Nobel Prize in Physiology or Medicine 2025: Regulatory T Cells and Peripheral Immune Tolerance

This note covers the Nobel Prize in Physiology or Medicine 2025: who won it, what peripheral immune tolerance and regulatory T cells are, how Mary E.

Brunkow, Fred Ramsdell and Shimon Sakaguchi made their discoveries, how the work unfolded over several decades, why it matters for autoimmune disease and cancer treatment, and quick facts for exams.

What was the Nobel Prize in Physiology or Medicine 2025 awarded for?

The official citation reads: "for their discoveries concerning peripheral immune tolerance". This is the exact wording used by the prize-giving body.

In plain words, the three laureates discovered how the immune system stops itself from attacking the body's own healthy tissues.

Our immune system constantly fights off viruses, bacteria and other invaders, but it must also learn to leave our own cells alone.

The laureates found a special group of cells, now called regulatory T cells, that act like security guards inside the immune system, calming down other immune cells that might otherwise turn against the body.

This matters because when this control fails, the result is autoimmune disease, in which the immune system damages a person's own organs.

The prize's full official name is the Nobel Prize in Physiology or Medicine, and it was awarded jointly to all three scientists, each receiving one third of the prize.

Who are the laureates?

Mary E. Brunkow

Mary E. Brunkow was born on 23 April 1961 in Portland, OR, USA. At the time of the award she was affiliated with the Institute for Systems Biology, Seattle, WA, USA, where she worked as a Senior Program Manager.

She holds a Ph.D. from Princeton University. She received one third of the prize.

Brunkow, working with Fred Ramsdell, identified the gene mutation responsible for a severe disease in a mouse strain known as "scurfy", and named the newly discovered gene Foxp3.

Fred Ramsdell

Fred Ramsdell (full name Frederick J. Ramsdell) was born on 4 December 1960 in Elmhurst, IL, USA. At the time of the award he was affiliated with Sonoma Biotherapeutics, San Francisco, CA, USA, as a Scientific Advisor.

He holds a Ph.D. from the University of California, Los Angeles (1987). He received one third of the prize.

Ramsdell worked with Brunkow on the scurfy mouse project and together they showed that mutations in the human equivalent of the Foxp3 gene, FOXP3, cause a serious human autoimmune disease called IPEX.

Shimon Sakaguchi

Shimon Sakaguchi was born on 19 January 1951 in Nagahama, Shiga, Japan. At the time of the award he was a Distinguished Professor at the Immunology Frontier Research Center, affiliated with The University of Osaka, Osaka, Japan.

He holds an M.D. (1976) and Ph.D. (1983) from Kyoto University. He received one third of the prize.

In 1995, Sakaguchi identified a previously unknown class of immune cells, regulatory T cells, that protect the body from autoimmune disease. In 2003 he showed that the Foxp3 gene controls the development of these cells, linking his discovery to Brunkow and Ramsdell's work.

What problem were the laureates trying to solve?

Every day, the body is exposed to thousands of different microbes trying to invade it. Many of these microbes have evolved to look similar to our own cells, as a form of disguise.

This raises a basic question: how does the immune system tell friend from foe, attacking invaders while sparing the body's own tissues?

By the 1980s, researchers understood one part of the answer: immune cells called T cells mature inside an organ called the thymus, where they undergo a kind of test. T cells that react strongly against the body's own proteins are eliminated there. This process is called central tolerance.

However, central tolerance was known to be imperfect; some self-reactive T cells escape this test in the thymus and enter circulation.

Some researchers in the 1970s had proposed the existence of "suppressor T cells" that might deal with these escaped cells, but the evidence behind this idea turned out to be flawed, and the whole research field was largely abandoned when it became clear that a key genetic marker these cells were said to carry did not actually exist.

It was in this climate of scepticism that Shimon Sakaguchi chose to pursue the question again, working at the Aichi Cancer Center Research Institute in Nagoya, Japan, where he had been inspired by an earlier experiment: removing the thymus from newborn mice three days after birth caused their immune systems to run amok, producing a range of autoimmune diseases, as if a protective cell type had been removed along with the thymus.

How did Sakaguchi identify regulatory T cells?

Sakaguchi set out to find the "security guard" cells that his earlier work suggested must exist. He used genetically identical mice so that any effect he saw could be attributed to the cells themselves rather than genetic differences.

