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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.

总结一个最好定义的“危险”信号，提醒先天免疫系统细胞损伤，是细胞外ATP，触发通过嘌呤能受体P2 RX 7的离子流。P2 RX 7在相比之下，适应性免疫系统就不那么清楚了。我们最近发现，P2 RX 7是至关重要的，产生和维持长寿的CD 8 + T细胞记忆。这涉及到P2 RX 7信号促进在分化记忆性CD 8 + T细胞中建立线粒体维持和代谢“适应性”，但我们还发现证据表明，持续的P2 RX 7信号需要维持预先存在的记忆CD 8 + T细胞。这表明这种“危险”信号被重新用于为CD 8 + T细胞提供稳态生存信号。然而，关于P2 RX 7信号传导如何影响T细胞记忆，还有很多问题有待了解。目标1：将我们的注意力转向CD 4 + T细胞：虽然P2 RX 7对于记忆性CD 8 + T细胞的产生至关重要，但某些记忆性CD 4 + T细胞亚群（包括滤泡辅助细胞样中央记忆细胞）的存活率增加，当P2 rx 7被消融时，我们探索了P2 rx 7刺激对CD 4+和CD 4+细胞的这些差异效应的基础。 CD 8+记忆T细胞亚群。在目标2中，我们探索了记忆性CD 8 + T细胞如何能够提供自分泌功能，通过Pannexin 1通道输出其“自身”ATP刺激P2 RX 7。最后，P2 RX 7具有在生物学的另一个领域--慢性疼痛中也发挥着重要作用。持续刺激先天性免疫细胞上的P2 RX 7被认为是导致各种形式的神经性和炎性疾病的原因。疼痛（与神经损伤、自身免疫性疾病、癌症等相关）和药理学阻断 P2 RX 7已经在动物模型中显示出缓解这种慢性疼痛。这就提出了一个关键问题，使用这种治疗性阻断是否导致预先存在的T细胞记忆的退化-特别是，这种治疗是否会损害CD 8 + T细胞介导的持续性病毒感染控制。我们解决这在目标3中，也研究了P2 RX 7的定向刺激（而不是阻断）是否可以用作治疗。一种可行的方法，以改善长期生存的CD 8 + T细胞记忆的产生，并有可能提高控制慢性病毒感染，但也可能失调的CD 4 + T细胞记忆区室。所有这些这些研究代表了一种新颖的和非常重要的研究，即先天免疫触发因子是如何被选择进入调节适应性免疫记忆，以及如何利用这一途径实现治疗目标，可能应用于临床。

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.