CD8+ T cell metabolic flexibility elicited by CD28-ARS2 axis-driven alternative splicing of PKM supports antitumor immunity Journal Article
| Authors: | Holling, G. A.; Chavel, C. A.; Sharda, A. P.; Lieberman, M. M.; James, C. M.; Lightman, S. M.; Tong, J. H.; Qiao, G.; Emmons, T. R.; Giridharan, T.; Hou, S.; Intlekofer, A. M.; Higashi, R. M.; Fan, T. W. M.; Lane, A. N.; Eng, K. H.; Segal, B. H.; Repasky, E. A.; Lee, K. P.; Olejniczak, S. H. |
| Article Title: | CD8+ T cell metabolic flexibility elicited by CD28-ARS2 axis-driven alternative splicing of PKM supports antitumor immunity |
| Abstract: | 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. © The Author(s) 2024. |
| Keywords: | signal transduction; controlled study; protein expression; unclassified drug; human cell; genetics; nonhuman; cd8+ t lymphocyte; cd8-positive t-lymphocytes; animal cell; mouse; metabolism; animal experiment; animal model; enzyme activation; phosphatidylinositol 3 kinase; lymphocyte activation; gamma interferon; messenger rna; alternative splicing; alternative rna splicing; tumor immunity; glucose; upregulation; c57bl 6 mouse; glycolysis; cd28 antigen; citric acid cycle; scaffold protein; glucose utilization; phosphatidylinositol 3-kinases; mrna splicing; cd8 t cells; pyruvate kinase; metabolic reprogramming; pyruvate kinase m2; pkm2; human; male; female; article; immunometabolism; ars2; cd28 antigens; adaptor protein arsenic resistance protein 2 |
| Journal Title: | Cellular & Molecular Immunology |
| Volume: | 21 |
| Issue: | 3 |
| ISSN: | 1672-7681 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-03-01 |
| Start Page: | 260 |
| End Page: | 274 |
| Language: | English |
| DOI: | 10.1038/s41423-024-01124-2 |
| PUBMED: | 38233562 |
| PROVIDER: | scopus |
| PMCID: | PMC10902291 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
