# 2025 Nobel Prize in Medicine: The cells that stop the body attacking itself > The 2025 Medicine prize honours the discovery of the immune system's peacekeepers. Regulatory T cells patrol the body and hold other immune cells back so they do not attack its own healthy tissue, a safeguard called peripheral tolerance. When that brake fails, the immune system turns on the body and autoimmune disease follows. - Laureates: Mary E. Brunkow (share 1/3, Institute for Systems Biology, Seattle, WA, USA); Fred Ramsdell (share 1/3, Sonoma Biotherapeutics, San Francisco, CA, USA); Shimon Sakaguchi (share 1/3, The University of Osaka, Osaka, Japan) - Official citation: “for their discoveries concerning peripheral immune tolerance” - Course page: https://nobelexplained.com/medicine/2025-regulatory-t-cells - Last updated: 2026-06-21 ## Explained simply (ELI5) Your immune system is an army trained to attack anything that does not belong, like germs and viruses. But there is a problem. A few of its soldiers are trained, by accident, to attack your own body. To keep the peace, the body has a special group of cells whose only job is to hold those soldiers back. They work like **security guards**. When a soldier cell is about to attack your own healthy tissue, a guard steps in front of it and tells it to stand down. > **Guards keep the army from turning on you** These guards are called regulatory T cells. Without them, the army turns on the body and you get an autoimmune disease, where the immune system attacks the very person it is supposed to protect. Every guard is built by the same instruction, a gene called **FOXP3**. FOXP3 is the master switch that tells a young cell to grow up into a guard instead of a soldier. Three scientists worked out who the guards are and which switch makes them. **Video transcript (37 seconds):** Fred Ramsdell was walking his dogs near Yellowstone when his wife started yelling. He thought a grizzly bear was close. Her phone held 200 text messages. He had won a Nobel Prize. Your immune system is an army. A few soldiers attack your own body by mistake. Guard cells tell them to stand down. Shimon Sakaguchi found the guards. Ramsdell and Mary Brunkow found FOXP3, the gene the guard cells need. Now researchers are testing ways to send guards to a new kidney, to keep it safe. ## Explained for undergraduates Your immune system has to solve a hard problem. It needs T cells aggressive enough to destroy infected or foreign cells, yet it must not let those same cells attack the body's own tissue. The first defence is **central tolerance**: as T cells mature in the thymus, those that react strongly to the body's own molecules are deleted before they ever reach the bloodstream. Central tolerance is not perfect. Some self-reactive T cells slip through and circulate in the body. For decades the textbook view held that deletion in the thymus was the whole story. In 1995 **Shimon Sakaguchi** showed it was not. > **An active brake, not just deletion** Sakaguchi found a small subset of T cells carrying a surface marker called CD25. When he removed these cells from mice, the animals developed severe autoimmune disease across several organs. The cells were not attacking; they were actively suppressing other T cells. This was the first clear evidence of a second, ongoing layer of protection, now called peripheral tolerance, and the cells became known as regulatory T cells. What actually makes a cell a regulatory T cell stayed unclear until a separate line of work cracked it. A mutant mouse strain called **scurfy** died young from a runaway autoimmune attack. In 2001 **Mary Brunkow** and **Fred Ramsdell** traced the defect to a single damaged gene, which they named Foxp3. They went further and showed that mutations in the human version of the gene cause IPEX, a rare and deadly autoimmune disease in children. - **1995**: Sakaguchi identifies CD25-bearing regulatory T cells that suppress autoimmunity in mice. - **2001**: Brunkow and Ramsdell find that Foxp3 mutations cause the scurfy mouse disease and human IPEX. - **2003**: Sakaguchi proves FOXP3 controls the development of regulatory T cells, uniting the two discoveries. Two years later Sakaguchi tied the threads together. He proved that the Foxp3 gene governs the development of the very cells he had found in 1995. **FOXP3 is the master switch**: turn it on in a developing T cell and the cell becomes a regulatory T cell, a guard rather than a fighter. **Video transcript (55 seconds):** At 1:30 in the morning, Mary Brunkow's phone showed a call from Sweden. She took it for spam and went back to sleep. Her story starts with scurfy, a mouse strain from 1940s Oak Ridge, Tennessee. The males died within weeks, attacked by their own T cells. Brunkow and Fred Ramsdell narrowed the mutation to about 20 genes. Only the last one they checked was broken. They named it Foxp3. In boys, a faulty human copy causes IPEX. Regulatory T cells hold back