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.

Document Type

Article

Publication Date

1-2024

Notes/Citation Information

© The Author(s) 2024

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creativecommons.org/licenses/by/4.0/.

Digital Object Identifier (DOI)

https://doi.org/10.1038/s41423-024-01124-2

Funding Information

We thank members of the Lee laboratory for insightful discussion about the manuscript, Louise Carlson for maintaining the CD28-mutant mice, Dr. Fumito Ito for providing PMEL mice for breeding, Jessie Chiello for performing the Seahorse assays, and Dr. Prashant Singh for consultation on RNA-seq analysis. This work was 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 Resources, and by 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).

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