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. © 2024. The Author(s).

Citation

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. CD8+ T cell metabolic flexibility elicited by CD28-ARS2 axis-driven alternative splicing of PKM supports antitumor immunity. Cellular & molecular immunology. 2024 Mar;21(3):260-274

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PMID: 38233562

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