T cells that slip past the thymus. Tumours can hide behind a wall of them, and researchers are trying to break it down. Shimon Sakaguchi had discovered these cells in 1995. In 2003, he showed that Foxp3 controls how they develop. ## Explained for experts Immune tolerance is built in two layers. **Central tolerance** operates in the thymus, where developing thymocytes that bind self-peptide-MHC too strongly are removed by clonal deletion. This purges most dangerous clones, but the process is leaky, and self-reactive T cells routinely escape into the periphery. **Peripheral tolerance** is the set of mechanisms that restrains those escapees in the tissues and lymph nodes. The 2025 prize recognises the discovery that a dedicated cell lineage enforces it. > **A suppressive CD4+CD25+ lineage** Sakaguchi and colleagues showed that a minor population of CD4+ T cells expressing the IL-2 receptor alpha-chain (CD25) is required for self-tolerance. Transferring T cells depleted of this CD25+ fraction into immunodeficient mice triggered multi-organ autoimmunity, and restoring the CD25+ cells prevented it. The implication was radical for its time: tolerance is maintained not only by deleting self-reactive cells, but by an active, ongoing suppressive population, the regulatory T cell. The lineage still needed a molecular definition, and that came from genetics. The **scurfy** mouse, an X-linked mutant, dies of a fatal CD4+ T cell lymphoproliferative and inflammatory disorder. In 2001 Brunkow, Ramsdell and colleagues mapped the defect to a novel forkhead/winged-helix gene they named Foxp3 (the protein, scurfin). In parallel, mutations in human **FOXP3** were shown to cause IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked), the human counterpart of scurfy. > **FOXP3 is the master regulator** In 2003 Sakaguchi's group, alongside the labs of Rudensky and Ramsdell, demonstrated that Foxp3 is both necessary and sufficient to program the regulatory T cell fate. Enforced Foxp3 expression converts conventional CD4+ T cells into suppressive cells, and loss of Foxp3 abolishes the lineage. This united the two strands: the CD25+ cells Sakaguchi found in 1995 are defined by the gene Brunkow and Ramsdell found in 2001. FOXP3+ regulatory T cells suppress through several routes: consuming local IL-2, secreting inhibitory cytokines such as IL-10 and TGF-beta, and engaging CTLA-4 to dampen antigen-presenting cells. The clinical stakes run in both directions. Too little regulatory T cell activity permits autoimmunity, as in IPEX, type 1 diabetes and inflammatory bowel disease. Too much shields a target from the immune system, which is exactly how many tumours evade attack, since regulatory T cells inside a tumour blunt the anti-cancer response. **Why peripheral tolerance is a therapeutic target** - Autoimmune disease: expanding or boosting regulatory T cells aims to restore tolerance in conditions such as type 1 diabetes and inflammatory bowel disease without broadly suppressing the whole immune system. - Transplantation: regulatory T cells can promote acceptance of a graft and curb graft-versus-host disease, an approach now being tested in cell therapies. - Cancer: tumours often recruit regulatory T cells to hide from immune attack, so selectively removing or disabling them is a strategy to unleash anti-tumour responses. - Cell therapy: regulatory T cells are being engineered as living drugs, the direction reflected in Fred Ramsdell's work at Sonoma Biotherapeutics. **Video transcript (64 seconds):** Mice that lost their thymus 3 days after birth developed autoimmune disease. In 1982, Shimon Sakaguchi prevented it with T cells from normal mice. In 1983 the I-J locus, said to encode suppressor T cells, turned out not to exist. The field faded, but Sakaguchi kept splitting the CD4 pool. In 1995 he removed the CD25-positive cells, and athymic mice given the rest got autoimmunity in several organs. Adding those cells back prevented it. Mary Brunkow and Fred Ramsdell found the scurfy mutation, a 2-base-pair insertion in an unknown forkhead gene, causing a premature stop codon. They named it Foxp3 and tied its human version to IPEX. In 2003, Sakaguchi's group showed that transferring Foxp3 turns conventional CD4 T cells into regulatory T cells. More than 200 clinical trials now involve these cells. ## Think first **Q:** Your immune system is trained to destroy anything foreign. So why does it not normally destroy your own body, which is full of cells it could attack? **A:** **Because a standing guard of cells holds the attackers back.** Some self-reactive immune cells always slip through training, so the body keeps a population of regulatory T cells that actively suppress them. This second layer of protection is called peripheral tolerance. Without it, the immune system would turn on the body's own tissue. **Q:** A baby is born with a single broken gene called FOXP3 and develops severe autoimmune disease as an infant. How can one gene set the whole immune system against the body? **A:** **FOXP3 is the master switch that builds the body's guard cells.