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Sunday, April 14, 2024

The Case of the Incredibly Long-Lived Mouse Cells

David Masopust has long imagined how to push immune systems to their limits—how to rally the most powerful army of protective cells. But one of the big mysteries of immunology is that so far, nobody knows what those limits are. So he hatched a project: to keep mouse immune cells battle-ready as long as possible. “The idea was, let’s keep doing this until the wheels fall off the bus,” says Masopust, a professor of immunology at the University of Minnesota.

But the wheels never fell off. He was able to keep those mouse cells alive longer than anyone thought possible—indeed, much longer than the mice themselves.

When your body first detects foreign bacteria, cancer, a virus, or vaccine, the immune system’s T cells log the presence of that invader, kill the cells it’s infected, and form new T cells that carry the memory of how to fight it. Should the same intruder return later on, that protective T-cell army will swell to meet it. 

But researchers have noticed that if you stimulate these T cells too many times, they’ll get exhausted—they’ll become less responsive to threats and eventually die. “It was a concern,” says Masopust. “Raising too large of an army would turn the army into a bunch of zombie soldiers.” Immunologists have considered this a fundamental limit on T cells’ capacity to fight threats. Masopust, however, wasn’t sold. “We wanted to test this principle.”

His team’s experiment began by dosing mice with a viral vaccine that stirs up T cells. About two months later, they gave them another shot to rally the cells again for stronger immune memory. Then a third boost two months later. At this point, the immunized mouse T cells were absolutely amped. “They were too good at destroying whatever I gave them,” Masopust says. “The viruses get snuffed out too quickly.” 

This didn’t satisfy Masopust, so his team took cells from the immunized mice’s spleens and lymph nodes, expanded the cell populations in test tubes, injected about 100,000 into new mice, and began immunizing them the same way. Once again, the mice got three shots over about 6 months. And once again, the T-cells kept fighting.

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So the scientists repeated the process again, taking the cells from this second generation of mice and injecting them into a third. And a fourth. And ultimately a seventeenth. They had created a kind of relay, in which the immune cells passed from one generation of mice to another eventually outlived the original mice. (They also outlasted the gigs of the first two researchers assigned to the project.) In results published on January 18 in Nature, Masopust’s team reports keeping this T-cell army alive and active for 10 years—longer than four mouse lifespans. It’s the first evidence of such extreme longevity.

“T cells are born to be sprinters, but can be trained to become marathon runners” thanks to repeated exposure to a challenge—like a virus—followed by rest periods, Masopust says. The genetic changes exhibited by these cells after 10 years of this “training” may well describe what an extraordinarily fit T cell looks like. Masopust thinks that researchers can glean lessons from this experiment in order to treat cancer, create better vaccines, and understand or even slow human aging: “It’s spun off into so many different interesting questions that transcend immunology.”

“It’s probably one of the most extraordinary papers in immunology that I’ve seen, easily in the past decade,” says John Wherry, director of the Institute of Immunology at the University of Pennsylvania’s Perelman School of Medicine, who was not involved in the study. “It tells us that immunity can be incredibly durable, if we understand how to generate it properly.” 

Andrew Soerens, a postdoctoral immunologist who inherited the project 21 immunizations in, didn’t expect it to become his main responsibility. “It felt like it could be the worst project ever, because it had no endpoint in mind. Or, it could be pretty cool because it was interesting biology,” he recalls. 

This project is not something a researcher would ever write a grant proposal for. It’s an exploration that threatens to reverse an entrenched idea—that T cells have an intrinsically limited capacity to fight—with no guarantee of success. “It’s almost a historically monumental experiment to do. No one does an experiment that lasts 10 years,” says Wherry. “It’s antithetical to funding mechanisms, and a five-year funding cycle—which really means every three years you have to be doing something new. It’s antithetical to the way we train our students and postdocs who typically are in a lab for four or five years. It’s antithetical to the short attention span of scientists and the scientific environment we live in. So it really says something fundamental about really, really wanting to address a critically important question.”

