Adnkronos Milan, October 6 (Adnkronos Salute) – The 2025 Nobel Prize in Medicine or Physiology has been awarded to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their "groundbreaking discoveries in peripheral immune tolerance, which prevents the immune system from harming the body."
"Their discoveries have laid the foundation for a new field of research and stimulated the development of new treatments, for example for cancer and autoimmune diseases," the citation reads.
The winners were announced at the Karolinska Institutet in Stockholm, Sweden, by the Secretary General of the Nobel Assembly, Thomas Perlman. The three scientists will share 11 million Swedish kronor, the same amount as the last two years, equivalent to approximately 1 million euros.
Our immune system has a security system that ensures immune cells don't miss their target and attack our own body. These security guards are regulatory T cells, discovered by Brunkow, Ramsdell, and Sakaguchi. "Their discoveries were crucial for understanding how the immune system works and why not all of us develop serious autoimmune diseases," says Olle Kämpe, chairman of the Nobel Committee.
This story begins in 1995, when Japanese scientist Shimon Sakaguchi (74) made the first fundamental discovery, going against the prevailing belief held by many researchers at the time that immune tolerance developed solely through the elimination of potentially harmful immune cells in the thymus, through a process called central tolerance. Sakaguchi demonstrated, instead, that the immune system is more complex and discovered that a previously unknown class of immune cells protects the body from autoimmune diseases. This was a first milestone.
The powerful human immune system, in other words, must be regulated, otherwise it could attack our own organs. Sakaguchi and the Americans Mary E. Brunkow (64) and Fred Ramsdell (65) discovered how to keep it under control. Their research on peripheral immune tolerance revolutionized the view that science had until then had of the sentinels of our body. Sentinels that protect us every day from thousands of different microbes that try to invade us. These all look different, and many have developed similarities with human cells as a form of camouflage. How does the immune system decide what to attack and what to defend? This is where Nobel-winning studies come into play.
Following Sakaguchi's insights, Brunkow and Ramsdell made another fundamental discovery in 2001: the experts were able to explain why a specific strain of mice was particularly vulnerable to autoimmune diseases. These rodents had a mutation in a gene Brunkow and Ramsdell named Foxp3, also demonstrating that mutations in the human equivalent of this gene cause a serious autoimmune disease, Ipex syndrome. Two years later, Sakaguchi intervened again, successfully connecting the discoveries: he demonstrated that the Foxp3 gene regulates the development of the cells he identified in 1995. These cells, now known as regulatory T cells, monitor other immune cells and ensure that our immune system tolerates our tissues. The winners' discoveries sparked a research path exploring the secrets of peripheral tolerance, spurring the development of medical treatments for cancer and autoimmune diseases. This field could also lead to more effective transplants. Many of the treatments are now in clinical trials.
The immune system is an evolutionary masterpiece. Without it, we wouldn't survive. One of its marvels is its ability to identify pathogens and differentiate them from the body's own cells. The "bad guys" don't wear a uniform; they have different appearances, they blend in. Researchers have long believed they knew the answer to the question of how the immune system identifies enemies and spares friendly cells: an answer linked to the fact that immune cells mature through a process called central immune tolerance. But, as the new award winners demonstrate, things are more complex. This is laying the foundation for a new field of research that is bearing fruit. And the hope is to be able to treat or cure autoimmune diseases, provide more effective anti-cancer strategies, and prevent serious complications after stem cell transplants.
The protagonists of this story, the immune system's T cells, are our vital protectors, essential players in the body's defense. Our system contains helper T cells that constantly patrol the body and, if they detect an invading microbe, alert other immune cells, which trigger an immune response. Killer T cells then spring into action, eliminating cells infected by viruses or other pathogens and can also attack tumor cells. And of course, there are other immune cells with different functions. But returning to T cells, they have special proteins on their surfaces called T cell receptors, which are like sensors. Using them, these cells can scan other cells to detect whether the body is under attack. T cell receptors are special because, like puzzle pieces, they have different shapes. They are made up of many randomly arranged genes. In theory, this means the body could produce a huge number of different T-cell receptors, as many as 10 to the 15th power (in the order of trillions). And this ensures that there will always be some capable of detecting an invading microbe, including new viruses like the one responsible for the Covid-19 pandemic.
