Our immune system serves as the body’s first line of defense, waging an invisible war against pathogens, viruses, bacteria, and other agents that threaten to invade us each day. To ensure that this defense system doesn’t mistakenly turn against the body’s own tissues and organs, it relies on a critical safeguard mechanism known as peripheral immune tolerance. The groundbreaking discovery of this mechanism—and its profound role in advancing our understanding of immune regulation—has been recognized with the 2025 Nobel Prize in Physiology or Medicine.
The prize and its accompanying 11 million Swedish kronor (1.2 million USD) will be shared among “Mary Brunkow, a molecular biologist at the Institute for Systems Biology in Seattle, Washington; Fred Ramsdell, a scientific adviser at Sonoma Biotherapeutics, also in Seattle; and Shimon Sakaguchi, an immunologist at Osaka University in Japan,” Nature reports. Their decades of research culminated in the discovery of regulatory T cells, a special class of immune cells that act as the peacekeepers of the body’s defense system. Ordinary T cells are white blood cells that attack invading pathogens while regulatory T cells ensure that these attacks cease once the threat is eliminated. Without that balance, the immune system can mistakenly turn on the body’s own tissues, leading to autoimmune diseases.
In 1995, Dr. Shimon Sakaguchi discovered regulatory T cells. At the time, scientists believed that the thymus, a small lymphatic gland responsible for creating and training T cells, also eliminated them once they had completed their task through a process known as central tolerance. Dr. Sakaguchi’s discovery revealed another layer of complexity in how the immune system regulates itself, showing that there are additional safeguards beyond the thymus that keep it from attacking the body’s own tissues.
This idea was later supported by the work of Dr. Fred Ramsdell and Dr. Mary Brunkow in 2001, when the team set out to understand why certain strains of mice were more prone to autoimmune disease. Their experiments revealed that the mice carried a mutation in the Foxp3 gene, located on the X chromosome. Further studies showed that humans with the same mutation develop immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, a rare autoimmune disorder that appears at birth. IPEX causes eczema, chronic diarrhea from immune attacks on the gut, type 1 diabetes, and other hormonal imbalances when the immune system targets insulin-producing and endocrine organs.
Two years later, Dr. Sakaguchi linked these discoveries together and demonstrated that the Foxp3 gene is responsible for producing regulatory T cells. Mutations in this gene disrupt immune balance and lead directly to autoimmune disease. This discovery launched the field of peripheral tolerance, which revealed new strategies to control the immune system and inspired breakthroughs in treating autoimmune disorders, cancer, and transplant rejection. What began as a mystery of self-recognition has become a cornerstone of modern immunology, one that will continue to guide therapies for autoimmune disease, cancer, and more.
