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.

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.”