San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Diabetes. 2018 May;67(5):936-945. doi: 10.2337/db17-1390. Epub 2018 Mar 5.
Stem memory T cells (Tscm) constitute the earliest developmental stage of memory T cells, displaying stem cell-like properties, such as self-renewal capacity. Their superior immune reconstitution potential has sparked interest in cancer immune therapy, vaccine development, and immune reconstitution, whereas their role in autoimmunity is largely unexplored. Here we show that autoreactive CD8 Tscm specific for β-cell antigens GAD65, insulin, and IGRP are present in patients with type 1 diabetes (T1D). In vitro, the generation of autoreactive Tscm from naive precursors required the presence of the homeostatic cytokine interleukin-7 (IL-7). IL-7 promotes glucose uptake via overexpression of GLUT1 and upregulation of the glycolytic enzyme hexokinase 2. Even though metabolism depends on glucose uptake, the subsequent oxidation of pyruvate in the mitochondria was necessary for Tscm generation from naive precursors. In patients with T1D, high expression of GLUT1 was a hallmark of circulating Tscm, and targeting glucose uptake via GLUT1 using the selective inhibitor WZB117 resulted in inhibition of Tscm generation and expansion. Our results suggest that autoreactive Tscm are present in patients with T1D and can be selectively targeted by inhibition of glucose metabolism.
干细胞记忆 T 细胞（Tscm）构成了记忆 T 细胞的最早发育阶段，具有干细胞样特性，如自我更新能力。它们在癌症免疫治疗、疫苗开发和免疫重建方面具有优越的免疫重建潜力，而它们在自身免疫中的作用在很大程度上尚未得到探索。在这里，我们表明，针对β细胞抗原 GAD65、胰岛素和 IGRP 的自身反应性 CD8 Tscm 存在于 1 型糖尿病（T1D）患者中。在体外，从幼稚前体中产生自身反应性 Tscm 需要存在稳态细胞因子白细胞介素 7（IL-7）。IL-7 通过过表达 GLUT1 和上调糖酵解酶己糖激酶 2 来促进葡萄糖摄取。尽管代谢依赖于葡萄糖摄取，但随后在线粒体中丙酮酸的氧化对于从幼稚前体中产生 Tscm 是必要的。在 T1D 患者中，GLUT1 的高表达是循环 Tscm 的标志，并且使用选择性抑制剂 WZB117 通过 GLUT1 靶向葡萄糖摄取导致 Tscm 生成和扩增的抑制。我们的结果表明，自身反应性 Tscm 存在于 T1D 患者中，并且可以通过抑制葡萄糖代谢来选择性地靶向。
