胞的活性提供原理证明。

项目成果

GATA3 controls mitochondrial biogenesis in primary human CD4 + T cells during DNA damage

GATA3 在 DNA 损伤期间控制原代人 CD4 T 细胞的线粒体生物合成

• DOI: 10.1101/727479
• 发表时间: 2019
• 作者: Callender L

The role of senescent T cells in immunopathology.

衰老T细胞在免疫病理学中的作用。

• DOI: 10.1111/acel.13272
• 发表时间: 2020-12
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Covre LP;De Maeyer RPH;Gomes DCO;Akbar AN
• 通讯作者: Akbar AN

Circulating Senescent T Cells Are Linked to Systemic Inflammation and Lesion Size During Human Cutaneous Leishmaniasis

• DOI: 10.3389/fimmu.2018.03001
• 发表时间: 2019-01-04
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Covre, Luciana P.;Martins, Regia F.;Gomes, Daniel C. O.
• 通讯作者: Gomes, Daniel C. O.

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

An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory.

• DOI: 10.1038/s41556-022-00991-z
• 发表时间: 2022-10
• 期刊: Nature cell biology
• 影响因子: 21.3
• 作者: Lanna A;Vaz B;D'Ambra C;Valvo S;Vuotto C;Chiurchiù V;Devine O;Sanchez M;Borsellino G;Akbar AN;De Bardi M;Gilroy DW;Dustin ML;Blumer B;Karin M
• 通讯作者: Karin M