Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40536.
Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40536;
Immunohorizons. 2020 May 8;4(5):231-244. doi: 10.4049/immunohorizons.2000020.
CD8 T cells and NK cells are the two major cytotoxic lymphocytes that carry out cell-mediated immunity and regulate other immune responses. However, we do not completely understand human CD8 T cell and NK cell metabolic requirements and they have not been compared in the same experiments. We activated human CD8 T cells by two anti-CD3/CD28 mAb methods, and we stimulated both CD8 T cells and NK cells with IL-12/IL-18. When glucose (Glc) could not be used, human CD8 T cells either died or became hypofunctional, depending upon the anti-CD3/CD28 activation method. In contrast, Glc starvation did not decrease the percentage of IL-12/IL-18-stimulated human NK cells that made IFN-γ. NK cells were relatively fuel resilient and used Glc, glutamine (Gln), fatty acid, or acetate to power IFN-γ expression. Surprisingly, strongly activated human CD8 T cells required Gln for glycolysis and Glc uptake. We showed that human CD8 T cells regulate Glc uptake by a novel mechanism related to the TXNIP pleiotropic protein. These conditions may be relevant to septic patients who have high blood Glc but low Gln. Under the conditions tested, Gln did not change human NK cell TXNIP expression. Our experiments reveal fundamental differences in human CD8 T cell and NK cell metabolism and the fuels needed for IFN-γ production.
CD8 T 细胞和自然杀伤（NK）细胞是执行细胞介导免疫和调节其他免疫反应的两种主要细胞毒性淋巴细胞。然而，我们并不完全了解人类 CD8 T 细胞和 NK 细胞的代谢需求，也没有在相同的实验中对它们进行比较。我们通过两种抗 CD3/CD28 mAb 方法激活人类 CD8 T 细胞，并通过 IL-12/IL-18 刺激 CD8 T 细胞和 NK 细胞。当葡萄糖（Glc）无法被利用时，人类 CD8 T 细胞要么死亡，要么功能低下，这取决于抗 CD3/CD28 的激活方法。相比之下，Glc 饥饿并不会减少产生 IFN-γ 的 IL-12/IL-18 刺激的人类 NK 细胞的百分比。NK 细胞相对具有较强的燃料弹性，可利用 Glc、谷氨酰胺（Gln）、脂肪酸或乙酸盐来表达 IFN-γ。出人意料的是，强烈激活的人类 CD8 T 细胞需要 Gln 进行糖酵解和 Glc 摄取。我们表明，人类 CD8 T 细胞通过与 TXNIP 多功能蛋白相关的新型机制来调节 Glc 摄取。这些条件可能与血糖高但 Gln 低的败血症患者有关。在测试的条件下，Gln 不会改变人类 NK 细胞 TXNIP 的表达。我们的实验揭示了人类 CD8 T 细胞和 NK 细胞代谢以及产生 IFN-γ 所需燃料之间的根本差异。
