The 2025 Nobel Prize in Physiology or Medicine has been awarded to Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi for their groundbreaking discoveries concerning peripheral immune tolerance, the mechanism that prevents the immune system from harming the body. Their work identified the immune system’s security guards, the regulatory T cells, which prevent immune cells from attacking our own body. These discoveries have laid the foundation for a new field of research, transforming the understanding of immune regulation and opening avenues for novel treatments in autoimmune diseases, cancer, and organ transplantation.
Understanding the Immune System
The human body’s immune system is powerful and has complex defence mechanisms that constantly fight off thousands of microbes attempting to invade. Microbes vary widely, with many camouflaging themselves to resemble human cells. The immune system must, therefore, make a crucial distinction, recognising between what to attack and what to protect. It must also identify the body’s own healthy cells to avoid self-destruction. When this identification process fails, autoimmune diseases develop. Similarly, in organ or stem cell transplants, there is always a risk of the immune system attacking newly transplanted cells. Thus, understanding how the immune system distinguishes between friend and foe is vital.
The immune system’s key soldiers are T cells. Helper T cells patrol the body and raise alarms when they detect any invading microbe, while killer T cells eradicate cells which have been infected by virus or other pathogens. For decades, it was believed that the thymus, an organ behind the sternum, played the central role in this selection process. In the thymus, T cells were thought to undergo an examination, those that mistakenly attacked the body’s own cells were eliminated, while the others were released into circulation. This mechanism, known as central tolerance, was long considered the main safeguard against autoimmunity.
However, despite this selection, some autoreactive T cells persisted in healthy individuals. This observation hinted that additional mechanisms must be operating outside the thymus, in the periphery, to keep immune responses under control. It is in this context that the three Nobel laureates’ discoveries proved revolutionary.
Shimon Sakaguchi and the Discovery of Regulatory T Cells
Shimon Sakaguchi began investigating immune regulation at the Aichi Cancer Center Research Institute in Nagoya, Japan, in the late 1970s. By the 1980s, scientists had realised that removing the thymus from newborn mice led not to a weakened immune system, but no hyperactivity. The immune system turned against the body itself, producing multiple autoimmune disorders. This paradoxical result suggested that the immune system possessed some internal ‘security guards’ that prevented such attacks.
Veering away from prevailing scientific belief, Sakaguchi postulated that certain specialised T cells act as suppressors, calming down overly aggressive immune responses. His research revealed that when these cells were removed, the mice developed autoimmune diseases and when reintroduced, the diseases were prevented. In 1995, he presented an entirely new class of T cells to the world. These were characterised not only by carrying CD4 on their surface, but also a protein called CD25, these were the regulatory T cells.
Regulatory T cells suppress other T cells that might attack the body’s own tissues, maintain a balance and prevent autoimmunity. Yet, Sakaguchi’s discovery initially faced scepticism, as other experiments at the time had failed to produce convincing evidence of such cells. Nevertheless, his hypothesis that an additional mechanism operated in the periphery, a form of ‘peripheral immune tolerance’, would later become one of the most significant breakthroughs in immunology.
Brunkow, Ramsdell, and the FOXP3 Gene
While Sakaguchi worked in Japan, Mary E. Brunkow and Fred Ramsdell were investigating a different mystery in the US. At Celltech Chiroscience, a biotechnology company in Bothell, Washington, they were studying a strain of male mice named scurfy mice. These mice developed severe multi-organ autoimmunity, their tissues destroyed by their own T cells, and most of them died within weeks of birth.
Through meticulous genetic studies, Brunkow and Ramsdell traced the cause of this disease to a mutation on the X chromosome. They identified an insertion in the DNA that truncated a previously unknown gene, which they named FOXP3. They found that the loss of this gene led to immune collapse. Around the same time, clinical studies in humans revealed that mutations in the FOX3 gene caused a rare and fatal autoimmune disorder called immuno dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome.
Two years later, Sakaguchi and others confirmed that the FOXP3 gene controls the development of regulatory T cells. It functions as molecular switch that governs the differentiation and maintenance of these cells, enabling them to suppress self-reactive immune responses. Together, these discoveries, Sakaguchi’s identification of regulatory T cells and Brunkow and Ramsdell’s discovery of the FOXP3 gene, established the basis of peripheral immune tolerance.
