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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)260-274
Number of pages15
JournalCellular and Molecular Immunology
Volume21
Issue number3
DOIs
StatePublished - Mar 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Keywords

  • ARS2
  • CD8 T cells
  • Immunometabolism
  • PKM2
  • mRNA splicing

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Fingerprint

Dive into the research topics of 'CD8+ T cell metabolic flexibility elicited by CD28-ARS2 axis-driven alternative splicing of PKM supports antitumor immunity'. Together they form a unique fingerprint.

Cite this