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 i...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.展开更多
基金supported by National Cancer Institute grants R00CA175189,R01AI155499(both to SHO),R01CA205246(to EAR),R01CA121044(to KPL),T32CA085183(to GAH and MML),and P30CA016056,involving the use of the Roswell Park Comprehensive Cancer Center Flow and Image Cytometry,Genomics,Laboratory Animal,and Immune Analysis Shared Resourcesby the Roswell Park Alliance Foundation.NMR experiments were carried out at the Center for Environmental and Systems Biochemistry Shared Resource Facility funded in part by the Markey Cancer Center(P30CA177558).
文摘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.
