Breaking
On 6 October 2025, the Nobel Assembly at the Karolinska Institute announced that the 2025 Nobel Prize in Physiology or Medicine had been awarded to three scientists "for their discoveries concerning peripheral immune tolerance": Shimon Sakaguchi (74), Specially-Appointed Professor at Osaka University's Immunology Frontier Research Center; Mary E. Brunkow of the Institute for Systems Biology in Seattle; and Fred Ramsdell of Sonoma Biotherapeutics in the United States.
For Japan, the award is the sixth Physiology or Medicine laureate in the country's history and the first in seven years, following Tasuku Honjo's 2018 award.
Three Decades in Search of the Immune Brake
Sakaguchi's path began in the 1980s with a stubborn observation: if the thymus — the training ground for T cells — was surgically removed from newborn mice, the animals spontaneously developed a spectrum of autoimmune diseases. The classical model could not explain the result. Sakaguchi proposed that the thymus produces not only attacking T cells but also a counterpart population that actively restrains them.
In 1995, using the IL-2 receptor alpha chain (CD25) as a surface marker, he isolated this elusive population and named it the regulatory T cell, or Treg. The field was skeptical at first — the idea of a dedicated immunological brake cell was radical — and it took several years of reproduction and molecular characterization by laboratories around the world before Tregs became textbook immunology.
Foxp3: The Master Switch
While Sakaguchi's group was defining Tregs phenotypically, Brunkow and Ramsdell were pursuing a human genetic disease called IPEX, a lethal early-onset autoimmune syndrome. In 2001 they identified the causative gene, Foxp3.
From 2003 onward, the two lines of work converged dramatically. Foxp3 was shown to be the master transcription factor required for Tregs to differentiate and to maintain their identity — the molecular switch behind Sakaguchi's cellular discovery. Together, these independent paths laid the foundation for modern immunology's understanding of self-tolerance.
What the Prize Recognizes
The core contributions can be summarized as follows.
- Self-tolerance is not achieved by thymic selection (central tolerance) alone
- In peripheral tissues, Tregs actively and continuously restrain immune responses
- Autoimmune disease, allergy, and transplant rejection share a common root here
- Releasing that brake selectively opens new avenues for cancer immunotherapy
Clinical Horizons: Cancer, Allergy, and Transplantation
The therapeutic implications are substantial. Boosting Treg activity may help control autoimmune diseases such as rheumatoid arthritis and type 1 diabetes, as well as allergies and the rejection of transplanted organs. Conversely, selectively depleting Tregs that accumulate inside tumors can unleash the body's own cytotoxic cells against cancer. Several Treg-targeting drugs and cell therapies are already in clinical trials.
Speaking to reporters after the announcement, Sakaguchi expressed strong conviction that "an era in which cancer can be cured will certainly come," and framed Tregs as a cornerstone for the next generation of medicine.
Seven Years Since Japan's Last Medicine Laureate
Two days after Sakaguchi's award, the 2025 Nobel Prize in Chemistry was given to Susumu Kitagawa of Kyoto University — giving Japan two laureates in a single week, a rare event in recent memory. At press conferences following both announcements, the laureates called repeatedly for sustained, long-term public support of basic research. Treg biology's thirty-year arc is itself a reminder that fundamental discoveries seldom fit short-term metrics.
Closing
Immunity without a brake becomes self-destructive; braking too hard leaves the body defenseless against pathogens and tumors. Sakaguchi's quarter-century pursuit of the cells that hold this balance, together with Brunkow's and Ramsdell's elucidation of the molecular switch that defines them, is recognized as a bridge from basic biology to clinical medicine. The translation of Treg research into patient care is expected to accelerate in the years ahead.