Why Doesn't The Body Destroy Itself? The Answer Won The 2025 Nobel Prize in Medicine

Three scientists, Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi, received the 2025 Nobel Prize in Physiology or Medicine for revealing how the immune system learns not to attack its own body. Sakaguchi identified the guard cells, Brunkow and Ramsdell discovered the gene that controls them, and together they explained how the immune system knows what to attack and what not to attack. This discovery, about something called peripheral immune tolerance, explains why most people do not develop autoimmune diseases, in which the body turns against itself.

The immune system is our body's army. It recognizes and destroys viruses, bacteria, and foreign cells that can cause disease. But sometimes this army can make mistakes and attack healthy organs, as happens in lupus, type 1 diabetes, or rheumatoid arthritis.

Therefore, the immune system needs "braking" mechanisms to ensure it attacks only the right enemy. The laureates' discovery showed how these brakes work and who the "guards" are that keep the peace within the body.

Illustrations: Mattias Karlén ©The Nobel Assembly at Karolinska Institutet

The First Clue: Shimon Sakaguchi's Work

In the 1980s and 1990s, Japanese immunologist Shimon Sakaguchi, then a young researcher, made an observation that contradicted popular belief. At the time, it was thought that the body learned not to attack itself solely within the thymus, an organ located in the chest responsible for "training" immune system cells. In this process, known as central tolerance, dangerous cells (that could attack the body) were eliminated before "leaving" the thymus.

But Sakaguchi realized that this wasn't the whole story. He observed that, even after leaving the thymus, the immune system had a way of actively controlling itself.

To understand this, he experimented with mice without a thymus and saw that they developed severe autoimmune diseases, as if their immune systems had gone haywire. When he injected them with certain T cells (a type of defense cell), the animals were protected.

Illustrations: Mattias Karlén ©The Nobel Assembly at Karolinska Institutet

In other words, there was a special type of cell that prevented attacks from the immune system itself. He called them regulatory T cells, or Tregs. In 1995, Sakaguchi published this historic finding, identifying these cells by two proteins on their surface: CD4 and CD25. At the time, many scientists were skeptical. It seemed too good to be true.

The Missing Link: The Mysterious Gene Discovered By Brunkow And Ramsdell

Meanwhile, in the United States, two other scientists, Mary Brunkow and Fred Ramsdell, were working at a biotechnology company interested in autoimmune diseases. They were studying an ancient strain of mice known as "scurfy," which were born sick, with severe inflammation, and died young.

These mice had something wrong with their immune systems; their T cells were attacking their own organs. Brunkow and Ramsdell decided to find out which gene was causing this. In the 1990s, doing this was a huge challenge: they had to analyze millions of pieces of DNA to find the defective gene.

After years of work, they found the answer: a mutation in a gene on the X chromosome, which they named Foxp3. When this gene was damaged, mice didn't produce the cells that control the immune system, and the result was total chaos.

Soon after, they discovered that a mutation in the same gene in humans caused a rare and serious autoimmune disease called IPEX, which also causes the body to attack itself.

Illustrations: Mattias Karlén ©The Nobel Assembly at Karolinska Institutet

The Final Connection: Sakaguchi Puts The Pieces Together

Two years later, Shimon Sakaguchi completed the cycle: he demonstrated that the Foxp3 gene is responsible for forming regulatory T cells, the cells he had discovered years earlier. In other words, the Foxp3 gene is the "instruction manual" that teaches the body how to produce the guardians of the immune system.

These regulatory T cells function like police officers patrolling the body's defenses, ensuring that immune cells do not attack healthy tissue.

Before these discoveries, it was believed that immune system control was "automatic." Now we know that there is an active surveillance system within us, controlled by regulatory T cells and the Foxp3 gene. This understanding has opened a new field of research called peripheral immune tolerance, or the mechanisms that keep the immune system in check outside the thymus.

Illustrations: Mattias Karlén ©The Nobel Assembly at Karolinska Institutet

Thanks to these studies, scientists are now developing treatments that activate or inhibit these regulatory T cells. This can help both autoimmune diseases (by increasing the "brakes") and cancer (by reducing the "brakes" preventing the body from attacking the tumor). There is also promising research in organ transplants, attempting to prevent rejection without the need for strong immunosuppressive drugs.

Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi have each shown, in their own way, how the body finds a balance between defense and tolerance. Sakaguchi identified the guard cells, Brunkow and Ramsdell discovered the gene that controls them, and together they explained how the immune system knows what to attack and what not to attack.

Thanks to them, we better understand what happens when the immune system loses control, and now we have concrete ways to restore this harmony in serious diseases.

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The Nobel Assembly at Karolinska Institutet 

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