Machine learning reveals key differences in immune cell inner workings

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Using machine learning techniques, researchers at ETH Zurich found that more than half of killer T cells exhibit nuclear invaginations, a special cellular structure that allows such cells to mount a faster and stronger response to pathogens.

From the outside, most T cells are small, spherical and look the same. Now, a team of researchers led by Berend Snijder at the Institute of Molecular Systems Biology at ETH Zurich has used advanced techniques to peer inside these cells. Their findings show that the intracellular spatial organization of cytotoxic T cells, which Snijder calls its cytoarchitecture, has a profound effect on the cell's fate.

Properties that determine cell fate

When cells with nuclear invaginations encounter a pathogen, they transform into potent effector cells that proliferate rapidly and kill the pathogen. Cells with spherical nuclei, i.e., without nuclear invaginations, evolve at a slower pace, taking longer to activate and eventually differentiating into long-lived memory cells that protect the organism from future attacks by the same pathogen.

Scientists identified two functionally distinct populations of T cells about 50 years ago, “but until now we didn't know what properties determine whether a T cell will become an effector cell or a memory cell,” says Ben Hale, a postdoctoral researcher in Snyder's research group and lead author of a paper recently published in the journal Neurology. External PagesScienceCalled.

To identify these features, the researchers developed a platform to automatically analyze microscopic images of immune cells. They then presented the platform with thousands of T cells taken from 24 healthy volunteers who had donated blood to the Swiss Red Cross's Zurich Blood Donation Service.

Unexpected differences

Using a machine learning approach, the platform classified the cells into three distinct groups. “We had already seen how some T cells become bottle-shaped upon activation,” Snyder says, “but we didn't expect the platform to separate the round cells into two distinct groups.”

Upon further investigation, the researchers found that the differences in cytoarchitecture between the two types of round cells also have functional implications: “Cells with nuclear invaginations are designed to activate rapidly, with many of them transforming into bottle-shaped effector cells within 24 hours,” Hale says.

“They also respond more strongly when activated, and proliferate much faster than cells without nuclear invaginations,” Snyder adds. He and his team also identified a molecular mechanism that leads to faster and stronger activation of cells with nuclear invaginations. “The specialized structure of cells with nuclear invaginations facilitates the influx of calcium ions,” Snyder says.

Both researchers emphasize that there are many questions that remain to be answered: For example, Snijder and his team are currently hoping to understand how the organism consistently ensures that around 60% of cytotoxic T cells in the blood have nuclear invaginations, 35% do not, and the remaining 5% are bottle-shaped.

Making treatment more clinically effective

Snyder and Hale note that their findings are not only “important for better understanding how immune cells work,” but also play an important role in the fight against cancer. For example, “many new therapies use T cells to kill cancer cells,” Snyder says. “If we could find a way to specifically select and deploy these cellular structures, we might be able to improve the clinical efficacy of such therapies.”

reference: Hale BD, Severin Y, Graebnitz F, et al. Cellular architecture shapes naive T cell responses. Science2024;384(6700):eadh8697. doi: 10.1126/science.adh8967

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