Your immune system is constantly walking a tightrope. It has to be aggressive enough to wipe out viruses and bacteria but calm enough not to attack your own cells. When that balance fails, you get autoimmune diseases like type 1 diabetes, multiple sclerosis, or lupus. The 2025 Nobel Prize in Physiology or Medicine went to three scientists who figured out one of the main reasons our immune system (usually) stays in balance. Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi were selected “for their discoveries concerning peripheral immune tolerance” (2025 Nobel Prize Press Release)

For a long time, textbooks said the immune system avoided attacking the body mostly through a process called central tolerance. T cells, which coordinate much of the immune response, develop in an organ called the thymus. During training there, any T cells that react too strongly to the body’s own proteins are deleted. The story was that if the thymus did its job, self-reactive cells simply would not make it into circulation. Reality turned out to be messier. Some potentially dangerous cells do escape into the bloodstream, yet most of us do not spend our lives in an autoimmune crisis. Something else, outside the thymus, must be keeping these T cells in check.

In 1995, Shimon Sakaguchi provided the first big clue. Working in mice, he noticed that if a particular subset of T cells was removed, the animals developed severe autoimmune disease. These cells expressed a marker called CD25 and, instead of attacking, they seemed to suppress harmful immune responses. Sakaguchi had stumbled upon a special class of “peacekeeper” cells that patrol the body and calm down other T cells when they are about to cause trouble. He called them regulatory T cells, or Tregs. Without them, the immune system turned on the host. With them, it stayed mostly peaceful.

A few years later, Mary Brunkow and Fred Ramsdell tackled a different mystery: why a certain mouse strain, known as scurfy, developed devastating autoimmune symptoms. By tracking down the genetic cause, they found a mutation in a previously mysterious gene. They named it FOXP3. Mice with faulty FOXP3 lacked functional regulatory T cells and developed aggressive autoimmunity responses. Around the same time, they and others discovered that mutations in the human version of FOXP3 cause a rare but deadly autoimmune syndrome called IPEX in young children. FOXP3 turned out to be a kind of master switch that tells developing T cells to become regulatory T cells instead of fighters.

Put together, Sakaguchi’s Tregs and Brunkow and Ramsdell’s FOXP3 gene gave a new picture of immune tolerance. It is not just about deleting dangerous cells in the thymus. There is also a second layer of control out in the body, called peripheral immune tolerance, where regulatory T cells actively restrain other immune cells that might overreact. If you think of the immune system as an army, central tolerance is about careful recruitment and training. Peripheral tolerance adds something like military police and rules of engagement on the ground. This second layer is what the Nobel committee recognized.

That shift in understanding is not just an academic detail. It changes how we think about treating disease. If regulatory T cells are the immune system’s security guards, then tweaking them gives doctors a new way to move the balance point between attack and restraint. In autoimmune diseases, where the immune system is too aggressive, the goal is to strengthen

Treg activity or increase their numbers, so they can calm the attack on the body’s own tissues. In cancer, where tumors sometimes hijack Tregs to hide from the immune system, the goal is often the opposite: weaken or reprogram Tregs in the tumor so that ordinary T cells can attack more freely.

This is why the Nobel committee said the discoveries have “laid the foundation for a new field of research” and spurred the development of new treatments (2025 Nobel Prize Information). Clinical trials are testing drugs and cell therapies that boost Tregs in autoimmune conditions like type 1 diabetes or inflammatory bowel disease, in the hope of restoring tolerance without shutting the immune system down completely. Other trials are exploring ways to block or modulate Tregs inside tumors to improve the effectiveness of cancer immunotherapies. The same principles may help reduce complications after stem cell transplants when the donor’s immune system sometimes attacks the recipient’s body.

Of course, adjusting the immune system’s brakes is risky. Push too hard on restraint and patients may become vulnerable to infections or cancer. Release the brakes too much and autoimmunity can flare. Tregs themselves are complex and sometimes unstable, and FOXP3 is just one of many genes that shape their behavior. A lot of work remains to turn basic discoveries into safe, precise therapies that work for large numbers of people, not just in rare cases.

Still, the core insight behind the 2025 Nobel Prize in Physiology or Medicine is simple and powerful. A healthy immune system is not only about strong defenses. It is also about smart restraint. Brunkow, Ramsdell, and Sakaguchi showed that our bodies have specialized cells and genes whose entire job is to say “stand down” at the right moment. Thanks to them, we now see immune balance not as a lucky accident, but as an active, tunable system. That understanding is already reshaping how scientists think about treating autoimmunity, cancer, and transplant rejection, and it will likely guide immune therapies for decades to come.