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<sup>+</sup> T cells after yellow fever vaccination using flow cytometry and single-cell RNA sequencing. As assessed by protein translation rates, CD8<sup>+</sup> 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<sup>+</sup>CD62L<sup>+</sup>CD45RA<sup>-</sup> central memory T cells were the most metabolically active subset, whereas CD8<sup>+</sup>CD62L<sup>-</sup>CD45RA<sup>+</sup> effector T cells underwent metabolic shutdown. Weakly differentiated CD8<sup>+</sup>CD62L<sup>+</sup>CD45RA<sup>+</sup>CD95<sup>-</sup> 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.
Authors
- Jan Esse (ORCID: https://orcid.org/0000-0003-0601-8837)
- Kilian Schober (ORCID: https://orcid.org/0000-0001-9323-9472)
- Mauricio Grotz
- Katharina Kocher (ORCID: https://orcid.org/0000-0003-2331-3838)
- Theresa Hiltner (ORCID: https://orcid.org/0000-0001-7933-0966)
- Veit R. Buchholz (ORCID: https://orcid.org/0000-0003-0441-3913)
- Christine Schülein
- Jürgen Pahle (ORCID: https://orcid.org/0000-0002-7637-7547)
- Frederik Graw (ORCID: https://orcid.org/0000-0002-1198-6632)
- Felix Drost (ORCID: https://orcid.org/0000-0002-2600-4048)
- Dirk Hans Busch (ORCID: https://orcid.org/0000-0001-8713-093X)
- Johannes Träger
- Christian Bogdan (ORCID: https://orcid.org/0000-0002-2300-0631)
- Rayya Alsalameh
- Ev-Marie Schuster
- Simon Rothenfußer
- Sina Frischholz
- J. Benz
- Jürgen Held
- Luca Gattinoni
- Benjamin Schubert
- Bernd Spriewald
- Lucia Klotz
- Szilard Varga
Institutions
- German Cancer Research Center (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Heidelberg University (DE)
- Helmholtz Zentrum München (DE)
- LMU Klinikum (DE)
- University Hospital Regensburg (DE)
- Universitätsklinikum Erlangen (DE)
- German Center for Infection Research (DE)
- Leibniz Institute for Immunotherapy
- University of Regensburg (DE)
- Technical University of Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
- Heidelberg University (US)
Publication Details
- Journal
- Nature Immunology
- Published
- 2026-02-24
- DOI
- https://doi.org/10.1038/s41590-026-02421-w
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 0.00