Redefining the Immune System
The laureates’ work defined the immune system from an on/off defence apparatus into a dynamic ecosystem of activation and restraint. Central immune tolerance, which occurs in the thymus, eliminates many self-reactive T cells during their development. But peripheral immune tolerance, the focus of Nobel winning research of 2025, ensures that any autoreactive cells that escape this initial screening are kept under control throughout life.
This insight fundamentally changed scientific understanding. As the Nobel Committee noted, the laureates’ discoveries have been decisive for explaining how the immune system functions and why most people do not develop serious autoimmune diseases. The identification of regulatory T cells provided a biological explanation for how immune responses are moderated, preventing the immune system from turning against the body it is meant to protect.
Implications for Medical Science
The discoveries of regulatory T cells and the FOXP3 gene have launched an entirely new field of immune regulation research. The findings hold far-reaching implications for medical science, especially in the treatment of autoimmune diseases, cancer, and transplantation medicine.
In autoimmune diseases such as type 1 diabetes, multiple sclerosis, celiac disease or rheumatoid arthritis, the immune system mistakenly attacks the body’s own tissues. Experimental therapies are now exploring how to expand or stabilise regulatory T cells to mitigate these harmful immune reactions. Early clinical trials suggest that reinforcing this population of cells could control autoimmune activity without the need for broad immunosuppression.
In transplantation medicine, researchers are engineering regulatory T cells to improve graft acceptance, thereby reducing the risk of organ rejection. By enhancing the immune system’s tolerance mechanisms, these approaches aim to enable safer and more durable transplants.
In cancer research, the focus is reversed. Tumours often exploit the presence of regulatory T cells as a protective shield, preventing immune system from attacking cancerous cells. Scientists are investigating strategies to selectively dismantle or reprogramme these tumour-associated regulatory T cells, allowing immune cells to target and destroy tumours more effectively.
More than 200 studies involving regulatory T cells are currently in progress, underscoring the potential of this discovery to revolutionise therapy. The laureates’ work continues to influence research into chronic inflammation, allergy, and beyond.
Broader Significance and Legacy
The Nobel Assembly at Sweden’s Karolinska Institute awarded this year’s prize, valued at 11 million Swedish crowns, recognising discoveries that have transformed the scientific understanding of autoimmune regulation. The winners for medicine also received a gold medal presented by Sweden’s king. The laureates’ findings have not only advanced immunology but further demonstrated how curiosity-driven research could lead to breakthroughs with immense practical relevance.
Mary E. Brunkow, born in 1961, has a Ph.D. from Princeton University, Princeton, USA. She works at the Institute for Systems Biology in Seattle, USA. Fred Ramsdell, born in 1960, completed his Ph.D. in 1987 from the University of California, Los Angeles, USA and serves at the Sonoma Biotherapeutics in San Francisco, USA. Shimon Sakaguchi, born in 1951, completed his M.D. in 1976 and Ph.D. in 1983, from Kyoto University, Japan. He is a Distinguished Professor at the Immunology Frontier Research Center, Osaka University, Japan. Their work exemplifies international scientific collaboration and persistence over decades in unravelling the complexities of the immune system.
Beyond scientific impact, the discoveries highlight the growing interface between academia and biotechnology. Brunkow and Ramsdell’s work within the private sector demonstrated that industrial research could yield profound contributions to fundamental science. At the same time, their findings have raised ethical and policy questions, especially as cell-based therapies remain costly and inaccessible to many.
A Transformative Discovery
More than a century after the first Nobel Prizes, the 2025 award in physiology or medicine underscores the enduing importance of basic scientific inquiry. By revealing how the immune system keeps itself in check, Brunkow, Ramsdell, and Sakaguchi provided the missing link in understanding self-tolerance, how the body distinguishes between self and non-self.
Their revolutionary discoveries concerning peripheral immune tolerance have redefined the field of immunology and reshaped medical research. The regulatory T cells they identified and the FOXP3 gene that controls them together constitute a biological safeguard essential for health. From preventing autoimmune diseases to designing targeted cancer therapies, their work continues to influence medicine and the promise of future treatments. They have conferred the greatest benefit to humankind.
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