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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+ 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.

More information Original publication

DOI

10.1038/s41556-025-01835-2

Type

Journal article

Publication Date

2026-01-01T00:00:00+00:00

Volume

28

Pages

66 - 81

Total pages

15

Keywords

Animals, CD8-Positive T-Lymphocytes, Autophagy, Mitochondria, Mice, Inbred C57BL, Mice, Immunologic Memory, Cell Lineage, Mice, Knockout, Cell Differentiation