We all lose a step with age. Our immune systems do, too. That’s one reason why older adults can be more vulnerable to diseases like COVID-19.

Much about how our immune cells transform over time remains a mystery. But a study in Nature Immunology sheds new light on the changes that ripple through the ranks of T cells, key players that are trained to hunt down and destroy infected cells.

Using a powerful method developed at the Allen Institute for Immunology, researchers compared populations of T cells in healthy children and older adults. They discovered two surprising aspects of a shifting immune landscape: profound molecular changes in a type of T cell that was thought to resist aging, and a new subtype present in children that vanishes with age.

Together, the findings may offer new insights into how and why our immune responses change over time, said Claire Gustafson, Ph.D., an assistant investigator at the Allen Institute for Immunology.

“In aging, T cells are one of the most impacted cell types in the immune system, but the picture has always been muddled,” she said. “In this study, we had the right tool to definitively look at what happens to these cells as we age.”

That tool, dubbed TEA-seq, acts like a high-definition lens that can zoom in on the diversity of immune cells. It captures three different features of individual cells at once: their surface proteins, active genes, and DNA structure.

Scientists use that information to sort immune cells into different types. But before TEA-seq, they couldn’t measure all three key markers—protein, DNA, and RNA—at the same time, said Peter Skene, Ph.D., Director of Molecular Biology.

“You could use computational technologies to try and bring them together, but the puzzle pieces never fit perfectly,” said Skene, who led development of the method. “With TEA-seq, we wanted to cut out that knowledge gap and get a complete picture of what’s going on in each individual cell.”

New insights into T cells across age

TEA-seq’s greater depth of detail helped challenge the long-held belief that “naïve helper T cells,” which circulate in the blood awaiting threats, resist aging. The study revealed that, despite retaining a youthful look in their surface proteins, these cells undergo huge molecular changes under the hood—more so than any other T cell population, Gustafson said.

Further exploration uncovered the novel subtype of “killer T cell” in children, which had blended into the background with other single-cell approaches. TEA-seq brought it into focus.

The proteins that dot this cell type’s surface suggest it fights infection in tissues, Gustafson said. Intriguingly, it vanished from the blood of children who contracted COVID during the study, only to reappear after recovery.

For now, no one knows the implications of the cell type’s disappearance in adults. But the study’s insights could pave the way for tailoring vaccines and treatments to different age groups, Gustafson said.

“The key takeaway is that immune cells in a child are programmed differently than those in an adult,” she said. “Understanding these changes could help us design better vaccines and therapeutics.”

The team plans to use TEA-seq to study other key players in our immune systems, like B cells. And they hope to refine the method to make it easier and cheaper for other labs to adopt and unravel their own mysteries.

“The power of TEA-seq is that it can yield so much information about what’s going on in each individual cell,” said Zach Thomson, the study’s lead author. “This is just one experiment, and we’ve barely scratched the surface.”