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

代谢重编程支持效应器的分化、扩增和功能成熟 记忆T细胞。它还有助于T细胞功能的去调节，如T细胞衰竭。 肿瘤微环境，或自身免疫性疾病的耐受性破坏。了解不同的代谢 计划受到规范，以促进特定血统的发展和功能将提供重要的见解 设计针对T细胞新陈代谢的新疗法。INKT细胞是一组先天的T细胞，扮演着 在许多病理条件下发挥重要作用。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，嘌呤能受体P2X7是一种新的 INKT细胞分化调节因子。这项研究的总体目标是定义P2X7如何 调节子集专门化和功能成熟。在目标1中，我们将确定P2X7作为一个 在iNKT细胞分化过程中，ATP调节的钙通道促进最佳的钙信号。我们将探索 P2X7和TCR激活之间的联系以及作为线粒体重要辅助因子的钙离子 呼吸。在目标2中，我们将确定P2X7在iNKT细胞分化和分化过程中作为代谢调节因子的作用 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了新的新陈代谢 组件/过程，如细胞外ATP(eATP，P2X7的配体)，钙信号，和线粒体， 它可以特异性地调节iNKT亚群的分化和效应器功能。来自科布雷的支持 Grant将使我们能够朝着我们的长期目标迈出关键的一步，瞄准先天T细胞新陈代谢 用来治疗人类疾病。

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.