Fernández-García Juan, Franco Fabien, Parik Sweta, Altea-Manzano Patricia, Pane Antonino Alejandro, Broekaert Dorien, van Elsen Joke, Di Conza Giusy, Vermeire Ines, Schalley Tessa, Planque Mélanie, van Brussel Thomas, Schepers Rogier, Modave Elodie, Karakach Tobias K, Carmeliet Peter, Lambrechts Diether, Ho Ping-Chih, Fendt Sarah-Maria
Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, 3000 Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), 3000 Leuven, Belgium.
Department of Oncology, University of Lausanne, 1066 Lausanne, Switzerland; Ludwig Institute of Cancer Research, University of Lausanne, 1066 Lausanne, Switzerland.
Cell Rep. 2022 Nov 15;41(7):111639. doi: 10.1016/j.celrep.2022.111639.
T cells dynamically rewire their metabolism during an immune response. We applied single-cell RNA sequencing to CD8 T cells activated and differentiated in vitro in physiological medium to resolve these metabolic dynamics. We identify a differential time-dependent reliance of activating T cells on the synthesis versus uptake of various non-essential amino acids, which we corroborate with functional assays. We also identify metabolic genes that potentially dictate the outcome of T cell differentiation, by ranking them based on their expression dynamics. Among them, we find asparagine synthetase (Asns), whose expression peaks for effector T cells and decays toward memory formation. Disrupting these expression dynamics by ASNS overexpression promotes an effector phenotype, enhancing the anti-tumor response of adoptively transferred CD8 T cells in a mouse melanoma model. We thus provide a resource of dynamic expression changes during CD8 T cell activation and differentiation, and identify ASNS expression dynamics as a modulator of CD8 T cell differentiation.
T细胞在免疫反应过程中会动态地重塑其代谢。我们对在生理培养基中体外激活并分化的CD8 T细胞应用单细胞RNA测序，以解析这些代谢动态变化。我们确定了激活T细胞在不同时间对各种非必需氨基酸合成与摄取的依赖性差异，并通过功能测定法证实了这一点。我们还通过根据代谢基因的表达动态对其进行排名，确定了可能决定T细胞分化结果的代谢基因。其中，我们发现天冬酰胺合成酶（Asns），其表达在效应T细胞中达到峰值，并在向记忆形成阶段衰减。通过ASNS过表达破坏这些表达动态会促进效应细胞表型，增强在小鼠黑色素瘤模型中过继转移的CD8 T细胞的抗肿瘤反应。因此，我们提供了CD8 T细胞激活和分化过程中动态表达变化的资源，并确定ASNS表达动态是CD8 T细胞分化的调节因子。
