Metabolic quiescence of naïve-like memory T cells precedes and maintains antigen-specific T-cell memory

Metabolic activity shapes cell fate but remains challenging to capture in vivo with high resolution. We performed longitudinal metabolic and phenotypic profiling of human antigen-specific CD8+ T cells after yellow-fever vaccination on the single-cell level. During the acute phase, T cells upregulated glycolysis to fuel anabolic needs of proliferation, but predominantly used oxidative phosphorylation for energy production, as assessed via protein translation rates. Central memory T cells were the most active subset, while effector cells underwent metabolic shut-down. In contrast, weakly differentiated naïve-like memory T cells showed minimal activity, relying solely on oxidative phosphorylation already during the acute phase. Reinforcing the link between cellular quiescence and longevity, naïve-like memory cells were preferentially maintained even 26 years post vaccination. This association between differentiation degree and metabolic activity was conserved after SARS-CoV-2 vaccination and in two murine infection models. Our study dissects the metabolic profile of antigen-specific T-cell responses ex vivo, highlighting quiescence as a key feature for long-term immunological memory formation in humans.