The Case of the Incredibly Long-Lived Mouse Cells

“It’s probably one of the most extraordinary publications in immunology that I’ve seen in the last decade,” says John Wherry, director of the Department of Immunology at the University of Pennsylvania’s Perelman School of Medicine, who was not involved in the learning. “It tells us that immunity can be incredible long-lived if we understand how to produce it properly.”

Andreas Sorens, a The postdoc immunologist who took on the 21 Vaccines project did not expect it to become his primary responsibility. “It felt like it could be the worst project ever because it didn’t have an end point in mind. Or it could be pretty cool because it was interesting biology,” he recalls.

A researcher would never write a grant application for this project. It’s a study that threatens to reverse a deeply held notion — that T cells have an intrinsically limited fighting ability — with no guarantee of success. “It is almost a historically monumental experiment. Nobody does an experiment that lasts 10 years,” says Wherry. “It contrasts with funding mechanisms and a five-year funding cycle — which really means you have to do something new every three years. This goes against the way we train our students and postdocs, who typically work in a lab for four or five years. It contrasts with the short attention spans of scientists and the scientific environment in which we live. So it says something fundamental about you really, really wanting to address a crucially important issue.”

In fact, the project went without funding for its first eight years, surviving only on the free time of lab members. But the central question was ambitious: Do immune cells have to age? In 1961, microbiologist Leonard Hayflick argued that all of our cells (except for eggs, sperm, and cancer) had a finite number of divisions. In the 1980s, researchers developed the idea that this might be due to the erosion of protective telomeres — a kind of needle at the end of chromosomes — that shorten as cells divide. After enough divisions, there is no telomere left to protect the genes.

This project challenged Hayflick’s limit and soon occupied most of Soerens’ time: he raced to the mouse colony to immunize, sample, and start new cohorts of T-cell armies. He counted cells and analyzed the mix of proteins they produced, noting what had changed over the years. Such differences can indicate changes in the genetic expression of a cell – or even mutations in the gene sequence.

One day, one change stood out: high levels of a protein associated with cell death, called PD1. It’s usually a sign of cellular depletion. But these cells were not exhausted. They continued to multiply, fight off microbial infections, and form long-lived memory cells, all functions the lab considered markers of fitness and longevity. “I was kind of shocked,” says Sörens. “That was probably the first time I felt really, really confident that that was the case some.”

So the lab went on and on. Finally, says Masopust, “the question was, how long is long enough to keep this going before you made your point?” Ten years or four lifetimes felt right. “An extreme nature display was where it was good enough for me.” (For the record, all of these cell cohorts are still on the way.)