The body’s powerful immune system constantly protects us from countless microbes that attempt to invade. However, without proper regulation, this defense system could mistakenly attack our own organs.
Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi received the Nobel Prize in Physiology or Medicine 2025 for discovering how peripheral immune tolerance prevents the immune system from harming the body. Their findings revolutionized immunology and laid the foundation for new treatments for cancer and autoimmune diseases.
The Immune System: A Complex Guardian
Every day, our immune system identifies and eliminates pathogens while distinguishing them from our body’s own cells. This remarkable ability is essential for survival. Still, researchers long wondered how the immune system avoids attacking its host.
Initially, scientists believed that central immune tolerance, a process in which self-reactive T cells are eliminated during development in the thymus, provided the full answer. Yet, discoveries by Brunkow, Ramsdell, and Sakaguchi revealed a more intricate mechanism—peripheral immune tolerance—that further regulates immune balance.
T Cells: The Body’s Key Defenders
T cells are crucial for immune defense. Helper T cells alert other immune cells when they detect a pathogen, while killer T cells destroy infected or cancerous cells. Each T cell carries a unique receptor that functions like a sensor, scanning for invaders.
Although this diversity allows the immune system to recognize nearly any pathogen, it also means some T cells mistakenly recognize the body’s own tissues. Normally, these self-reactive cells are destroyed in the thymus—a process known as central tolerance. But some escape this checkpoint, requiring another layer of control.
Shimon Sakaguchi and the Discovery of Regulatory T Cells
In the early 1980s, Shimon Sakaguchi at the Aichi Cancer Center in Japan questioned why mice without a thymus developed severe autoimmune diseases. His experiments revealed a population of T cells capable of suppressing excessive immune activity.
Over a decade of research led Sakaguchi to identify these special cells, which he named regulatory T cells (Tregs). In 1995, he showed that these cells express two surface proteins—CD4 and CD25—and act as the immune system’s “security guards,” preventing harmful autoimmune reactions.
The Clue from Mutant “Scurfy” Mice
Meanwhile, in the United States, researchers studying radiation-exposed mice in the 1940s noticed a strain with scaly skin, enlarged spleens, and fatal immune disorders. Known as scurfy mice, these animals carried a mutation on the X chromosome that caused their immune systems to attack their own tissues.
In the 1990s, Mary Brunkow and Fred Ramsdell at Celltech Chiroscience in Washington began investigating this mysterious mutation to understand autoimmune diseases better.
Finding the Genetic Key: The FOXP3 Gene
Through painstaking DNA mapping, Brunkow and Ramsdell pinpointed the defective gene responsible for the scurfy mice’s condition. They named it Foxp3, part of a family of genes known as forkhead box (FOX) genes that control gene regulation and cell development.
Their breakthrough came when they connected mutations in the human equivalent of FOXP3 to a rare autoimmune disorder called IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome). In 2001, they published their findings in Nature Genetics, showing that FOXP3 mutations cause both scurfy disease in mice and IPEX in humans.
Connecting the Dots: FOXP3 and Regulatory T Cells
Two years later, Sakaguchi and other researchers proved that FOXP3 is essential for the development of regulatory T cells. These cells maintain peripheral immune tolerance by stopping other T cells from attacking the body’s own tissues.
Regulatory T cells also play a crucial role in calming the immune system after infections have been cleared, ensuring that immune activity does not spiral out of control.
Transforming Medicine: From Discovery to Therapy
The discovery of regulatory T cells and FOXP3 has sparked innovative therapeutic strategies.
In cancer, researchers are testing ways to block regulatory T cells that shield tumors from immune attack. In autoimmune diseases, scientists are exploring treatments that boost regulatory T cell production using interleukin-2 (IL-2). Clinical trials are also assessing IL-2 therapy to prevent organ rejection after transplantation.
In some approaches, scientists even extract and multiply regulatory T cells in the lab before reintroducing them to patients. Modified versions of these cells can be directed to specific organs, such as a transplanted kidney or liver, to prevent immune damage.
Lasting Impact
The pioneering work of Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi has transformed our understanding of how the immune system maintains balance. Their discoveries have opened new paths for treating cancer, autoimmune diseases, and transplant complications—demonstrating how basic research can profoundly benefit humanity.