The story so far: The Nobel Prize season for 2025 began with the announcement of the Physiology or Medicine Prize on October 6. The three awardees — U.S.-based researchers, Mary E. Brunkow and Fred Ramsdell, and Japan’s Shimon Sakaguchi — were chosen for their “discoveries concerning peripheral immune tolerance.” Their discovery enabled a fundamental understanding of how the immune system works — how it is regulated and kept in check. This has led to the evolution of several new potential treatment options, currently being tested, including for cancer.
What does their discovery mean?
Unless the body’s immune system is kept in check, it can attack its own organs. In that case, why do most people not develop autoimmune conditions where the body turns on itself? U.S. and Japanese scientists, working independently, arrived at an explanation for how the immune system is kept in check. It is for their work in making discoveries concerning what prevents the immune system from attacking the body that the Nobel was awarded. The laureates identified the immune system’s regulatory T cells which perform the precise task of preventing immune cells from launching an attack on the body.
Literally every day the immune system, a formidable army, is on guard, battling pathogens that try to invade the body. The question here is how do these cells “know what they should attack and what they should defend”, as the Nobel Committee pointed out. “Their discoveries have been decisive for our understanding of how the immune system functions and why we do not all develop serious autoimmune diseases,” said Olle Kämpe, chair of the Nobel Committee.
What are regulatory T cells?
The story goes back to Sakaguchi when he was working at the Aichi Cancer Centre Research Institute, Japan, some four decades ago. All T cells have special proteins called T-cell receptors on their surface. These receptors can be likened to a type of sensor. Using them, T cells can scan other cells to discover whether the body is under attack. There are a vast number of T cells with different receptors that can detect invaders, including new viruses. But they also have receptors that can attach to human tissues. But then, intuitively, is there a switch mechanism that warns the T cells off body cells?
In the 1980s, scientists realised that when T cells mature in the thymus, a small gland located in the upper chest behind the breastbone and in front of the heart that plays a crucial role in the immune system, they are taught to recognise and eliminate the body’s own proteins in a process called central tolerance. By the time Sakaguchi began his research into trying to understand this mechanism, his colleagues had already reportedly performed an experiment on newborn mice. They hypothesised that the mice would develop fewer T cells and have a weaker immune system if they removed the thymus. Instead, the immune system went into overdrive and ran amok, with the little mice developing several autoimmune conditions. This experiment might not have satisfied its primary goal, but in it was the idea for a Nobel that would come about 30 years later. Sakaguchi took off from where the experiment stopped. He injected these mice with T cells and it appeared that the T cells could protect the mice from autoimmune diseases.
Veering off from the current scientific wisdom of the time, Sakaguchi was convinced that the immune system must have some form of security guard — one that calms down T cells and keeps them in check; in this case, protecting the mice from the autoimmune condition. It took him over a decade, but in 1995, he presented to the world, a new class of T cells to the world, those that carried an extra protein called CD25 on their surface. This was called the regulatory T cell. But other researchers were not convinced yet of this idea.
It would take a second act, and efforts from Brunkow and Ramsdell, to concretely prove the experiment. A new set of mice, being studied since the Manhattan Project in fact, stood up to the occasion. In this instance, half of all the male mice were sickly and died in a few weeks, while the females thrived. It turned out the male’s organs were being attacked by T cells that destroyed the tissues. The Nobel-winning pair, who were then working at a biotech company Celltech Chiroscience in the U.S., realised that the mice could provide important clues in their work. After years of study, at an age when molecular biology was at best infantile, with a great deal of patience, they narrowed down on the faulty, mutant gene and named it Foxp3. They finally had an explanation for why a specific mouse strain was particularly vulnerable to autoimmune diseases. They also showed that mutations in the human equivalent of this gene cause a serious autoimmune disease, IPEX.
Two years later, Sakaguchi and others could prove, this time, convincingly, that the Foxp3 gene controls the development of the regulatory T cells, being able to prevent other T cells from mistakenly attacking the body’s own tissue, in a process that is called peripheral immune tolerance. Regulatory T cells also ensure that the immune system calms down after it has attacked invaders, answering Sakaguchi’s initial question.
What are the specific uses in medicine?
While specific therapies are yet to hit the market, over 200 studies involving regulatory T cells are currently in progress, said Thomas Perlmann, secretary-general of the Nobel Assembly, while making the announcement of the prize on October 6. These stand testimony to the potential slew of new treatment modalities to address various conditions.
This includes work on cancer — dismantling the regulatory T cells so that the immune system can access the tumours and set to work on them; and on autoimmune disorders where researchers are trying to promote the growth of more regulatory T cells, inside the body, but also outside of it, in order to make sure that the immune system does not attack its own body.
It is also believed that this research will have far-reaching implications for organ transplantation by regulating organ acceptance. Clinical studies are afoot to test many of these pathbreaking treatment modalities.
Published – October 12, 2025 02:37 am IST
