2. Academic Validation
  3. Targeting pyruvate metabolism generates distinct CD8+ T cell responses to gammaherpesvirus and B lymphoma

Targeting pyruvate metabolism generates distinct CD8+ T cell responses to gammaherpesvirus and B lymphoma

  • JCI Insight. 2025 Aug 22;10(16):e187680. doi: 10.1172/jci.insight.187680.
Taewook Kang 1,  Young-Kwang Usherwood 1,  Julie A Reisz 2,  Sukrut C Kamerkar 3,  Rachel Culp-Hill 2,  Owen M Wilkins 4 5,  Andreia F Verissimo 6,  Fred W Kolling 4th 4,  Anton M Hung 4,  Shawn C Musial 1,  Pamela C Rosato 1,  Angelo D'Alessandro 2,  Henry N Higgs 3,  Edward J Usherwood 1
Affiliations

Affiliations

  • 1 Microbiology and Immunology Department, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire, USA.
  • 2 Metabolomics core, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  • 3 Department of Biochemistry and Cell Biology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA.
  • 4 Genomics and Molecular Biology Shared Resource, Dartmouth Cancer Center, Lebanon, New Hampshire, USA.
  • 5 Department of Biomedical Data Science, Geisel School of Medicine, and.
  • 6 Institute for Molecular Targeting, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA.
PMID: 40857407 DOI: 10.1172/jci.insight.187680
Abstract

T cells rely on different metabolic pathways to differentiate into effector or memory cells, and metabolic intervention is a promising strategy to optimize T cell function for immunotherapy. Pyruvate dehydrogenase (PDH) is a nexus between glycolytic and Mitochondrial Metabolism, regulating pyruvate conversion to either lactate or acetyl-CoA. Here, we retrovirally transduced pyruvate dehydrogenase kinase 1 (PDK1) or pyruvate dehydrogenase Phosphatase 1 (PDP1), which control PDH activity, into CD8+ T cells to test effects on T cell function. Although PDK1 and PDP1 were expected to influence PDH in opposing directions, by several criteria they induced similar changes relative to control T cells. Seahorse metabolic flux assays showed both groups exhibited increased glycolysis and Oxidative Phosphorylation. Both groups had improved primary and memory recall responses following Infection with murine gammaherpesvirus-68. However, metabolomics using labeled fuels indicated differential usage of key fuels by metabolic pathways. Importantly, CD8+ T cell populations after B cell lymphoma challenge were smaller in both groups, resulting in poorer protection, which was rescued by glutamine and acetate supplementation. Overall, this study indicates that PDK1 and PDP1 both enhance metabolic capacity, but the context of the antigenic challenge significantly influences the consequences for T cell function.

Keywords

Adaptive immunity; Immunology; Immunotherapy; Metabolism.

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