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The human immune system is our body’s primary line of defense against harmful microbes, viruses, and other invaders—but that defense line can sometimes run amok and attack healthy cells. This is the basis of many autoimmune diseases, from cancer to rheumatoid arthritis to type 1 diabetes. The 2025 Nobel Prize in Physiology or Medicine was awarded to the scientists who conducted fundamental research on peripheral immune tolerance, a system that pumps the brakes on the immune system and keeps it from harming the body.

Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi jointly won the prize, which was announced on Monday in Stockholm. Sakaguchi is a distinguished professor at the Immunology Frontier Research Center at Osaka University in Japan. Brunkow is now a senior program manager at the Institute for Systems Biology in Seattle and Ramsdell is a scientific advisor for Sonoma Biotherapeutics in San Francisco. The Nobel Committee recognized the awardees’ body of work for spurring clinical trials on potential new treatments, such as therapies that may propagate immune cells called regulatory T cells that can suppress overreactive immune responses in an autoimmune disease or organ transplant.

“This year’s Nobel Prize in Physiology or Medicine relates to how we keep our immune system under control so we can fight all imaginable microbes and still avoid autoimmune disease,” said Marie Wahren-Herlenius, a member of the 2025 Nobel Committee for Physiology or Medicine, at a livestreamed press conference today in Stockholm.

“Only three people can be recognized for the Nobel Prize, but there are so many pioneers who worked on this,” says Maria-Luisa Alegre, a professor of medicine at the University of Chicago. Her lab specializes in T cell responses during organ transplantation. The Nobel recognition “gives us a lot of further momentum in trying to develop therapies for transplantation as well as for autoimmunity. I’m just thrilled, really, that this is the field that has been chosen.”

Around the 1970s, scientists first proposed that there might be a distinct population of T cells that can suppress the immune response. It was thought that such T cells, dubbed suppressor T cells at the time, could potentially unlock a new understanding of the immune system—and of autoimmune disease. Early experiments trying to prove the existence of these cells came up empty handed, however; the theory was ultimately abandoned as being too fringe.

The early research “identified activities without clear molecular understanding,” says immunologist Jeffrey Bluestone, who co-founded Sonoma Biotherapeutics alongside Nobel winner Ramsdell. “Some of the work was hard to replicate, and so by the end of the decade, a lot of people were very skeptical that such a system existed.”

Years later, Sakaguchi, then an immunologist at Aichi Cancer Center Research Institute in Nagoya, Japan, picked up the work on suppressor T cells. “The basic hope was to discover a telltale molecular feature at the surface of such cells—a ‘marker’ by which suppressor T cells could be distinguished from other cells,” Sakaguchi wrote in a 2006 article for Scientific American that was coauthored by immunologist Zoltan Fehervari, now a senior editor at Nature.

Sakaguchi and his colleagues focused on the thymus, an organ located in the chest where T cells mature and are taught to avoid targeting healthy cells. The thymus is supposed to eliminate any faulty T cells—but in certain autoimmune conditions, these bad actors can fly under the radar. In a series of experiments on mice, Sakaguchi found that helper T cells produced in the thymus (identified by the surface protein CD4) didn’t all function the same way. Cells that had an additional novel surface protein, CD25, appeared necessary to prevent the immune system from attacking the body itself. In experiments in which Sakaguchi and his colleagues wiped the mice of T cells with CD25, various organs—thyroid, stomach, gonads, pancreas, and salivary glands—succumbed to white blood cell attacks and resulted in “dramatic inflammation,” Sakaguchi and Fehervari wrote in Scientific American.

The discovery of CD25, first detailed in a key 1995 paper in the Journal of Immunology, helped Sakaguchi establish the new class of T cells, which he dubbed regulatory T cells.

“It wasn’t a high-profile paper at the time. He was just sort of plugging away, publishing paper after paper on this topic to refine his findings,” says Peter Savage, a professor of pathology at the University of Chicago who studies regulatory T cells. “The idea of suppressor cells had fallen out of favor. It was Sakaguchi who really, through a meticulous series of experiments, pursued this idea and was able to define a population of CD4 T cells that had really potent suppressor activity or ‘peacekeeper’ activity.”

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