1. He isolated T cells that had matured normally in genetically identical mice.
2. He injected these T cells into mice that lacked a thymus and were prone to autoimmune disease.
3. He observed that some of the injected T cells appeared to protect the mice from developing autoimmune disease.
4. He distinguished the protective T cells using surface marker proteins: Helper T cells carry a protein called CD4, while the protective subset also carried a second protein, CD25.
5. In 1995, after more than a decade of work, he published this finding in The Journal of Immunology, defining an entirely new class of T cells.

This new class became known as regulatory T cells. Many researchers remained sceptical at first, given the earlier collapse of the "suppressor T cell" idea, and wanted further proof before accepting Sakaguchi's discovery.

Draw a simplified immune system with ordinary (effector) T cells attacking a labelled "self tissue".

Add a smaller population of regulatory T cells (marked CD4+CD25+) sitting between the effector T cells and the tissue, holding back the attack, with an arrow showing them calming the effector cells.

How did Brunkow and Ramsdell find the Foxp3 gene?

The second thread of the story began decades earlier and far from Japan. In the 1940s, in a laboratory in Oak Ridge, Tennessee, studying the effects of radiation as part of the Manhattan Project, researchers noticed some male mice were unexpectedly born with scaly, flaky skin, a greatly enlarged spleen and lymph glands, and a lifespan of only a few weeks.

This strain was named "scurfy". Because only males were affected, researchers correctly reasoned the mutation lay on the X chromosome.

In the 1990s, Mary Brunkow and Fred Ramsdell, working at a biotech company called Celltech Chiroscience in Bothell, Washington, became interested in scurfy mice because the company developed medicines for autoimmune diseases. They set out to find the exact mutant gene responsible.

1. They mapped the likely location of the mutation to the middle of the mouse X chromosome, which has around 170 million nucleotides.
2. They narrowed the candidate region down to about 500,000 nucleotides.
3. They mapped this region in detail and found it contained about 20 potential genes.
4. They compared each of these genes, one by one, between healthy mice and scurfy mice.
5. Only on examining the twentieth and final gene did they find the mutation: a gene with similarities to a family called forkhead box (FOX) genes, which they named Foxp3.

Because IPEX was also linked to the X chromosome, Brunkow and Ramsdell suspected it might be the human version of the scurfy disease, and searched a database of newly discovered genes to find the human equivalent of Foxp3.

With help from paediatricians worldwide, they collected samples from boys with IPEX and, in 2001 in the journal Nature Genetics, showed that mutations in the human FOXP3 gene cause both the mouse scurfy disease and human IPEX.

How did Sakaguchi connect the two discoveries?

By 2001, two separate lines of work existed: Sakaguchi's regulatory T cells, defined by their surface proteins CD4 and CD25, and Brunkow and Ramsdell's Foxp3 gene, linked to a devastating autoimmune disease in mice and humans. The two findings needed to be joined together.

Two years later, in 2003, Sakaguchi proved that the Foxp3 gene governs the development of the regulatory T cells he had identified in 1995.

In other words, this one gene acts as the master switch that tells a developing T cell to become a regulatory T cell rather than an ordinary, attacking T cell.

This connection explained why mice and humans lacking a working Foxp3/FOXP3 gene suffer such severe, body-wide autoimmune disease: without the gene, the body cannot make its population of security-guard cells, so other T cells attack the body's own tissues unchecked.

This whole mechanism, by which regulatory T cells patrol tissues throughout the body and keep other immune cells in check, became known as peripheral immune tolerance, distinct from the earlier-known central tolerance that happens only inside the thymus.

The Nobel Committee's chair, Olle Kämpe, said the discoveries "have been decisive for our understanding of how the immune system functions and why we do not all develop serious autoimmune diseases".

How did the work unfold?

Why does this discovery matter?

The discoveries launched an entirely new field of research into peripheral immune tolerance. Understanding regulatory T cells has led to several directions of medical research now being tested in clinical trials.

In cancer, tumours are known to attract large numbers of regulatory T cells that shield them from immune attack. Researchers are trying to find ways to reduce these protective regulatory T cells around tumours so the immune system can reach and destroy cancer cells.

In autoimmune diseases, the opposite strategy is being tried: researchers are working to increase the number or activity of regulatory T cells. One approach gives patients a substance called interleukin-2, which helps regulatory T cells thrive.

Another isolates a patient's own regulatory T cells, multiplies them in the laboratory, and returns them to the body in greater numbers.

In transplantation, scientists are testing whether boosted regulatory T cells, sometimes modified with antibodies that act like an address label, can be directed to protect a transplanted organ such as a liver or kidney from immune rejection, and whether interleukin-2 can help prevent organ rejection.

