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Their work revealed a peripheral mechanism that keeps immune system from causing harm.
Announcement of the Nobel Prize in Physiology or Medicine 2025 awarded by the Nobel Assembly to scientists Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi at the Nobel Forum of Karolinska Institute, Stockholm City, Sweden, October 6, 2025. Credit: Getty | Narciso Contreras
Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi were awarded the 2025 Nobel Prize in Physiology or Medicine on Monday for their collective work in the discovery of specialized immune cells that roam the body and keep potentially harmful immune responses in check—preventing them from attacking the body directly (autoimmune responses) or causing harm with overzealous responses to invaders.
Those specialized cells—regulatory T cells—are now well established as playing a key role in peripheral immune tolerance. That is, a non-central process that allows the immune system to strike a delicate balance between being appropriately responsive and aggressive toward intruding germs or foreign dangers while also not running amok.
Before the trio of prize winners came along, researchers thought that such immune tolerance occurred centrally, in the thymus, the primary lymphoid organ that sits in the center of the chest. There, T cells mature, including into two key types: T helper cells, which go on to trigger immune responses when they recognize foreign dangers; and the aptly named T killer cells, which kill cells, including foreign cells, cancer cells, and cells infected by a virus.
Extra protection
In the thymus, T cells are tested before their release to ensure they won't attack components of the body, causing autoimmune diseases. Thymus cells do this by dangling forbidden targets made from tidbits of the body. If any T cells lock onto such an endogenous target via one of their unique, randomly generated receptors, then it means they have the ability to cause autoimmune responses. As such, they are promptly killed off.
However, researchers had inklings that there were other mechanisms to tone down immune responses, ones outside the thymus. These peripheral systems might help catch rogue T cells that somehow pass the central test but still have the ability to attack the body. For a time in the 1970s. researchers floated the idea of "suppressor T cells," but the field was riddled with inconsistencies and false leads that led many to largely abandon the notion.
One of the researchers who didn't give up, though, was Sakaguchi. Alongside colleagues in Japan in the 1980s and 1990s, Sakaguchi wanted to figure out why, when batches of immune cells from healthy mice were injected into mice that had their thymuses removed, the cells didn't trigger an autoimmune disease. The finding suggested something in the immune cell injection was producing immune tolerance, and that it wasn't dependent on the thymus.
In a landmark 1995 study, Sakaguchi and colleagues pinpointed the cells responsible—T helper cells that also contained a protein on their surfaces called CD25. They did this using experiments again with the mice that had their thymuses removed. If they gave the mice just batches of immune cells that were normal T helper cells—no CD25—the mice developed autoimmune diseases. But if they gave them the T helper cells plus T helper cells that had the CD25, the mice were healthy. The experiment indicated that the CD25-carrying T helper cells were promoting immune self-tolerance in the mice, and Sakaguchi and colleagues coined these cells regulatory T cells, which caught on.
Scurfy mice
Here is where Brunkow and Ramsdell—today's other two Nobel laureates—come in. In the 1990s, they were working for a pharmaceutical company in Bothell, Washington, called Celltech Chiroscience, which developed treatments for autoimmune diseases. Weird mutant mice, called scurfy mice, had grabbed their attention.
The mutants were identified in the 1940s by researchers at the Department of Energy's Oak Ridge National Laboratory in Tennessee, who were working on the effects of radiation as part of the Manhattan Project. A spontaneous mutation in a line of mice caused a severe autoimmune disease that was fatal—but only for males of the line; the females were fine. This signaled that the mutation was somewhere on the X chromosome, since females have two of those, and presumably one lacked the killer mutation. Brunkow and Ramdsell wanted to know what the mutation was that caused the autoimmune disease—and potentially use that knowledge to develop treatments for autoimmune diseases.
Today, finding a mutation on the X chromosome would be relatively easy. But in the 1990s, it was a labor-intensive effort. After narrowing the mutation's location down to a stretch of 500,000 nucleotides that included 20 genes, they carefully scanned 19 of them before finding a mutation in the very last one; it was a small, two-base pair insertion that threw the coding out of frame and resulted in a stunted protein. The mutated gene hadn't been studied before, but it looked like others that were classified as forkhead/winged-helix genes, so Brunkow and Ramsdell called it Foxp3.
The pair then did genetic rescue experiments, putting normal Foxp3 genes back into scurfy mice—doing it in five lines, for good measure. The genetic rescue prevented the severe autoimmune disease in the male scurfy mice and confirmed that the mutant Foxp3 was the source of the problem. The researchers then connected dots between scurfy mice and a disease in humans, called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked). IPEX causes a fatal autoimmune disease in young boys. Brunkow and Ramsdell demonstrated that mutations in the human version of Foxp3 were also behind IPEX, which they published, along with all of their scurfy findings, in 2001.
Putting it together
Back in Japan, Sakaguchi's team connected more dots in the two years after that, realizing that Foxp3 was selectively turned on in their regulator T cells. Further, if they forced regular T helper cells to activate Foxp3, those cells then became regulatory T cells.
It turns out the Foxp3 protein is the master control for regulatory T cells. That is, it's a protein that controls the activity of a large suite of genes that collectively give T cells the ability to halt autoimmune responses and temper strong immune responses after an infection is cleared.
Overall, the findings have opened up new lines of research into peripheral immune tolerance. Researchers are now working on manipulating regulatory T cells for good, such as ensuring they can't protect cancerous tumors, engineering them to treat autoimmune diseases, and recruiting them to specifically protect transplanted organs and tissues.
The collective work to discover and understand T regulatory cells provided fundamental knowledge on how our immune systems work, the Nobel Committee concluded: "They have thus conferred the greatest benefit to humankind."
