What determines the fate of a T cell?

Researchers at the Max Delbrück Center have found that a cellular housekeeping mechanism called autophagy plays a major role in ensuring that T stem cells undergo normal cell division. The findings, published in “Nature Cell Biology,” could help boost vaccine response in older adults.

When killer T cells of our immune system divide, they normally undergo asymmetric cell division (ACD): Each daughter cell inherits different cellular components, which drive the cells toward divergent fates – one cell becomes a short-lived fighter called an effector T cell, the other cell becomes a long-lived memory T cell.

Research by Professor Mariana Borsa at the University of Oxford and colleagues in the Cell Biology of Immunity lab of Professor Katja Simon at the Max Delbrück Center has shown for the first time that cellular autophagy – a “housekeeping” mechanism by which cells degrade and recycle cell cargo – plays a critical role in this decision process. 

“Our study provides the first causal evidence that autophagy plays a central role in ensuring that T cells go through ACD normally,” says Borsa, first author of the paper 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,” says Borsa. “By understanding this process, we can start to think about ways to intervene to preserve the function of immune memory cells as we age.”

Split personality

To study ACD in greater detail, the researchers used a novel “MitoSnap” mouse model in which they could 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 daughter cells, they found that in healthy cells, autophagy was crucial in ensuring that one daughter cell was clear of old mitochondria. This inheritance profile sent the cell down the path toward becoming a long-lived memory precursor cell ­– immune cells that “remember” a pathogen and begin rapidly dividing when the pathogen is encountered again. Meanwhile, the other daughter cell that took on the older mitochondria became a short-lived effector T-cell ­– a type of immune cell that rapidly divides to fight off immediate threat. These cells die when the threat is cleared. 

When autophagy was disrupted, however, this careful sorting broke down. Both daughter cells inherited damaged mitochondria and hence, were destined to become short-lived cells.

“It was surprising to see that autophagy plays a role beyond just cellular housekeeping,” says Borsa. “Our findings suggest asymmetric inheritance of mitochondria as a potential therapeutic target for memory T cell rejuvenation.”

Boosting vaccine response

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.

What’s more, the researchers 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.

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 says.

“In the long run, this research could inform strategies to rejuvenate the aging immune system, making vaccines more effective and strengthening protection against infections,” adds Simon. The researchers are planning to further validate their findings in human T-cells. 

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