Role of purinergic receptor P2X7 in the differentiation and function of iNKT cell subsets

嘌呤能受体P2X7在iNKT细胞亚群分化和功能中的作用

基本信息

批准号：
10090983
负责人：
Meng Zhao
金额：
$ 34.96万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-05 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10090983
关键词：
Ablation Affect Agonist Antigens Autoimmune Diseases Autophagocytosis Bacterial Infections Bioenergetics Biological Assay CD8-Positive T-Lymphocytes Cell physiology Cells Cellular Metabolic Process Centers of Research Excellence Cytokine Signaling Cytotoxic T-Lymphocytes Development Enzymes Flow Cytometry Gene Expression Genetic Glucose Goals Grant Homeostasis IL4 gene Image Inflammatory Interleukin-4 Ligands Lipids Mainstreaming Maintenance Mediating Memory Metabolic Metabolic Pathway Metabolism Mitochondria Nutrient Oklahoma Organ Organ Culture Techniques Oxidative Phosphorylation Pathologic Pathway interactions Play Population Process Production Purinoceptor Radiolabeled Research Respiration Role Signal Transduction Specificity Stream System T cell differentiation T cell regulation T cell therapy T memory cell T-Cell Development T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets T-cell receptor repertoire TCR Activation Testing Thymus Gland Tracer base calcium uniporter design exhaustion extracellular glucose metabolism human disease inhibitor/antagonist insight metabolic phenotype new therapeutic target novel novel therapeutics oxidation programs sensor targeted treatment tumor microenvironment

项目摘要

Metabolic reprogramming supports the differentiation, expansion and functional maturation of effector and memory T cells. It is also contributing to the de-regulation of T cell functions, such as T cell exhaustion in the tumor microenvironment, or break of tolerance in autoimmune diseases. Understanding how distinct metabolic programs are regulated to facilitate lineage specific development and function will provide important insight for designing new therapeutics targeting T cell metabolism. iNKT cells are a group of innate-like T cells, playing important roles in many pathological conditions. iNKT cell differentiation into mature functional subsets NKT1, 2 and 17 in the thymus represents an alternative paradigm of T cell development. In our preliminary study, we have identified distinctive metabolic features of iNKT cell subsets, and the purinergic receptor P2X7 as a new regulator for iNKT cell differentiation. The overall goal of this study is to define the mechanism how P2X7 modulates subset specialization and functional maturation. In Aim 1, we will determine the role of P2X7 as an ATP gated Ca2+ channel to promote optimal Ca2+ signals during iNKT cell differentiation. We will explore the connections between P2X7 and TCR activation, as well as Ca2+ as an important co-factor for mitochondria respiration. In Aim 2, we will define the role of P2X7 as a metabolic regulator during iNKT cell differentiation and activation. We will test if and how P2X7 regulates glucose metabolism, and if the energy sensor AMPK acts down stream of P2X7 activation. The immediate contribution of this study is to reveal novel metabolic components/processes, such as extracellular ATP (eATP, ligands for P2X7), Ca2+ signal, and mitochondria, which can specifically modulate iNKT subsets differentiation and effector functions. The support from a COBRE grant will enable us to take a critical step towards our long-term goal, targeting innate-like T cell metabolism to treat human diseases.

代谢重编程支持效应器和效应器的分化、扩展和功能成熟记忆T细胞。它还导致 T 细胞功能失调，例如 T 细胞耗竭肿瘤微环境，或自身免疫性疾病的耐受性破坏。了解代谢有何不同对程序进行监管以促进谱系特定的发展和功能将为设计针对 T 细胞代谢的新疗法。 iNKT 细胞是一组先天性 T 细胞，在在许多病理状况中发挥重要作用。 iNKT 细胞分化为成熟功能亚群 NKT1, 2 胸腺中的 17 代表了 T 细胞发育的另一种范例。在我们的初步研究中，我们已经确定了 iNKT 细胞亚群独特的代谢特征，并且嘌呤能受体 P2X7 作为一种新的 iNKT 细胞分化的调节因子。本研究的总体目标是确定 P2X7 的机制调节子集专业化和功能成熟。在目标 1 中，我们将确定 P2X7 的角色： ATP 门控 Ca2+ 通道可在 iNKT 细胞分化过程中促进最佳 Ca2+ 信号。我们将探索 P2X7 和 TCR 激活之间的联系，以及 Ca2+ 作为线粒体的重要辅助因子呼吸。在目标 2 中，我们将定义 P2X7 在 iNKT 细胞分化过程中作为代谢调节剂的作用，以及激活。我们将测试 P2X7 是否以及如何调节葡萄糖代谢，以及能量传感器 AMPK 是否起作用 P2X7 激活的下游。这项研究的直接贡献是揭示新的代谢成分/过程，例如细胞外 ATP（eATP、P2X7 配体）、Ca2+ 信号和线粒体，它可以特异性调节 iNKT 亚群分化和效应功能。 COBRE 的支持这笔赠款将使我们能够朝着我们的长期目标迈出关键的一步，针对先天性 T 细胞代谢来治疗人类疾病。