G. Aaron Holling, Colin A. Chavel, Anand P. Sharda, Mackenzie M. Lieberman, Caitlin M. James, Shivana M. Lightman, Jason H. Tong, Guanxi Qiao, Tiffany R. Emmons, Thejaswini Giridharan, Shengqi Hou, Andrew M. Intlekofer, Richard M. Higashi, Teresa W. M. Fan, Andrew N. Lane, Kevin H. Eng, Brahm H. Segal, Elizabeth A. Repasky, Kelvin P. Lee, Scott H. Olejniczak
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引用次数: 0
摘要
代谢灵活性已成为 CD8+ T 细胞抗肿瘤活性的一个关键决定因素,但驱动 T 细胞代谢灵活性的机制尚未确定。在这项研究中,我们研究了核帽结合复合体(CBC)适配蛋白 ARS2 对成熟 T 细胞的影响。在此过程中,我们发现了一个新的信号轴,它赋予活化的 CD8+ T 细胞葡萄糖分解代谢的灵活性。CD28 信号驱动的 ARS2 上调加强了剪接因子对前核糖核酸的招募,并影响了大约三分之一的 T 细胞活化诱导的替代剪接事件。在这些影响中,CD28-ARS2 轴抑制了丙酮酸激酶 M1 异构体的表达,而有利于 PKM2 的表达,PKM2 是 CD8+ T 细胞葡萄糖利用、γ 干扰素产生和抗肿瘤效应功能的关键决定因素。重要的是,PKM 替代剪接的发生与 CD28 驱动的 PI3K 通路激活无关,揭示了成本刺激重新规划 CD8+ T 细胞葡萄糖代谢的一种新方法。
CD8+ T cell metabolic flexibility elicited by CD28-ARS2 axis-driven alternative splicing of PKM supports antitumor immunity
Metabolic flexibility has emerged as a critical determinant of CD8+ T-cell antitumor activity, yet the mechanisms driving the metabolic flexibility of T cells have not been determined. In this study, we investigated the influence of the nuclear cap-binding complex (CBC) adaptor protein ARS2 on mature T cells. In doing so, we discovered a novel signaling axis that endows activated CD8+ T cells with flexibility of glucose catabolism. ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events. Among these effects, the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2, a key determinant of CD8+ T-cell glucose utilization, interferon gamma production, and antitumor effector function. Importantly, PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation, revealing a novel means by which costimulation reprograms glucose metabolism in CD8+ T cells.
期刊介绍:
Cellular & Molecular Immunology, a monthly journal from the Chinese Society of Immunology and the University of Science and Technology of China, serves as a comprehensive platform covering both basic immunology research and clinical applications. The journal publishes a variety of article types, including Articles, Review Articles, Mini Reviews, and Short Communications, focusing on diverse aspects of cellular and molecular immunology.