Metabolic quiescence of naive-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. 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.