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

Abstract Metabolic activity shapes cell fate but remains challenging to capture in vivo with high resolution. Here we performed longitudinal metabolic and phenotypic profiling of human antigen-specific CD8 + T cells after yellow fever vaccination using flow cytometry and single-cell RNA sequencing. As assessed by protein translation rates, CD8 + T cells upregulated glycolysis to fuel anabolic needs for proliferation but predominantly used oxidative phosphorylation for energy production during the acute phase (days 7–28) after vaccination. Simultaneously, CD8 + CD62L + CD45RA − central memory T cells were the most metabolically active subset, whereas CD8 + CD62L − CD45RA + effector T cells underwent metabolic shutdown. Weakly differentiated CD8 + CD62L + CD45RA + CD95 − naive-like memory T cells showed minimal activity, relied solely on oxidative phosphorylation and were preferentially maintained 26 years postvaccination, reinforcing the link between cellular quiescence and longevity. Our study highlights quiescence as a key feature for long-term immunological memory formation in humans.