CD8+ T cell metabolic flexibility elicited by CD28-ARS2 axis-driven alternative splicing of PKM supports antitumor immunity

• DOI: 10.1038/s41423-024-01124-2
• Publication Date: 2024-01-18T03:02:47Z
• Authors: G. Aaron Holling; Colin A. Chavel; Anand P. Sharda; Mackenzie M. Lieb...; Caitlin M. James; Shivana M. Lightman; Jason H. Tong; Guanxi Qiao; Tiffany R. Emmons; Thejaswini Giridh...; 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
• Keywords: 0303 health sciences; 03 medical and health sciences; Immunometabolism; ARS2; CD8 T cells; mRNA splicing; PKM2; Article

AbstractMetabolic 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.