Meet Brunkow, Ramsdell and Sakaguchi — the Nobel Prize-winning trio who taught the world how the immune system knows when to stop

When the Nobel Assembly at Karolinska Institutet announced this year’s winners of the Nobel Prize in Physiology or Medicine, it wasn’t just recognising a single discovery. It was celebrating three scientists who, from different corners of the world, helped decode one of life’s most delicate balancing acts, how the body’s immune system knows when to attack and when to stand down.

Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi share the 2025 Nobel for “their discoveries concerning peripheral immune tolerance.” Their work, decades in the making, transformed how we understand the immune system’s self-control, and offered a blueprint for new treatments for cancer, autoimmune disorders, and transplant rejection.

Shimon Sakaguchi
Back in 1995, a young immunologist in Japan dared to question what everyone else believed. At the time, scientists thought the immune system learned self-restraint in a single place, the thymus, where dangerous immune cells were eliminated in a process called central tolerance.

Also Read: Nobel Prize 2025 in Medicine awarded to Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi for discoveries in immune tolerance

Shimon Sakaguchi wasn’t convinced. Working at Kyoto University, he began tracing patterns others had overlooked. He found a small subset of T cells that seemed to suppress immune attacks rather than launch them.

Against conventional wisdom, Sakaguchi proposed that immune tolerance also existed beyond the thymus, a peripheral system of control that kept the body’s defences from turning inward.

That discovery, published in 1995, introduced the world to regulatory T cells, or Tregs, the peacekeepers of the immune system. At first, few believed him. The idea that the immune system actively restrained itself ran counter to decades of dogma. But Sakaguchi’s persistence paid off. Over time, his findings reshaped immunology and offered new ways to understand, and treat, autoimmune disease.

Today, Sakaguchi is a distinguished professor at Osaka University’s Immunology Frontier Research Center, still driven by the same curiosity that made him challenge orthodoxy thirty years ago.

Mary Brunkow and Fred Ramsdell
While Sakaguchi was charting the immune system’s behaviour, two American scientists were unravelling its genetic logic. In 2001, Mary Brunkow, a Ph.D. graduate from Princeton and now senior program manager at the Institute for Systems Biology in Seattle, was studying a strain of mice unusually prone to autoimmune disease.

Working with Fred Ramsdell, then at Immunex and now scientific advisor at Sonoma Biotherapeutics in San Francisco, she discovered the culprit: a mutation in a previously unknown gene they named Foxp3. This genetic defect disrupted immune regulation, leaving the mice unable to suppress harmful immune responses.

The duo soon traced the same gene in humans. Mutations in Foxp3, they found, caused a rare but severe autoimmune disorder known as IPEX syndrome, in which the body’s immune system destroys its own organs.

Their findings revealed that the Foxp3 gene acted as a master switch, the key to generating regulatory T cells.

The pieces come together
Two years later, Sakaguchi linked it all. He proved that the Foxp3 gene governed the development of the same regulatory T cells he had discovered in 1995. The puzzle was complete: Brunkow and Ramsdell had found the gene; Sakaguchi had revealed the cells it controlled.

Together, their work explained how the immune system maintains its precarious balance, aggressive enough to kill pathogens, restrained enough to avoid self-destruction.

The trio’s discoveries gave birth to the field of peripheral immune tolerance. What began as an academic question now forms the basis of experimental treatments for autoimmune diseases, more precise cancer immunotherapies, and safer organ transplants. Several of these therapies are already in clinical trials.

“Their discoveries have been decisive for our understanding of how the immune system functions and why we do not all develop serious autoimmune diseases,” said Olle Kämpe, chair of the Nobel Committee.

The human side of science
Each of the laureates took a different path into immunology. Sakaguchi, born in 1951, trained as both a physician and scientist, earning his M.D. and Ph.D. from Kyoto University. Brunkow, born in 1961, pursued molecular biology at Princeton before moving into systems biology in Seattle. Ramsdell, born in 1960, earned his Ph.D. from UCLA and became one of the leading figures bridging research and biotechnology in the United States.

Their shared curiosity has brought them together in Stockholm this year, to receive the Nobel Prize and split the 11 million Swedish kronor award. But beyond the medals, their work has reshaped medicine’s understanding of what it means to stay healthy.

A legacy
Since 1901, the Nobel Prize in Physiology or Medicine has honoured 229 scientists whose discoveries advanced human health. This year’s award reminds us that scientific progress is not just about curing disease, but about understanding balance, between defence and destruction, attack and restraint.