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Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi have been awarded the 2025 Nobel Prize in Physiology or Medicine for their pioneering discoveries on peripheral immune tolerance—the mechanisms that prevent the immune system from attacking the body’s own tissues. Their breakthrough centred on the identification and understanding of regulatory T cells, the immune system’s “security guards,” which play a vital role in suppressing harmful immune responses. The prize of 11 million Swedish kronor ($1.2 million) will be shared equally among the three laureates. Announcing the award, Olle Kämpe, chair of the Nobel Committee, stated, “Their discoveries have been decisive for our understanding of how the immune system functions and why we do not all develop serious autoimmune diseases.”

Brunkow is currently a senior programme manager at the Institute for Systems Biology in Seattle, Ramsdell serves as a scientific adviser at Sonoma Biotherapeutics in San Francisco, and Sakaguchi is a professor at Osaka University.

Scientific Developments Behind the Breakthrough

The immune system protects us from countless invading microbes every day. To do so effectively, it must distinguish between what is foreign and what belongs to the body. Many pathogens mimic human cells to escape detection, making immune regulation essential—an unregulated immune system can attack the body’s own organs.

In 1995, Shimon Sakaguchi made the first pivotal discovery in this field. At the time, the scientific consensus was that immune tolerance was established primarily in the thymus through the elimination of potentially harmful immune cells—a process known as central tolerance. Sakaguchi challenged this view by identifying a previously unknown class of immune cells that prevented autoimmune reactions. His work revealed that immune tolerance is more complex and extends beyond the thymus.

The second major discovery came in 2001, when Mary Brunkow and Fred Ramsdell investigated a mouse strain prone to severe autoimmune disease. They identified a mutation in a gene they named Foxp3, and subsequently showed that mutations in the human equivalent cause a rare but devastating autoimmune disorder, IPEX syndrome. Two years later, Sakaguchi linked the findings by demonstrating that Foxp3 governs the development of the same protective cells he had identified in 1995. These “regulatory T cells,” or Tregs, serve as monitors that prevent other immune cells from attacking healthy tissues.

Significance of the Laureates’ Discovery

Scientists and clinicians have widely praised the laureates’ contributions, calling them foundational to modern immunology. Their work redefined the understanding of T-cell biology and established the field of peripheral tolerance. Because misplaced immune attacks cause autoimmune diseases such as type 1 diabetes and multiple sclerosis, the discovery of regulatory T cells opened new pathways for developing therapies to modulate the immune response.

Prof. Danny Altmann of Imperial College London noted, “A huge part of the advance over the past 30 years in understanding the immune system has come with the description, definition and characterisation of regulatory T-cells in diverse aspects of health and disease.”

Prof. Marie Wahren-Herlenius of the Karolinska Institute highlighted how these discoveries have inspired potential treatments. Clinical trials are underway to boost regulatory T-cell numbers to suppress damaging immune reactions in autoimmune disorders or after organ transplantation. In cancer treatment, the strategy takes the opposite direction. “Cancer cells can make use of our regulatory T-cells to avoid immune reactions that could destroy the cancer cells,” she said. As a result, therapies aim to downregulate or remove these cells to allow the immune system to attack tumours.

According to Thomas Perlmann of the Karolinska Institute, no regulatory T-cell–targeted therapy has yet gained market approval, but more than 200 human clinical trials are ongoing. Among the prominent companies racing to develop such treatments is Ramsdell’s Sonoma Biotherapeutics, partly funded by U.S. drugmaker Regeneron, which is working on therapies for conditions such as inflammatory  bowel disease.