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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