DEFINING THE FUNCTION OF EXTRACELLULAR ATP SENSING FOR MEMORY CD8+ T CELL GENERATION AND LONGEVITY

定义细胞外 ATP 传感对记忆 CD8 T 细胞生成和寿命的功能

基本信息

批准号：
10181261
负责人：
Henrique Borges da Silva
金额：
$ 24.9万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-17 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10181261
关键词：
ATP Receptors Ablation Adenosine Triphosphate Antigens Antiviral Agents Automobile Driving CD8-Positive T-Lymphocytes Cell Death Cell Maintenance Cell Survival Cell physiology Cells Cessation of life Data Development Eukaryota Event Funding Future Gene Deletion Generations Genes Goals Homeostasis Human Immune Immune response Immune system Immunity Immunization Immunotherapy In Vitro Infection Inflammation Knock-out Knowledge Learning Longevity Lymphocyte Maintenance Measures Mediating Memory Metabolic Metabolic Control Metabolism Mitochondria Modeling Molecular Mus Nature Nucleotides Pathway interactions Pattern Pharmacology Phase Phenotype Play Publishing Purinoceptor Research Research Personnel Resources Role Shapes Signal Transduction Source T cell differentiation T memory cell T-Lymphocyte Techniques Testing Time Vaccines Virus Virus Diseases Work adaptive immune response antigen challenge base cell injury design extracellular fitness immune activation improved insight long term memory novel therapeutics pathogen receptor response tool

项目摘要

Project summary Extracellular adenosine triphosphate (ATP) is an evolutionary conserved “danger signal” used to sense cellular damage. In mice and humans, extracellular ATP (eATP) is recognized by purinergic receptors. Among those receptors, P2RX7 is particularly relevant since it is preferentially expressed in immune cells, being able to activate both innate and adaptive immune responses. Functional adaptive immune responses – especially T cell memory – are crucial for the control of viral infections. Notably, our recently published work shows that P2RX7 is crucial for the generation and maintenance of virus-specific long-lived memory CD8+ T cells. P2RX7 seems to control the metabolic fitness – in particular, mitochondrial function and viability – of CD8+ T cells throughout the immune response. Although these findings indicate that P2RX7 is required at different time points during an effector immune response, it is not clear when during an immune response P2RX7/eATP signaling is required for the full development of memory CD8+ T cells. Another unexplored question lies on the source of eATP for P2RX7 activation in CD8+ T cells throughout the immune response. eATP can originate from the surrounding microenvironment (being CD8+ T cell-extrinsic), which is likely to happen during primary or secondary antigen responses, or can be released by the own CD8+ T cell via Pannexin 1 (Panx1) channels (being CD8+ T cell- intrinsic) – this can be particularly relevant during long-term memory, when inflammation recedes. In Aim 1, we will use P2RX7 and Panx1 ablation tools to elucidate whether P2RX7/eATP sensing is required throughout the effector phase or only during early activation – as well as the source of eATP for this stage. It is also unclear whether sustained P2RX7/eATP signaling is required for long-term survival of memory CD8+ T cells. In Aim 2 we will use tools to knockout P2RX7 and Panx1 after memory establishment to answer this question and to elucidate the eATP source potentially involved in long-term survival maintenance. Finally, in Aim 3, we will evaluate if the recall responses of memory CD8+ T cells in response to a secondary antigen encounter (and the subsequent protective immune response) requires P2RX7-mediated eATP signaling. These studies will help elucidate the role of eATP sensing for memory CD8+ T cell homeostasis and will provide key insights on how “danger signals” and the sensing of cellular damage help build not only short-term but also long-term immunity against pathogens. This will provide the basis for the improvement of future vaccine and antiviral immunotherapy designs.

项目摘要细胞外三磷酸腺苷（ATP）是一种进化保守的“危险信号”，用于感知细胞损害。在小鼠和人类中，细胞外ATP（EATP）被嘌呤能受体识别。其中受体，P2RX7特别相关，因为它优选在免疫细胞中表达，能够激活先天和适应性免疫调查。功能自适应免疫调查员 - 尤其是T细胞记忆 - 对于控制病毒感染至关重要。尤其，我们最近发表的作品显示P2RX7 对于病毒特异性长期记忆CD8+ T细胞的生成和维持至关重要。 P2RX7似乎是控制CD8+ T细胞的代谢适应性，特别是线粒体功能和生存能力 - 免疫反应。尽管这些发现的指标表明在一个不同时间点需要P2RX7 效应子免疫反应，尚不清楚在免疫反应期间需要P2RX7/EATP信号传导为了完整发展记忆CD8+ T细胞。另一个出乎意料的问题在于吃的来源在整个免疫响应中，CD8+ T细胞中的P2RX7激活。 Eatp可以起源于周围微环境（是CD8+ T细胞 - 过时），可能在初级或次级抗原期间发生响应，也可以通过pannexin 1（Panx1）通道通过自己的CD8+ T细胞释放（为CD8+ T细胞 - 固有的） - 当发炎收缩时，这在长期记忆中可能特别相关。在AIM 1中，我们将使用P2RX7和PANX1消融工具来阐明整个过程中是否需要P2RX7/EATP感应效应子阶段或仅在早期激活期间 - 以及此阶段的EATP来源。还不清楚是否需要持续的P2RX7/EATP信号传导才能长期存储CD8+ T细胞的长期存活。在目标2中我们将使用工具来敲除内存后的p2rx7和panx1，以回答这个问题并阐明可能参与长期生存维持的EATP来源。最后，在AIM 3中，我们将评估记忆CD8+ T细胞的召回响应是否响应于二级抗原相遇（以及随后的受保护免疫响应需要P2RX7介导的EATP信号传导。这些研究将有助于阐明EATP感应记忆CD8+ T细胞体内稳态的作用，并将提供有关如何 “危险信号”和细胞损伤的敏感性不仅有助于短期，而且有助于长期免疫力反对病原体。这将为改善未来疫苗和抗病毒免疫疗法的基础提供基础设计。