However, receptors are also inevitably created that can attack parts of the body's own tissues. So what causes T cells to react only to hostile microbes? In the 80s, researchers understood that, as T cells mature in the thymus, they are subjected to a type of test that eliminates those that recognize the body's endogenous proteins. This is central tolerance. Some scientists also suspected the existence of suppressor T cells, which were believed to take care of the "colleagues" that had escaped the test in the thymus. But the conclusions of the initial experiments seemed unlikely. It was Sakaguchi who made the breakthrough, sailing against the current. The expert, then working at the Aichi Cancer Center Research Institute in Nagoya, Japan, realized that the immune system must have a security guard. In the early 80s, he therefore isolated T cells matured in genetically identical mice and injected them into those lacking a thymus. The effect is interesting: there appear to be T cells capable of protecting mice from autoimmune diseases. These and other data convinced Sakaguchi that the immune system must have T cells capable of "calming" others and keeping them under control. It was a new class of T cells, and it took him more than 10 years to introduce it to the world. The scientist, in fact, had to find a way to differentiate the various types of T cells. In the Journal of Immunology, he explained that regulatory T cells are characterized not only by carrying CD4 on their surface, but also by a protein called CD25.
Many researchers, however, were skeptical; they wanted more proof. Proof that would come from Brunkow and Ramsdell. This is the second act of the 2025 Nobel Prize in Medicine, which opens with the birth of "sickly" male mice in a 40s American laboratory. At this center, in Oak Ridge, Tennessee, the effects of radiation were being studied. The work was part of the Manhattan Project and the development of the atomic bomb. The strain of Nobel-winning mice is a fortuitous evolutionary case: what caught the attention of experts were some males—called "scurfy"—who were unexpectedly born with scaly skin, a greatly enlarged spleen and lymph glands, and who lived only a few weeks. At the time, molecular genetics was in its infancy, but researchers realized that the mutation causing the disease must be located on the X chromosome: half of the males were affected, and the females lived with the mutation by having two X chromosomes, one of which contained healthy DNA. Females then pass on the scurfy mutation to new generations.
In the 90s, as molecular tools became more sophisticated, researchers began investigating the causes of the scurfy mouse disease, discovering that the organs were being attacked by tissue-destroying T cells. The mutation appeared to cause a mutiny in the immune system. Among the researchers interested in the scurfy mutation were Brunkow and Ramsdell. Both worked at a biotech company, Celltech Chiroscience, in Bothell, Washington, that developed drugs for autoimmune diseases. Brunkow and Ramsdell made a crucial decision: hunt for the mutant gene. In the 90s, it was like looking for a needle in a giant haystack, but they found it. They demonstrated that the scurfy mutation was somewhere in the center of the X chromosome, narrowed the area to 500 nucleotides, then began the enormous mapping effort and narrowed the focus to 20 potential genes. The challenge began to compare them in healthy and scurfy mice. Brunkow and Ramsdell examined gene after gene, and only at the 20th and final one did they hit the jackpot: the Foxp3 gene. Studying it, they began to suspect that a rare autoimmune disease, Ipex, also X-linked, could be the human variant of the scurfy mouse disease. Searching a database, they found the human equivalent of Foxp3. With the help of pediatricians from around the world, they collected samples from children with Ipex and confirmed: they had harmful mutations in the Foxp3 gene.
In 2001, the results published in Nature Genetics sparked feverish activity in several laboratories. Two years later, Sakaguchi's next breakthrough, followed by other researchers, was that the Foxp3 gene controls the development of regulatory T cells. The impact of these fundamental discoveries? They pave the way for new therapeutic strategies. Today, several teams are studying ways to dismantle the barrier of regulatory T cells and allow the immune system to access tumors. In autoimmune diseases, however, they are trying to promote the formation of greater numbers of regulatory T cells by administering interleukin-2, which promotes their proliferation, in pilot studies. And they are also evaluating whether this could be used to prevent organ rejection after transplantation. Another strategy for slowing an overactive immune system is to isolate regulatory T cells from a patient and multiply them in the laboratory, then reintroduce them in greater numbers. In some cases, researchers apply antibodies to the surface of T lymphocytes that function as a tag, allowing them to send cellular security guards to a transplanted liver or kidney, protecting it from immune system attacks. A story yet to be written. (by Paola Olgiati and Lucia Scopelliti)