Glucose availability tunes latent CD8+ T cell expansion potential through a mitogen-independent, mTOR-dependent regulatory switch

Abstract

Mitogenic signals are understood to license cell cycle progression and the metabolic reprogramming required for cell division, with acquired nutrients serving as permissive substrates. Here, we show that nutrient availability instead functions as a mitogen-independent regulatory input that dynamically controls CD8+ T cell proliferative potential. Activating stimuli have been shown to set T cell expansion capacity through their control of c-Myc expression, with the rate of c-Myc decay functioning as a division timer. We demonstrate that nutrient availability is sufficient to control c-Myc expression dynamics and dictates how division potential is stored and later actualized. Glucose-restricted T cells sustain proliferative potential and exhibit high AKT and ERK phosphorylation, despite limited growth. Upon glucose restoration, these cells rapidly increase c-Myc expression, accelerate through the cell cycle, and return to the expansion potential of glucose-replete controls, even after days of enforced restriction. Glucose restriction thus maintains a latent metabolic and mitogenic signaling state that is rapidly realized upon recovery. Mechanistically, mTOR signaling is required for this glucose recovery-driven proliferation, despite c-Myc and pERK remaining elevated following mTOR inhibition, indicating that glucose and mitogen signals operate through parallel rather than hierarchical control points. Altogether, these findings reveal that nutrient availability is not merely rate-limiting for proliferation but dictates the kinetics at which mitogenic signals are dissipated and realized. While mitogenic and nutrient cues converge on a shared anabolic network, they operate through distinct regulatory arms to coordinate the tempo and magnitude of clonal expansion, with implications for protective immunity and immunotherapy. Significance StatementCD8+ T cells rapidly proliferate to fight infections and cancer, often in variable nutrient environments. Activation signals are understood to control T cell expansion potential by setting c-Myc expression and its subsequent decay, with nutrients providing fuel. Here we find that glucose availability functions as an independent regulatory switch. Glucose-restricted T cells remain proliferatively poised for days, keeping pro-growth signaling and metabolic capacity primed. Upon glucose restoration, cells undergo a proliferative burst and catch up to glucose-replete counterparts. Although c-Myc expression rises upon glucose restoration, accelerated division kinetics instead require mTOR activity. These findings reveal that nutrient availability operates in parallel with mitogenic signaling, tuning the rate at which T cells store and realize their expansion potential.