Several of these treatments are now undergoing clinical trials, and remain open, ongoing lines of research.

How does this connect to what you study?

This discovery connects directly to the biology topic of the immune system taught in school science. Concepts such as white blood cells, antibodies and how the body distinguishes self from non-self are the everyday foundation on which this Nobel-winning work was built.

It also illustrates how genes control cell behaviour: a single gene, Foxp3, decides whether a developing immune cell becomes an attacking cell or a protective regulatory cell, a clear example of how one gene can switch on an entire programme of cell identity and function.

For students interested in genetics, the scurfy mouse story also shows how scientists can trace a disease from an observed symptom, through chromosome mapping, all the way down to a single faulty gene, a method still used in modern medical genetics.

Quick facts for exams

The Nobel Prize in Physiology or Medicine 2025 was awarded jointly to Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi "for their discoveries concerning peripheral immune tolerance".

It was announced on 6 October 2025 by the Nobel Assembly at Karolinska Institutet. The laureates discovered regulatory T cells and the Foxp3/FOXP3 gene that controls them, cells that prevent the immune system from attacking the body's own tissues.

Brunkow and Ramsdell were born in the USA, while Sakaguchi was born in Japan; the total prize money was divided equally among the three. The discoveries have since inspired new approaches to treating autoimmune disease, cancer and transplant rejection.

Note: Source. The prize facts in this note are from the Nobel Prize's official site, nobelprize.org.

Glossary

• Immune system — the body's network of cells and organs that defends against microbes and other threats.
• T cell — a type of white blood cell that matures in the thymus and plays a central role in the immune response.
• Regulatory T cell — a subset of T cells, marked by CD4 and CD25, that suppresses other immune cells to prevent attacks on the body's own tissues.
• Central tolerance — the elimination of self-reactive T cells inside the thymus during their maturation.
• Peripheral tolerance — the control of self-reactive immune cells outside the thymus, in the rest of the body, mainly by regulatory T cells.
• Autoimmune disease — a condition in which the immune system mistakenly attacks the body's own tissues.
• Foxp3/FOXP3 — a gene (Foxp3 in mice, FOXP3 in humans) that controls the development of regulatory T cells.
• Scurfy mouse — a mutant mouse strain with a faulty Foxp3 gene that develops severe, fatal autoimmune disease.
• IPEX — a rare, severe human autoimmune disease caused by mutations in the FOXP3 gene.
• CD4, CD25 — surface marker proteins used to identify and distinguish types of T cells.
• Thymus — the organ in the chest where T cells mature and undergo central tolerance testing.
• Interleukin-2 — a signalling substance that helps regulatory T cells grow and survive.

Common errors and misconceptions

• Misconception: The prize was for discovering T cells in general. Correct: It was for discovering a specific regulatory subset of T cells and the gene controlling them.
• Misconception: One scientist alone made the full discovery. Correct: The work combined Sakaguchi's cell-biology finding with Brunkow and Ramsdell's gene-mapping work, later connected by Sakaguchi in 2003.
• Misconception: Regulatory T cells were discovered first through the Foxp3 gene. Correct: Sakaguchi identified the cells in 1995, before the Foxp3 gene was found in 2001.
• Misconception: Central tolerance and peripheral tolerance are the same mechanism. Correct: Central tolerance happens inside the thymus; peripheral tolerance, discovered by the laureates, happens afterwards, throughout the body.
• Misconception: The scurfy mouse was created deliberately for immunology research. Correct: It appeared as an unexpected mutant in a laboratory studying radiation effects as part of the Manhattan Project.
• Misconception: Treatments using regulatory T cells are already in routine medical use. Correct: Such treatments are being tested in clinical trials, not yet standard care.

Exam-style questions with model answers

Q1. What was the official citation for the Nobel Prize in Physiology or Medicine 2025? [1 mark]

1. "for their discoveries concerning peripheral immune tolerance".

Q2. Name the three laureates and their countries of birth. [2 marks]

1. Mary E. Brunkow (born in Portland, USA), Fred Ramsdell (born in Elmhurst, USA) and Shimon Sakaguchi (born in Nagahama, Japan).

Q3. What are regulatory T cells and why are they important? [3 marks]

1. Regulatory T cells are a class of immune cells, marked by the surface proteins CD4 and CD25, identified by Shimon Sakaguchi in 1995. They act as security guards within the immune system, suppressing other T cells that might attack the body's own tissues. Without enough regulatory T cells, or without a working Foxp3 gene that controls their development, the body suffers severe autoimmune disease, as seen in scurfy mice and in the human disease IPEX.

