13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8+T cells

Abstract

AbstractInfusion of 13C-labeled metabolites provides a gold-standard for understanding the metabolic processes used by T cells during immune responsesin vivo. Through infusion of 13C-labeled metabolites (glucose, glutamine, acetate) inListeria monocytogenes(Lm)-infected mice, we demonstrate that CD8+ T effector (Teff) cells utilize metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cellsin vivoshunt glucose primarily towards nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support ATP andde novopyrimidine synthesis. Additionally, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)—which regulatesde novoaspartate synthesis—for effector cell expansionin vivo. Importantly, Teff cells change fuel preference over the course of infection, switching from glutamine-to acetate-dependent TCA cycle metabolism late in infection. This study provides insights into the dynamics of Teff metabolism, illuminating distinct pathways of fuel consumption associated with Teff cell functionin vivo.TeaserInterrogating dynamics of fuel utilization by CD8+T cellsin vivoreveals new metabolic checkpoints for immune functionin vivo.