Autophagy-Driven Mitochondrial Inheritance Shapes CD8+ T Cell Fate, Division

Researchers at the Max Delbrück Center and the University of Oxford have found that a cellular housekeeping function called autophagy—by which cell components are broken down and recycled—plays a major role in ensuring that T stem cells undergo normal, asymmetric cell division (ACD). Studying a specific mouse model that allows researchers to sequentially tag mitochondria in mother and daughter cells, the team discovered that autophagy is involved in regulating the distribution of healthy and damaged mitochondria between daughter T cells, which then impacts T cell fate.

The researchers, led by Mariana Borsa, PhD, professor at the University of Oxford and colleagues in the Cell Biology of Immunity lab of Katja Simon, PhD, professor at the Max Delbrück Center, suggest that their findings identify potential strategies that could, in the future, enhance memory T cell production, and so boost vaccine response in older adults.

They reported on their findings in Nature Cell Biology, in a paper titled “Autophagy-regulated mitochondrial inheritance controls early CD8⁺ T cell fate commitment,” in which they concluded, “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.”

Efficient immune responses depend on what the authors describe as “… coordination among different immune cells and on generating diversity within the same cell type.” And in CD8⁺ T cells, one single cell can differentiate into daughter cells with different cell fates when activated.

When killer CD8⁺ T cells divide, they normally undergo asymmetric cell division. Each daughter cell inherits different cellular components. “These cells inherit several layers of asymmetry, including surface markers, transcription factors, centrosomes, divergent metabolic activity, and translation profiles,” the team noted. This asymmetry drives the cells toward different fates—one daughter cell becomes a short-lived fighter called an effector T cell, and the other becomes a long-lived memory T cell. “Activation of a naive T cell produces both short-lived effector cells that exert cytotoxic effector functions and long-lived memory cells that self-renew and differentiate upon antigenic rechallenge and are central to vaccination efficacy,” the investigators further explained.

However, they pointed out, “… direct causal evidence linking asymmetric inheritance of premitotic (preM) T cell cargo, and the future fate of emerging daughter cells in vivo is lacking not only in T cells but across primary immune cells in general.”

The study reported by first author Borsa, senior author Simon, and colleagues has now shown for the first time that cellular autophagy plays a critical role in ACD. To study this in greater detail, the investigators turned to a novel mouse model, called MitoSnap, in which it’s possible to tag mitochondria sequentially and discriminate between those in mother and daughter cells.

T cells contain many mitochondria. By tracking how old, damaged mitochondria were distributed between the daughter cells, the investigators found that in healthy cells, autophagy was crucial for ensuring that one daughter cell was clear of old mitochondria. This profile of mitochondrial inheritance sent the cell down the path toward becoming a long-lived memory precursor cell. These types of immune cells “remember” a pathogen and begin rapidly dividing when the pathogen is encountered again. The other daughter cell that took on the older mitochondria became a short-lived effector T cell.

This type of immune cell rapidly divides to fight off an immediate threat and then dies when the threat is cleared. “… 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,” the investigators wrote in summary.

“Our study provides the first causal evidence that autophagy plays a central role in ensuring that T cells go through ACD normally,” said Borsa, who is now at the University of Basel. “We found that when T stem cells divide, daughter cells inherit different mitochondria, which influences the T cell’s destiny. By understanding this process, we can start to think about ways to intervene to preserve the function of immune memory cells as we age.”

The team’s studies also showed that this careful mitochondrial sorting mechanism broke down when autophagy was disrupted. Both daughter cells inherited damaged mitochondria and hence were destined to become short-lived 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,” they stated. “Collectively, our results support the notion that unequal organelle inheritance plays an important role in CD8⁺ T cell fate decision and contributes to the metabolic status of cell progenies.”

“It was surprising to see that autophagy plays a role beyond just cellular housekeeping,” Borsa further commented. “Our findings suggest asymmetric inheritance of mitochondria as a potential therapeutic target for memory T cell rejuvenation.” The team suggests that by boosting autophagy before or during T stem cell division, it may be possible to enhance the generation of memory cells—the backbone of long-term immunity and vaccine effectiveness.

The researchers, in addition, analyzed daughter cells using single-cell transcriptomics, proteomics, and metabolomics, and found that effector cells burdened with damaged mitochondria depend heavily on a metabolic pathway called one-carbon metabolism. “Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programs, with one-carbon metabolism activated in cells retaining premitotic mitochondria,” the scientists further noted.

Targeting this pathway could offer another way to subtly shift the immune balance—nudging T stem cells toward becoming memory instead of effector cells, Borsa suggested. “In the long run, this research could inform strategies to rejuvenate the aging immune system, making vaccines more effective and strengthening protection against infections,” added Simon.

The scientists are planning to further validate their findings in human T cells. “Overall, our data will pave the way for the development of more efficient therapeutic strategies in the context of regenerative medicine and particularly important in the context of aging,” they stated.