Q4. Describe how Brunkow and Ramsdell found the Foxp3 gene. [4 marks]

1. Brunkow and Ramsdell studied scurfy mice, a strain with severe autoimmune disease linked to the X chromosome. They mapped the mutation's likely location to the middle of the chromosome, then narrowed the candidate region to about 500,000 nucleotides. Within this region they found about 20 possible genes and compared each one, in healthy and scurfy mice, one by one. Only the twentieth gene showed the mutation, a gene they named Foxp3 due to its similarity to other forkhead box genes.

Q5. Explain how Sakaguchi's and Brunkow and Ramsdell's discoveries were eventually connected, and why this mattered. [6 marks]

1. In 1995, Shimon Sakaguchi identified a new class of regulatory T cells, marked by CD4 and CD25, which protected mice from autoimmune disease when transferred into thymus-less animals. Separately, in 2001, Mary Brunkow and Fred Ramsdell discovered that a gene they named Foxp3 was mutated in scurfy mice, causing their fatal autoimmune disease, and showed that mutations in the human equivalent, FOXP3, cause the disease IPEX in boys. These were two separate discoveries about the same underlying problem of immune self-tolerance. In 2003, Sakaguchi proved the missing link: the Foxp3 gene governs the development of the regulatory T cells he had identified eight years earlier. This connection explained why a single faulty gene could cause such widespread autoimmune disease, since it meant the body could not produce its population of regulatory, self-tolerance-maintaining cells. The joined discovery launched the field of peripheral immune tolerance and has since guided research into treatments for autoimmune disease, cancer and transplant rejection.

Q6. What is the difference between central tolerance and peripheral tolerance? [3 marks]

1. Central tolerance is the process by which T cells that strongly react against the body's own proteins are eliminated inside the thymus while they are maturing, before they reach the bloodstream. Peripheral tolerance, the focus of this year's prize, happens afterwards, outside the thymus, and relies mainly on regulatory T cells patrolling tissues to keep any surviving self-reactive T cells in check throughout the body.

Q7. Give two potential medical applications of regulatory T cell research. [2 marks]

1. Reducing regulatory T cells around tumours to help the immune system attack cancer, and increasing regulatory T cells (for example using interleukin-2) to treat autoimmune disease or protect transplanted organs from rejection.

Key takeaways

• Brunkow, Ramsdell and Sakaguchi won the 2025 Medicine Nobel for discoveries on peripheral immune tolerance.
• Regulatory T cells, found by Sakaguchi in 1995, suppress other immune cells to protect the body's own tissues.
• Brunkow and Ramsdell found the Foxp3 gene in 2001 while studying the scurfy mouse strain.
• Mutations in the human FOXP3 gene cause the severe autoimmune disease IPEX.
• In 2003, Sakaguchi showed Foxp3 governs the development of regulatory T cells, linking the two discoveries.
• This work founded the field of peripheral immune tolerance, distinct from central tolerance in the thymus.
• Applications being tested include reducing tumour-protecting regulatory T cells and boosting them to treat autoimmune disease and transplant rejection.
• The prize was announced on 6 October 2025 and shared equally among the three laureates.

Test yourself

What protein markers identify regulatory T cells?

Regulatory T cells carry both CD4 and CD25 on their surface, the markers Sakaguchi used to separate them from ordinary helper T cells.

Where was the mutation in scurfy mice eventually found to lie, and why only in males?

It lies on the X chromosome. Males have only one X chromosome, so a single faulty copy caused disease, while females had a second, healthy X chromosome.

What human disease is caused by mutations in FOXP3?

Mutations in the human FOXP3 gene cause IPEX, a serious, often fatal autoimmune disease affecting young boys.

In which year did Sakaguchi link the Foxp3 gene to regulatory T cell development?

In 2003, when he showed the gene governs the development of the regulatory T cells he had identified in 1995.

Name the organ where central tolerance takes place.

Central tolerance takes place in the thymus, where self-reactive T cells are tested and eliminated as they mature.

What substance is given in some clinical trials to help regulatory T cells thrive?

Interleukin-2 is given in pilot studies because it helps regulatory T cells grow, survive and remain active in patients.

How do regulatory T cells protect tumours from the immune system?

Tumours gather large numbers of regulatory T cells around themselves, forming a protective wall that shields them from immune attack.

Who announced the Nobel Prize in Physiology or Medicine 2025, and when?

The Nobel Assembly at Karolinska Institutet announced the prize on 6 October 2025, naming all three laureates jointly.