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

Frischholz S, Schuster EM, Grotz M, Schülein C, Benz J, Kocher K, Klotz L, Varga S, Hiltner T, Alsalameh R, Esse J, Träger J, Held J, Graw F, Pahle J, Spriewald B, Gattinoni L, Buchholz VR, Drost F, Schubert B, Rothenfußer S, Busch DH, Bogdan C, Schober K (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Nature Immunology Nature Research

Book Volume: 27

Pages Range: 452-462

Journal Issue: 3

DOI: 10.1038/s41590-026-02421-w

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.

Authors with CRIS profile

Sina Frischholz Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Ev-Marie Schuster Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Myriam Grotz Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Christine Schülein Lehrstuhl für Biochemie und Molekulare Medizin Julia Benz Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Katharina Kocher Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Lisa Klotz-Weigand Lehrstuhl für Biochemie und Molekulare Medizin Szilard Varga Department of Medicine 5 – Haematology and Oncology Rayya Alsalameh Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Jan Esse Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Johannes Träger Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Jürgen Held Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Frederik Graw Department of Medicine 5 – Haematology and Oncology Bernd Spriewald Department of Medicine 5 – Haematology and Oncology Christian Bogdan Lehrstuhl für Mikrobiologie und Infektionsimmunologie Kilian Schober Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene

Involved external institutions

Technische Universität München (TUM) DE Germany (DE) Ruprecht-Karls-Universität Heidelberg DE Germany (DE) Leibniz-Institut für Immuntherapie (LIT) / Leibniz Institute for Immunotherapy DE Germany (DE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Klinikum der Universität München (LMU Klinikum) DE Germany (DE)

How to cite

APA:

Frischholz, S., Schuster, E.-M., Grotz, M., Schülein, C., Benz, J., Kocher, K.,... Schober, K. (2026). Metabolic quiescence of naive-like memory T cells precedes and maintains antigen-specific T cell memory. Nature Immunology, 27(3), 452-462. https://doi.org/10.1038/s41590-026-02421-w

MLA:

Frischholz, Sina, et al. "Metabolic quiescence of naive-like memory T cells precedes and maintains antigen-specific T cell memory." Nature Immunology 27.3 (2026): 452-462.

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