Announcement of the Nobel Prize in Physiology or Medicine 2025 awarded by the Nobel Assembly to scientists Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi at the Nobel Forum of Karolinska Institute, Stockholm City, Sweden, October 6, 2025. Credit: Getty | Narciso Contreras
Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi were awarded the 2025 Nobel Prize in Physiology or Medicine on Monday for their collective work in the discovery of specialized immune cells that roam the body and keep potentially harmful immune responses in check—preventing them from attacking the body directly (autoimmune responses) or causing harm with overzealous responses to invaders.
Those specialized cells—regulatory T cells—are now well established as playing a key role in peripheral immune tolerance. That is, a non-central process that allows the immune system to strike a delicate balance between being appropriately responsive and aggressive toward intruding germs or foreign dangers while also not running amok.
Before the trio of prize winners came along, researchers thought that such immune tolerance occurred centrally, in the thymus, the primary lymphoid organ that sits in the center of the chest. There, T cells mature, including into two key types: T helper cells, which go on to trigger immune responses when they recognize foreign dangers; and the aptly named T killer cells, which kill cells, including foreign cells, cancer cells, and cells infected by a virus.
Extra protection
In the thymus, T cells are tested before their release to ensure they won't attack components of the body, causing autoimmune diseases. Thymus cells do this by dangling forbidden targets made from tidbits of the body. If any T cells lock onto such an endogenous target via one of their unique, randomly generated receptors, then it means they have the ability to cause autoimmune responses. As such, they are promptly killed off.
However, researchers had inklings that there were other mechanisms to tone down immune responses, ones outside the thymus. These peripheral systems might help catch rogue T cells that somehow pass the central test but still have the ability to attack the body. For a time in the 1970s. researchers floated the idea of "suppressor T cells," but the field was riddled with inconsistencies and false leads that led many to largely abandon the notion.
One of the researchers who didn't give up, though, was Sakaguchi. Alongside colleagues in Japan in the 1980s and 1990s, Sakaguchi wanted to figure out why, when batches of immune cells from healthy mice were injected into mice that had their thymuses removed, the cells didn't trigger an autoimmune disease. The finding suggested something in the immune cell injection was producing immune tolerance, and that it wasn't dependent on the thymus.
In a landmark 1995 study, Sakaguchi and colleagues pinpointed the cells responsible—T helper cells that also contained a protein on their surfaces called CD25. They did this using experiments again with the mice that had their thymuses removed. If they gave the mice just batches of immune cells that were normal T helper cells—no CD25—the mice developed autoimmune diseases. But if they gave them the T helper cells plus T helper cells that had the CD25, the mice were healthy. The experiment indicated that the CD25-carrying T helper cells were promoting immune self-tolerance in the mice, and Sakaguchi and colleagues coined these cells regulatory T cells, which caught on.
Scurfy mice
Here is where Brunkow and Ramsdell—today's other two Nobel laureates—come in. In the 1990s, they were working for a pharmaceutical company in Bothell, Washington, called Celltech Chiroscience, which developed treatments for autoimmune diseases. Weird mutant mice, called scurfy mice, had grabbed their attention.
The mutants were identified in the 1940s by researchers at the Department of Energy's Oak Ridge National Laboratory in Tennessee, who were working on the effects of radiation as part of the Manhattan Project. A spontaneous mutation in a line of mice caused a severe autoimmune disease that was fatal—but only for males of the line; the females were fine. This signaled that the mutation was somewhere on the X chromosome, since females have two of those, and presumably one lacked the killer mutation. Brunkow and Ramdsell wanted to know what the mutation was that caused the autoimmune disease—and potentially use that knowledge to develop treatments for autoimmune diseases.
Today, finding a mutation on the X chromosome would be relatively easy. But in the 1990s, it was a labor-intensive effort. After narrowing the mutation's location down to a stretch of 500,000 nucleotides that included 20 genes, they carefully scanned 19 of them before finding a mutation in the very last one; it was a small, two-base pair insertion that threw the coding out of frame and resulted in a stunted protein. The mutated gene hadn't been studied before, but it looked like others that were classified as forkhead/winged-helix genes, so Brunkow and Ramsdell called it Foxp3.
The pair then did genetic rescue experiments, putting normal Foxp3 genes back into scurfy mice—doing it in five lines, for good measure. The genetic rescue prevented the severe autoimmune disease in the male scurfy mice and confirmed that the mutant Foxp3 was the source of the problem. The researchers then connected dots between scurfy mice and a disease in humans, called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked). IPEX causes a fatal autoimmune disease in young boys. Brunkow and Ramsdell demonstrated that mutations in the human version of Foxp3 were also behind IPEX, which they published, along with all of their scurfy findings, in 2001.
Putting it together
Back in Japan, Sakaguchi's team connected more dots in the two years after that, realizing that Foxp3 was selectively turned on in their regulator T cells. Further, if they forced regular T helper cells to activate Foxp3, those cells then became regulatory T cells.
It turns out the Foxp3 protein is the master control for regulatory T cells. That is, it's a protein that controls the activity of a large suite of genes that collectively give T cells the ability to halt autoimmune responses and temper strong immune responses after an infection is cleared.
Overall, the findings have opened up new lines of research into peripheral immune tolerance. Researchers are now working on manipulating regulatory T cells for good, such as ensuring they can't protect cancerous tumors, engineering them to treat autoimmune diseases, and recruiting them to specifically protect transplanted organs and tissues.
The collective work to discover and understand T regulatory cells provided fundamental knowledge on how our immune systems work, the Nobel Committee concluded: "They have thus conferred the greatest benefit to humankind."
