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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：
10200672
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/10200672
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 immune activation improved insight long term memory metabolic fitness 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）是一种进化上保守的“危险信号”，损害在小鼠和人类中，细胞外ATP（eATP）由嘌呤能受体识别。人中受体，P2 RX 7是特别相关的，因为它优先在免疫细胞中表达，能够激活先天性和适应性免疫反应。功能性适应性免疫反应-特别是T细胞记忆-对于控制病毒感染至关重要。值得注意的是，我们最近发表的研究显示P2 RX 7 对于病毒特异性长寿命记忆性CD 8 + T细胞的产生和维持至关重要。P2 RX 7似乎控制整个过程中CD 8 + T细胞的代谢适应性-特别是线粒体功能和活力- 免疫反应尽管这些发现表明P2 RX 7在不同的时间点是必需的，在效应免疫应答中，尚不清楚何时需要P2 RX 7/eATP信号传导记忆性CD 8 + T细胞的完全发育。另一个未探索的问题在于eATP的来源，在整个免疫应答中，CD 8 + T细胞中的P2 RX 7活化。eATP可来源于周围环境微环境（是CD 8 + T细胞外源性），这可能发生在初级或次级抗原可以通过自身的CD 8 + T细胞通过Pannexin 1（Panx 1）通道（即CD 8 + T细胞-T细胞）释放。内在的）-这在炎症消退时的长期记忆中可能特别相关。目标1：将使用P2 RX 7和Panx 1消融工具阐明在整个消融期间是否需要P2 RX 7/eATP感知。效应期或仅在早期激活期间-以及该阶段的eATP来源。也不清楚持续的P2 RX 7/eATP信号传导是否是记忆性CD 8 + T细胞长期存活所必需的。在目标2中我们将在记忆建立后使用工具敲除P2 RX 7和Panx 1来回答这个问题，阐明eATP来源可能参与长期生存维持。在目标3中，我们将评估记忆性CD 8 + T细胞响应于第二抗原遭遇的回忆应答（和免疫应答）是否是免疫应答。随后的保护性免疫应答）需要P2 RX 7介导的eATP信号传导。这些研究将有助于阐明eATP传感对记忆CD 8 + T细胞稳态的作用，并将提供关于如何 “危险信号”和细胞损伤的感知不仅有助于建立短期免疫力，而且有助于建立长期免疫力对抗病原体这将为今后疫苗和抗病毒免疫治疗的改进提供依据的设计.