The case of incredibly long-lived mouse cells

“This is probably one of the most outstanding works on immunology that I have seen in the last decade,” says John Werry, director of the Immunology Institute at the Perelman School of Medicine at the University of Pennsylvania, who was not involved in the study. studying. “This tells us that immunity can be incredible durable if we understand how to create them correctly.

Andrew Serens, The immunology postdoctoral fellow who inherited the 21 Immunization Project did not expect this to become his primary responsibility. “It felt like it might 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.

The researcher will never write a grant proposal for this project. This is a study that threatens to overturn the long-held idea that T cells have an inherently limited ability to fight, with no guarantee of success. “This is almost a historically monumental experiment. No one is doing an experiment that lasts 10 years,” says Werry. “It goes against the funding mechanisms and the five-year funding cycle, which really means every three years you have to do something new. This is in contrast to the way we teach our students and postdocs, who usually work in the lab for four or five years. This is at odds with the short attention spans of scientists and the scientific environment in which we live. So it really says something fundamental that we really, really want to address a critical issue.”

Indeed, the project remained without funding for the first eight years, surviving only on the free time of the laboratory staff. But her central question was ambitious: Should immune cells age? In 1961, microbiologist Leonard Hayflick argued that all of our cells (except eggs, sperm, and cancer cells) can only divide a finite number of times. In the 1980s, researchers put forward the idea that this may manifest itself through the erosion of protective telomeres – a kind of aiguillettes at the ends of chromosomes – which are shortened during cell division. After enough divisions, there are no telomeres left to protect the genes.

This project defied Hayflick’s limit, and Soerens soon gave him most of his time, running to the mouse colony to immunize, sample, and build new cohorts of T-cell armies. He counted the cells and analyzed the mixture of proteins they produced, noting what had changed over the years. Such differences may indicate changes in the cell’s genetic expression or even mutations in the gene sequence.

One day, a change was discovered: high levels of a protein associated with cell death called PD1. This is usually a sign of cell depletion. But these cells were not exhausted. They continued to reproduce, fight off microbial infections, and form long-lived memory cells—all functions that the lab considered markers of fitness and longevity. “I was kind of shocked,” Serens says. “Perhaps this was the first time I was really sure that this something“.

So the lab went on and on. Finally, says Masopust, “the question was how long would it take before you had your say?” Ten years or four lives seemed right. “The extreme display of nature was where it was good enough for me.” (For the record: all of these cell cohorts still exist.)