On Monday, the 2025 Nobel Prize in Physiology or Medicine was awarded to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi. Their work recognised a fundamental shift in our understanding of immunology. It answered a question that had troubled researchers for generations: how does an immune system that is designed to attack foreign objects distinguish between the pathogen and self?
Brunkow, Ramsdell, and Sakaguchi discovered regulatory T cells, a specialised class of immune cells that actively suppress autoimmune reactions. This finding opened avenues for treating everything from cancer to organ rejection.
It also overturned decades of established thinking. For most of the twentieth century, scientists believed they understood how the immune system avoided self-destruction. The thymus, a small organ near the heart, was thought to serve as a training ground. Developing immune cells called T cells would learn to recognise the body's own proteins there. Any T cell that showed signs of wanting to attack the body's own tissue would be destroyed. Scientists called this process central tolerance, and the theory seemed complete.
Except it wasn't.
In the 1970s and early 1980s, some researchers proposed that additional immune cells existed beyond the thymus that could regulate immune responses. They called these hypothetical cells "suppressor T cells." But the field was plagued by experiments that couldn't be repeated and, in some cases, outright fraud. When the fabricated data was exposed, the entire scientific community abandoned the idea. Suggesting that the immune system had regulatory cells became a professional taboo.
Shimon Sakaguchi refused to accept this consensus. Working in Nagoya, Japan, during the 1980s, he was intrigued by an experiment that contradicted what everyone believed. When researchers surgically removed the thymus from three-day-old mice, the animals didn't develop weaker immune systems as expected. Instead, they developed severe autoimmune diseases—their immune systems turned violently against their own bodies.
The key insight for Sakaguchi was: if central tolerance (thymus-based training) was the ONLY mechanism, then the T cells that had already passed through the thymus in those first three days should have been perfectly safe. But they weren't—autoimmune disease still developed. This suggested that something beyond the thymus (the regulatory T cells) was needed to continuously keep other T cells in check.
Sakaguchi began extracting T cells from healthy mice and transferring them to sick mice developing autoimmune diseases. The sick mice recovered. This strongly suggested that some type of regulatory cell existed, but identifying these cells proved extraordinarily difficult. It took Sakaguchi over a decade to develop the right methods.
In 1995, he published his breakthrough. He had identified a distinct population of T cells that could be recognised by two protein markers on their surface, called CD4 and CD25. These regulatory T cells, as he named them, actively suppressed immune attacks. But the scientific community remained deeply sceptical, demanding more concrete molecular proof before accepting such a radical claim.
That proof came from an unexpected source: a strain of mice accidentally created during the Manhattan Project in the 1940s. Researchers at Oak Ridge National Laboratory studying radiation effects noticed that some male mice were born with devastating immune problems. These "scurfy" mice lived only a few weeks, their bodies ravaged by their own immune systems attacking vital organs. Scientists knew the mutation causing this was located on the X chromosome, but identifying exactly which gene was responsible would take decades more.
By the 1990s, Mary Brunkow and Fred Ramsdell, working at a biotechnology company in Washington state, recognised that finding the scurfy mutation could help them understand autoimmune diseases in humans. They undertook years of painstaking molecular detective work, searching through millions of DNA letters on the X chromosome.
With 1990s technology, finding a single mutated gene was like searching for a misplaced word in a library containing thousands of books. Brunkow and Ramsdell systematically narrowed their search, eventually identifying twenty possible genes. After testing each one, they finally found the culprit in the twentieth gene—a previously unknown gene they named Foxp3.
The discovery had immediate implications for human health. Brunkow and Ramsdell suspected a connection to IPEX syndrome, a rare genetic disorder in boys characterised by severe autoimmune problems, chronic intestinal inflammation, and hormone disruptions. Their 2001 publication confirmed that mutations in the FOXP3 gene caused both IPEX in humans and the scurfy disease in mice. The genetic blueprint of immune regulation was finally becoming clear.
In 2003, Sakaguchi and other researchers proved conclusively that the FOXP3 gene controls the development of regulatory T cells. Without a working version of this gene, regulatory T cells fail to develop properly, and the immune system attacks the body's own tissue without restraint.
Here's how it works: the immune system creates millions of different T cell receptors through a random mixing process, generating extraordinary variety. This diversity is crucial—it ensures the body can recognise and fight off new threats, including emerging viruses like SARS-CoV-2, which causes COVID-19. But this random process inevitably produces some T cells that recognise the body's own tissues as threats. Regulatory T cells act as peacekeepers, suppressing these potentially dangerous cells and calming down the immune system after an infection is cleared, preventing excessive inflammation.
The therapeutic possibilities have proven substantial. Cancer researchers discovered that many tumors recruit regulatory T cells to their surroundings, essentially building a protective wall that shields the tumor from immune attack. Current clinical trials are testing methods to remove or block these regulatory T cells within tumors, potentially allowing the immune system to destroy cancer more effectively.
For autoimmune diseases, the opposite approach makes sense—increasing regulatory T cells rather than decreasing them. Researchers are testing treatments that help regulatory T cells multiply, as well as more sophisticated approaches where a patient's own regulatory T cells are extracted, grown in large numbers in a laboratory, and then returned to the patient. Some experimental protocols even engineer these cells to travel specifically to transplanted organs, potentially preventing rejection without weakening the entire immune system.
The work of these three laureates demonstrates how scientific breakthroughs often require challenging established beliefs. Sakaguchi pursued a discredited idea because the experimental evidence demanded it. Brunkow and Ramsdell spent years on tedious molecular work that offered no guarantee of success. Their persistence revealed a fundamental principle: the immune system's extraordinary power requires equally powerful internal regulation.
The discovery of regulatory T cells represents more than a technical achievement in immunology. It reveals that our bodies maintain stability not through simple on-off switches, but through continuous, active regulation. The immune system's ability to distinguish self from foreign invaders doesn't come solely from eliminating dangerous cells during development. Instead, it requires ongoing suppression of these cells throughout our lives.
Understanding this principle has transformed how doctors and researchers approach cancer treatment, autoimmune diseases, and organ transplantation. From Sakaguchi's initial observations in the 1980s to the current generation of therapies based on regulatory T cells now being tested in patients, the field has progressed from controversial hypothesis to practical application in just thirty years. It stands as a testament to what fundamental scientific discovery can achieve when researchers refuse to accept incomplete answers.