** Without a working FOXP3 gene, regulatory T cells never form, so nothing restrains the self-reactive immune cells. In humans this causes the fatal disease IPEX; in mice the same broken gene causes the scurfy disorder. Connecting that gene to the guard cells is the discovery this prize celebrates. ## Tumours can hire the body's own guards to hide The same regulatory T cells that protect healthy tissue can be turned against us. Many tumours attract regulatory T cells to surround themselves, switching off the immune attack that would otherwise destroy them. Learning to remove or disable those guards inside a tumour is now a real strategy in cancer treatment. ## Key terms - **Peripheral immune tolerance**: The set of safeguards that stops self-reactive immune cells from attacking the body's own tissue once they are circulating outside the thymus. Regulatory T cells enforce it. - **Central tolerance**: The earlier safeguard in which T cells that react against the body's own molecules are deleted as they mature in the thymus, before they enter the bloodstream. - **Regulatory T cell (Treg)**: A specialised T cell that suppresses other immune cells, acting as a brake or security guard. It carries the CD25 marker and is defined by the FOXP3 gene. - **FOXP3**: The master-switch gene, and its protein scurfin, that programs a developing T cell to become a regulatory T cell. Mutations cause IPEX in humans and the scurfy disorder in mice. - **IPEX**: A rare and often fatal human autoimmune disease of infancy caused by FOXP3 mutations, the human counterpart of the scurfy mouse. - **Scurfy mouse**: A mutant mouse strain that dies young from runaway autoimmunity. Tracing its defect led Brunkow and Ramsdell to the Foxp3 gene. ## Check yourself 1. What is the main job of a regulatory T cell? - To swallow and digest bacteria - **To hold other immune cells back so they do not attack the body's own tissue** (correct) - To produce antibodies against viruses - To carry oxygen around in the blood - Why: Regulatory T cells act as the immune system's brakes, or security guards. They suppress other immune cells and stop them attacking the body's own healthy tissue, which is what maintains peripheral tolerance. 2. Sakaguchi's 1995 discovery challenged which prevailing belief? - **That the immune system only learned tolerance by deleting dangerous cells in the thymus** (correct) - That T cells exist at all - That bacteria cause disease - That antibodies are made of protein - Why: Before 1995 most researchers thought tolerance came only from central tolerance, the deletion of self-reactive cells in the thymus. Sakaguchi showed there is a second, active layer: regulatory T cells that suppress the escapees out in the body, called peripheral tolerance. 3. What did Brunkow and Ramsdell show about the FOXP3 gene in 2001? - That it makes red blood cells - **That mutations in it cause the scurfy mouse disease and the human disease IPEX** (correct) - That it has no effect on health - That it works only in plants - Why: They traced the scurfy mouse's fatal autoimmune disorder to a mutated gene they named Foxp3, and showed that mutations in the human version cause IPEX. Sakaguchi later proved FOXP3 controls regulatory T cell development. ## The laureates ### Mary E. Brunkow Working with Fred Ramsdell, in 2001 Brunkow tracked down the gene behind the scurfy mouse's fatal autoimmune disorder and named it Foxp3. The same gene, mutated in humans, causes the deadly autoimmune syndrome IPEX. Her genetic detective work gave regulatory T cells a molecular identity. ### Fred Ramsdell With Mary Brunkow, in 2001 Ramsdell showed that a single mutated gene, Foxp3, explained both the scurfy mouse's lethal autoimmunity and the human disease IPEX. That link pinpointed the master switch that builds the immune system's guard cells. ### Shimon Sakaguchi In 1995, against the prevailing view, Sakaguchi found a class of T cells marked by CD25 that hold other immune cells in check. Remove them from mice and severe autoimmune disease follows. In 2003 he proved that FOXP3 controls these cells, now known as regulatory T cells. ## Sources - [Press release: The Nobel Prize in Physiology or Medicine 2025 (NobelPrize.org)](https://www.nobelprize.org/prizes/medicine/2025/press-release/) - [The Nobel Prize in Physiology or Medicine 2025, popular information (NobelPrize.org)](https://www.nobelprize.org/prizes/medicine/2025/popular-information/) - [Regulatory T cell (Wikipedia)](https://en.wikipedia.org/wiki/Regulatory_T_cell) - [FOXP3 (Wikipedia)](https://en.wikipedia.org/wiki/FOXP3) --- From Nobel Explained (https://nobelexplained.com), a free, independent course on every Nobel Prize since 2020. Not affiliated with the Nobel Foundation. Facts are pinned from the official Nobel Prize API.