Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment
T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8<sup>+</sup> T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function.
Authors
- Felix Clemens Richter (ORCID: https://orcid.org/0000-0002-3415-3449)
- Amir Hossein Kayvanjoo (ORCID: https://orcid.org/0000-0003-1315-8336)
- Pekka Katajisto (ORCID: https://orcid.org/0000-0002-3033-4189)
- Emilia Kuuluvainen (ORCID: https://orcid.org/0000-0003-0227-4331)
- Edward Jenkins (ORCID: https://orcid.org/0000-0003-3789-6421)
- Ewoud B. Compeer (ORCID: https://orcid.org/0000-0002-3050-7633)
- Anna Katharina Simon (ORCID: https://orcid.org/0000-0002-4077-7995)
- Ana Victoria Lechuga‐Vieco (ORCID: https://orcid.org/0000-0001-5546-9752)
- Simon Rapp (ORCID: https://orcid.org/0000-0002-5141-0611)
- Michael Loran Dustin (ORCID: https://orcid.org/0000-0003-4983-6389)
- Hien Bui
- Yavuz F. Yazicioglu (ORCID: https://orcid.org/0000-0003-3731-9333)
- Robert J. Mitchell (ORCID: https://orcid.org/0000-0002-9608-5381)
- Linda V. Sinclair (ORCID: https://orcid.org/0000-0003-1248-7189)
- Mariana Borsa (ORCID: https://orcid.org/0000-0003-1519-2597)
- Tom Youdale
Institutions
- University of Helsinki (FI)
- University of Dundee (GB)
- Max Delbrück Center (DE)
- Karolinska Institutet (SE)
- University of Oxford (GB)
- Kennedy Center (DK)
- Institute for Research in Biomedicine (ES)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2025-12-19
- DOI
- https://doi.org/10.1038/s41556-025-01835-2
- Citations
- 1
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 1.35
Funders
- National Science Foundation
- University of Dundee
- Wellcome Trust
- University of Oxford
- European Commission
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung