Regulation of metabolic pathways in NKT cells

摘要 在传统的T细胞中，控制细胞新陈代谢的信号通路在决定 T细胞活化的结果及其效应器功能。静息的CD4和CD8 T细胞主要使用 氧化代谢，但刺激导致他们急剧增加葡萄糖代谢，并采取有氧 糖酵解是一种主要的代谢程序。然而，对代谢调节及其在糖尿病中的作用知之甚少。 自然杀伤T细胞(NKT)的细胞功能，尽管最近的研究表明 NKT细胞分化中的代谢。NKT细胞是一个异质性群体，显示出高度的 表型和功能专门化。与传统的T细胞不同，NKT细胞在激活时表现出快速的 以及强大的效应器功能，如细胞因子释放或细胞毒性。NKT细胞既可以在炎症中发挥作用 或调节功能，取决于组织类型，例如肝脏或脂肪组织，它们分别是 成矿地点。因此，NKT细胞的代谢调节可能在免疫过程中起着重要作用。 疾病。了解NKT细胞如何调节其新陈代谢以调节适当的免疫反应 在不同的环境下，我们测量了与代谢能力和 将其与CD4T细胞进行比较。我们的研究表明NKT细胞与CD4T细胞有很大的不同 在很多方面。NKT细胞的生存更多地依赖于氧化磷酸化和重新定位的GLC碳 用于优化细胞因子的表达。此外，NKT细胞的增殖依赖于谷氨酰胺(Gln)代谢 但不表达干扰素-。GLN饥饿的NKT细胞似乎不能有效地转换为葡萄糖(GLC)代谢， 这类似于谷氨酰胺成瘾的癌细胞。代谢数据显示NKT细胞升高 谷氨酰胺代谢产物在刺激前进一步支持谷氨酰胺代谢的重要作用。MTORC和 已知AMPK分别增加和减少谷氨酰胺代谢。与此相一致，NKT细胞 对mTORC抑制敏感，但AMPK缺乏会导致细胞过度增殖和细胞因子增加 表情。根据我们的数据，我们假设谷氨酰胺代谢的适当调节对NKT至关重要 细胞的生存和功能，这是由mTORC和AMPK活性之间的平衡控制的。要测试 假设，我们提出了两个具体的目标。目标1将研究谷氨酰胺控制NKT的机制 细胞的增殖和功能，目标2将重点放在mTORC-AMPK轴上，以识别Gln的调节 NKT细胞的新陈代谢。NKT细胞的代谢状态和调节几乎是未知的，因此， 研究NKT细胞代谢网络的调控具有很高的创新性。毫无疑问， 拟议的研究具有重要意义，因为这些研究将涉及一个知之甚少的领域，以及 这一结果将确定NKT细胞的特定和选择性代谢需求。

ABSTRACT In conventional T cells, signaling pathways that control cellular metabolism have a crucial role in dictating the outcome of T cell activation and their effector function. Resting CD4 and CD8 T cells use predominantly oxidative metabolism but stimulation leads them to sharply increase glucose metabolism and adopt aerobic glycolysis as a primary metabolic program. However, little is known about metabolic regulation and its role for cellular functions of Natural Killer T (NKT) cells although recent studies indicate an important role of metabolism in NKT cell differentiation. NKT cells are a heterogeneous population that shows a high degree of phenotypic and functional specialization. When activated, unlike conventional T cells, NKT cells exhibit a fast and robust effector function such as cytokine release or cytotoxicity. NKT cells can exert either an inflammatory or a regulatory function depending on the tissue type such as liver or adipose tissue, respectively, that are a site of metainflammation. Thus, the metabolic regulation in NKT cells likely plays an important role in immune diseases. To understand how NKT cells regulate their metabolism to mediate an appropriate immune response under a different environment, we measured parameters that associate with the metabolic capacity and compared them with that of CD4 T cells. Our study revealed that NKT cells are very different from CD4 T cells in many ways. NKT cells rely more on oxidative phosphorylation for their survival and repurposed Glc carbon is used for optimal cytokine expression. In addition, NKT cells rely on glutamine (Gln) metabolism for proliferation but not to express IFN-. Gln starved NKT cells seem to be inefficient to switch to glucose (Glc) metabolism, which is similar to Gln-addicted cancer cells. Metabolomic data revealed that NKT cells have elevated glutamine metabolites prior to stimulation further supporting an essential role of Gln metabolism. mTORC and AMPK is known to increase and decrease Gln metabolism, respectively. In line with this, NKT cells are sensitive to mTORC inhibition but AMPK deficiency results in hyperproliferation and increased cytokine expression. Based on our data, we hypothesize that the proper regulation of Gln metabolism is critical for NKT cells’ survival and function, which is controlled by the balance between mTORC and AMPK activity. To test the hypothesis, we propose two specific aims. Aim 1 will investigate the mechanisms by which Gln controls NKT cell proliferation and function, and Aim 2 will focus on the mTORC-AMPK axis to discern the regulation of Gln metabolism in NKT cells. Metabolic status and regulation in NKT cells is virtually unexplored and, therefore, investigating the regulation of the metabolic networks in NKT cells is highly innovative. Undoubtedly, the proposed studies are significant given the fact that these studies will address a poorly understood area, and the results will establish specific and selective metabolic demands of NKT cells.