T cells are small spherical immune cells with a standard shape and function that typically roam the circulatory system… right? Maybe not. Berend Snijder, PhD, and his team at the Institute of Molecular Systems Biology in Zurich, Switzerland, are working to answer this very question.

Using machine learning models to analyze images of T cells, which change shape from spherical to polarized bottle-shaped when activated, the researchers were able to group the cells into different categories based on activation level. “The cells with nuclear invaginations are designed to activate rapidly: many of them convert into bottle-shaped effector cells within 24 hours,” said Ben Hale, PhD, lead author of the new study. Snijder, Hale, and colleagues published their work, titled, “Cellular architecture shapes the naïve T cell response” in the latest issue of Science.

T cells of the immune system include many subtypes that denote varied life history and functionality. Externally though, T cells typically present with two distinct cell shapes—the canonical small spherical cells and a more bottle-shaped appearance for immune-activated T cells. Despite external similarities among spherical cells, internal morphology may hint at underlying differences in functionality.

For decades, researchers have understood that spherical cells with invaginated nuclei are more likely to activate rapidly into effector T cells when exposed to pathogens, while those with spherical nuclei tend to activate slowly and become memory cells to provide lasting immunity. “Until now, we weren’t sure which characteristics determined whether a T cell would become an effector cell or a memory cell,” Hale said.

The Swiss team developed an automated platform functioning with machine learning principles to analyze thousands of T-cell microscopy images obtained from blood samples of 24 healthy volunteer donors in Zurich.

The results of the analysis, which categorized the cells into three groups, were surprising to the researchers. “We’d already seen how some T cells appear bottle-shaped when activated,” Snijder said. “But we didn’t expect the platform to split the round cells into two different groups.”

Further analysis of the cells over time revealed that the spherical cells with nuclear invaginations were functionally different from the cells with spherical nuclei. “They also mount a stronger response when activated—and they proliferate much faster than cells without nuclear invaginations,” Snijder stated. The team was also able to clarify the mechanism by which these cells are activated more quickly. “Their special cellular architecture enables a heightened influx of calcium ions,” Snijder said.

Snijder and his team aim to further explore the balance of T cell types found in the blood. The body usually maintains a constant ratio of about 60% cytotoxic T cells with nuclear invaginations, 35% with spherical nuclei, and 5% bottle-shaped T cells.

Further research into the workings of T cells not only improves our fundamental understanding of the immune system but also holds promise for developing more effective treatments for diseases, including cancers.

“Many novel therapies use T cells to kill cancer cells,” Snijder said. “If we can find a way to specifically select and deploy these cellular architectures, we may be able to improve the clinical efficacy of such therapies.”

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