phagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.
Borsa M., Lechuga-Vieco AV., Kayvanjoo AH., Jenkins E., Yazicioglu Y., Compeer EB., Richter FC., Rapp S., Mitchell R., Youdale T., Bui H., Kuuluvainen E., Dustin ML., Sinclair LV., Katajisto P., Simon AK.
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.