Regulation of T cell responses by P2RX7

P2RX7 对 T 细胞反应的调节

基本信息

批准号：
10605308
负责人：
STEPHEN C JAMESON
金额：
$ 55.07万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-17 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10605308
关键词：
Ablation Adaptive Immune System Address Affect Agonist Animal Model Area Attention Autoimmune Diseases Biological Assay Biology CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Death Induction Cell Differentiation process Cell Maintenance Cell Survival Cell surface Cells Cellular Metabolic Process Cessation of life Chronic Clinic Clinical Cues Data Effector Cell Exposure to Generations Goals Health Human Immune Immune response Immune system Immunity Immunologic Memory Impairment In Vitro Infection Inflammasome Inflammation Innate Immune System Investigation Ions Knowledge Maintenance Malignant Neoplasms Mediating Memory Metabolic Metabolism Mitochondria Molecular Mus Natural Immunity Pathway interactions Pattern Pattern Recognition Pharmacologic Substance Pharmacological Treatment Play Population Production Property Proteins Publishing Purinoceptor Regulation Role Signal Pathway Signal Transduction Source T cell differentiation T cell regulation T cell response T memory cell T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Therapeutic Effect Time Tissues Virus Diseases Work acute infection antagonist autocrine cell injury chronic infection chronic pain chronic pain management clinically significant extracellular immune activation improved in vivo inflammatory pain inhibitor memory CD4 T lymphocyte metabolic fitness nerve damage nerve injury novel painful neuropathy pathogen pharmacologic preservation receptor response sensor therapy design

项目摘要

Summary One of the best defined “danger” signals, that alerts the innate immune system to cellular damage, is extracellular ATP, triggering ion flux through the purinergic receptor P2RX7. The roles of P2RX7 in the adaptive immune system, by contrast, are less clear. We recently showed that P2RX7 was essential for production and maintenance of long-lived CD8+ T cell memory. This involved P2RX7 signals promoting the establishment of mitochondrial maintenance and metabolic “fitness” in differentiating memory CD8+ T cells, but we also found evidence that sustained P2RX7 signals are needed to sustain pre-existing memory CD8+ T cells, suggesting this “danger” signal is repurposed to provide a homeostatic survival signal for CD8+ T cells. Much remains to be understood about how P2RX7 signaling influences T cell memory, however. In Aim 1, we turn our attention to CD4+ T cells: while P2RX7 is critical for generation of memory CD8+ T cells, certain subsets of memory CD4+ T cells (including follicular helper-like central memory cells), show increased survival when P2rx7 is ablated – we explore the basis for these differential effects of P2RX7 stimulation on CD4+ and CD8+ memory T cell subsets. In Aim 2, we explore how memory CD8+ T cells may be able to provide autocrine stimulation of P2RX7 through export of their “own” ATP, through the Pannexin 1 channel. Finally, P2RX7 has been shown to play an important role in another area of biology – in chronic pain. Sustained stimulation of P2RX7 on innate immune cells is thought to be responsible for various forms of neuropathic and inflammatory pain (associated with nerve damage, autoimmune diseases, cancer, etc.) and pharmacological blockade of P2RX7 has been shown in animal models to alleviate such chronic pain. This raises the key question of whether use of such therapeutic blockade leads to degradation of pre-existing T cell memory - in particular, whether such treatment would impair CD8+ T cell mediated control of persistent viral infections. We address this in Aim 3, also investigating whether directed stimulation (rather than blockade) of P2RX7 can be used as a viable way to improve the generation of long-lived CD8+ T cell memory and potentially to enhance control of chronic viral infections but may also dysregulate the CD4+ T cell memory compartment. Together, these studies represent a novel and highly significant investigation into how an innate immune trigger is co-opted into regulating adaptive immune memory, and how this pathway can be harnessed for therapeutic goals with possible application to the clinic.

概括最好定义的“危险”信号之一，它警告先天免疫系统对细胞损害的损害，是细胞外ATP，通过嘌呤能受体P2RX7触发离子通量。 P2RX7在相比之下，自适应免疫系统尚不清楚。我们最近表明P2RX7对于长期寿命CD8+ T细胞存储器的生产和维护。这涉及P2RX7信号促进在区分记忆CD8+ T细胞中建立线粒体维护和代谢“适应性”，但我们还发现证据表明需要持续的P2RX7信号来维持先前存在的内存CD8+ T 细胞，表明这种“危险”信号被重新使用以提供CD8+ T细胞的稳态存活信号。但是，关于P2RX7信号如何影响T细胞存储器的信号如何，还有许多待理解。在AIM 1中，我们将注意力转向CD4+ T细胞：虽然P2RX7对于生成记忆CD8+ T细胞至关重要，但记忆CD4+ T细胞的子集（包括卵泡辅助辅助辅助中心记忆细胞），显示出生存率增加当P2RX7被烧毁时 - 我们探索了P2RX7模拟对CD4+和 CD8+内存T细胞子集。在AIM 2中，我们探讨了内存CD8+ T细胞如何提供自分泌通过PANNEXIN 1通道出口其“自己的” ATP来刺激P2RX7。最后，P2RX7具有我们被证明在生物学的另一个领域中起着重要作用 - 在慢性疼痛中。持续的刺激先天性免疫核管上的P2RX7被认为是各种形式的神经性和炎症的原因疼痛（与神经损伤，自身免疫性疾病，癌症等有关）和药物阻滞 P2RX7已在动物模型中显示，以减轻这种慢性疼痛。这提出了一个关键问题使用这种治疗性阻滞是否会导致先前存在的T细胞存储器降解 - 特别是这种治疗是否会损害CD8+ T细胞介导的持续病毒感染的控制。我们解决在AIM 3中，还调查了P2RX7的定向刺激（而不是封锁）是否可以用作改善长寿命CD8+ T细胞记忆的生成的可行方法，并有可能增强对慢性病毒感染，但也可能导致CD4+ T细胞记忆室失调。在一起，这些研究代表了一种新颖而又非常重要的投资，用于如何将先天免疫触发触发为调节适应性免疫记忆，以及如何利用这种途径来实现治疗目标可能应用于诊所。

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）

The monoaminergic modulation of sensory-mediated aversive responses in Caenorhabditis elegans requires glutamatergic/peptidergic cotransmission.

DOI：
10.1523/jneurosci.0497-10.2010
发表时间：
2010-06-09
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Harris G;Mills H;Wragg R;Hapiak V;Castelletto M;Korchnak A;Komuniecki RW
通讯作者：
Komuniecki RW

Three distinct amine receptors operating at different levels within the locomotory circuit are each essential for the serotonergic modulation of chemosensation in Caenorhabditis elegans.

DOI：
10.1523/jneurosci.4585-08.2009
发表时间：
2009-02-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Harris GP;Hapiak VM;Wragg RT;Miller SB;Hughes LJ;Hobson RJ;Steven R;Bamber B;Komuniecki RW
通讯作者：
Komuniecki RW

Heterologous Expression in Remodeled C. elegans: A Platform for Monoaminergic Agonist Identification and Anthelmintic Screening.