The human immune system is a masterpiece of evolution — powerful enough to fend off millions of potential pathogens every day, yet finely regulated to protect the body’s own tissues. How this balance is achieved has long remained a mystery. Three researchers have made pivotal contributions to solving it: Mary E. Brunkow, PhD, molecular geneticist at the Institute for Systems Biology in Seattle; Fred Ramsdell, PhD, immunologist affiliated with Sonoma Biotherapeutics in San Francisco; and Shimon Sakaguchi, MD, PhD, clinical immunologist and professor at Osaka University, Osaka, Japan.

They will receive the Nobel Prize in Physiology or Medicine 2025 for their discoveries in peripheral immune tolerance, the immune system’s ability to regulate itself. Their research on regulatory T cells (Tregs) has opened a new chapter in immunology and demonstrated how closely intertwined genetic, cellular, and clinical research can be. Clinically, their findings are critical for understanding and treating autoimmune diseases such as type 1 diabetes, multiple sclerosis, and rheumatoid arthritis and have implications in cancer therapy and transplantation medicine.

Brunkow, Ramsdell, and Sakaguchi share a prize of 11 million Swedish krona (approximately $1.17 million).

Self-Attacking T Cells

The immune system recognizes pathogens via T cells equipped with highly variable receptors. This diversity ensures detection of new viruses or bacteria but also carries a risk: Among millions of T-cell variants, some inevitably target the body’s own tissues.

For decades, it was believed that the thymus eliminated misdirected T cells through a process called central immune tolerance. Yet autoreactive cells continue to emerge. Why, then, does the immune system usually avoid attacking the body?

A Forgotten Hypothesis Regains Relevance

In the 1980s, the concept of suppressor T cells fell out of favor due to conflicting experimental results. Only a few researchers posited that there must be a regulatory “brake” in the immune system. One of them was Sakaguchi, then at the Aichi Cancer Center Research Institute in Nagoya, Japan.

Through surgical experiments in mice, including thymus removal during the first days of life, Sakaguchi observed that the animals developed severe autoimmune diseases. He then isolated a population of CD4-positive T cells capable of suppressing these immune reactions.

After more than a decade of work, in 1995 he identified a previously unknown T-cell population expressing the surface protein CD25, which he named Tregs — the guardians of the immune system.

Initially met with skepticism, Sakaguchi’s discovery laid the foundation for a new field of research. Subsequent genetic studies in the US confirmed his findings, providing a link between molecular genetics and immune regulation.

From Diseased Mice to Genetic Insights

Experimental evidence also came from earlier work: In the 1940s, researchers identified a peculiar mouse strain with scaly skin, enlarged lymphoid organs, and a short lifespan, later called the scurfy mutation, inherited via the X chromosome. Decades later, this mutation became a crucial clue for understanding Treg biology.

In the 1990s, Brunkow and Ramsdell, at the US biotech company Celltech Chiroscience, investigated the genetic cause. After years of meticulous work, they identified the responsible gene in 2001: Foxp3.

Foxp3 encodes a transcription factor that regulates the activity of other genes. Mutations in this gene in humans cause the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, which is a rare, severe congenital autoimmune disorder affecting almost exclusively male infants. This provided genetic proof that functional FOXP3 protein is essential for Treg development. Without it, the immune system loses self-control.

Linking Genetics and Immunology

Within 2 years of the Foxp3 discovery, Sakaguchi and other groups confirmed the connection: FOXP3 is critical for Treg development, establishing peripheral immune tolerance as a second key protective mechanism.

While the thymus eliminates dangerous T cells through central tolerance, Tregs control immune responses throughout the body, preventing autoimmune reactions.

From Autoimmunity to Oncology

The discovery of Tregs has transformed immunology. Today, Tregs are recognized as central in multiple areas of medicine:

• Autoimmune diseases: Defective Tregs contribute to conditions such as type 1 diabetes, multiple sclerosis, and rheumatoid arthritis. Early clinical trials are exploring whether interleukin-2 therapy can stimulate Tregs and reduce symptoms.
• Transplantation medicine: Expanding a patient’s own Tregs in the laboratory may help prevent organ rejection.
• Cancer therapy: Tumors exploit Tregs by increasing their presence in the tumor microenvironment. Immunotherapies aim to disrupt this “protective barrier,” making tumor cells more vulnerable to attack. 

A Prize for Life’s Balance

“Through their revolutionary discoveries, Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi have provided fundamental knowledge of how the immune system is regulated and kept in check. They have thus conferred the greatest benefit to humankind,” the Nobel Committee stated.

Their work answered a fundamental question in biomedicine and paved the way for new treatment strategies in cancer, autoimmunity, and transplantation medicine.

This story was translated from Medscape’s German edition.