Indeed, the project remained unfunded for the first eight years, surviving just on lab members’ spare time. But its central question was ambitious: Must immune cells age? In 1961, microbiologist Leonard Hayflick argued that all of our cells (except eggs, sperm, and cancer) could only divide a finite number of times. In the 1980s, researchers advanced the idea that this might play out through the erosion of protective telomeres—a sort of aglet at the end of chromosomes—which shorten when cells divide. After enough divisions, there’s no more telomere left to protect the genes. 

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This project challenged the Hayflick limit, and it soon commanded most of Soerens’ time: He’d run down to the mouse colony to immunize, take samples, and start new cohorts of T-cell armies. He’d count cells and parse the blend of proteins they produced, noting what had changed over the years. Such differences can indicate changes in a cell’s genetic expression—or even mutations in the gene sequence.

One day, a change stood out: high levels of protein associated with cell death, called PD1. It’s usually a sign of cell exhaustion. But these cells were not exhausted. They continued to proliferate, combat microbial infections, and form long-lived memory cells, all functions the lab considered markers of fitness and longevity. “I was kind of shocked,” Soerens says. “That was probably the first time that I was actually very confident that this was something.” 

So the lab kept going, and going. Finally, says Masopust, “the question was, how long is long enough to keep this going before you’ve made your point?” Ten years, or four lifetimes, felt right. “An extreme of nature demonstration was where it was good enough for me.” (For the record: All those cell cohorts are still going.)

Susan Kaech, a professor and director of immunobiology at the Salk Institute for Biological Studies, points out that long-lived immune memory isn’t groundbreaking itself—human T cells can survive for decades if they remain unassailed. What’s really unprecedented is that these have been subjected to a 10-year beatdown: “It’d be like running a marathon every month,” says Kaech, “and you never got winded and your time never got longer.”

To Kaech, who was not involved in the study, the results hint that we’d benefit from tailoring vaccination programs to T cells, and beefing up the immune response by repeatedly challenging those cells, as Masopust’s triple-immunization strategy did for the mice. And immunologists have seen—with SARS-CoV-2 for example—that T cells bring the longest-lasting immunity. “As we saw the [SARS-CoV-2] virus mutate away from our antibody responses,” she says, “people were still protected—in part because they had a wide array of memory T cells that recognized other parts of the virus.”

The new study may also provide insights for treating cancer. Tumors hammer T cells nonstop, and eventually wear them down. “We see this exhaustion and this functional impairment kick in. We don’t really know exactly why,” says Jeff Rathmell, an immunologist at Vanderbilt University who was not involved in the work. “The whole goal of cancer immunotherapy is to overcome that. And this just shows you that it’s not like the cells have any intrinsic limit. They can continue to go and go and go.”

Rathmell thinks the insights from this paper might help advance a new approach called CAR-T therapy, in which doctors take a patient’s T cells and genetically modify them to better attack their tumor. Masopust’s team doesn’t yet know what genetic changes explain the mouse cells’ extraordinary fitness, but he and Rathmell think that mimicking those changes could make CAR-T more powerful. 

Alternatively, if the long-lived cells produce more of a certain protein that could support immune cell function in patients with cancer, chronic viral infections, or autoimmune diseases, that could be useful information for drug developers.

He and Wherry hope that Masopust’s mice can be a model for healthier aging. As people get older, their immune health declines as some T cells stay healthy, but others die or tire out. Pinpointing which genetic changes explain why some cells can achieve extreme longevity may offer clues about how to extend human immune health. “If T cells can stay alive forever,” Wherry wonders, “how do we actually keep the good T cells around?”

There are other big questions to answer, too, like why these mouse cells were able to proliferate without becoming cancerous—do they have some outrageous knack for repairing themselves to prevent mutation? Why does rest between viral challenges seem to be so important, and how long does that rest have to last? And was Hayflick perhaps too pessimistic? “The Hayflick limit has been around forever. But this data would say that it’s incomplete, or maybe even just wrong,” says Rathmell. “I mean, talk about a finding that changes dogma.”

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