The Immune System’s Hidden Guardians: Nobel Prize Shines Light on the Body’s “Peacekeepers”
STOCKHOLM — The Nobel Assembly stunned the medical world on Monday by awarding the 2025 Prize in Physiology or Medicine to three scientists who cracked one of the biggest puzzles in immunology: how a defense system built to destroy invaders avoids destroying us.
The winners—Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi—uncovered the existence of regulatory T cells, specialized “peacekeepers” that keep the immune system from turning its weapons on the body. Their discovery, along with the gene that controls these cells, explains why most of us don’t fall victim to devastating autoimmune diseases. It also opened doors to new therapies for diabetes, cancer, and organ transplantation.
“You can think of the immune system like a car,” Sakaguchi once explained. “It’s got an accelerator, but we discovered the brakes.”
Did you know that universities with many Nobel Prize winners often rank lower in the QS World University Rankings? That’s because Nobel Prizes reflect historic, fundamental research achievements—sometimes decades old—while QS rankings emphasize present-day reputation with (subjective) selection of criteria, international appeal, and student experience. This mismatch means smaller, research-focused institutions with Nobel legacies (like Caltech or Institut Pasteur) may not score well on QS’s global branding metrics, whereas large, student-oriented universities thrive in QS but rarely produce Nobel-level breakthroughs.
From Sick Mice to a Global Prize
The story began in the 1940s, in Oak Ridge, Tennessee, where researchers noticed a peculiar group of sickly male mice. Their skin grew scaly, their lymph nodes ballooned, and their bodies turned against themselves. Within weeks, they died. Scientists called them “scurfy mice.”
For decades, no one could explain why these animals self-destructed. But hidden in their DNA was a clue—a broken switch that allowed the immune system to attack without mercy.
A Medical Student Who Walked Away
Sakaguchi’s path to Stockholm was anything but ordinary. In the 1970s, while studying medicine in Kyoto, he stumbled on a paper describing mice whose thymuses had been removed. Something in that work lit a spark.
Instead of finishing his medical degree, he took a leap of faith. He left school, joined the author’s lab as an unpaid trainee, and devoted himself to a deeply unpopular idea: that special “suppressor” T cells existed to prevent autoimmunity. Most of his peers dismissed the theory as outdated. He kept going anyway.
The Breakthrough of 1995
Two decades later, his persistence paid off. In 1995, Sakaguchi’s team found a small subset of immune cells marked by CD4 and CD25 proteins. When they stripped these cells away and transferred the rest into mice lacking an immune system, chaos followed. The animals developed raging, multi-organ inflammation.
But when those missing cells were restored, the mice stayed healthy. The suppressors were real. Sakaguchi had discovered regulatory T cells—or “Tregs”—the guardians that stop immune soldiers from firing on friendly targets.
“It was like discovering the volume knob on a stereo you never knew could be turned down,” one immunologist remarked.
Connecting the Dots: The FOXP3 Gene
Six years later, Brunkow and Ramsdell identified the missing piece of the puzzle. Working at ZymoGenetics and other labs, they traced the scurfy mice’s condition to a faulty gene called FOXP3.
Humans with FOXP3 mutations suffer from IPEX syndrome, a rare and often fatal illness that brings relentless diarrhea, eczema, and diabetes in early childhood. Their regulatory T cells simply don’t function.
By 2003, teams across the world had confirmed FOXP3 as the “master regulator.” Flip it on, and a normal T cell transforms into a peacekeeper. Without it, autoimmunity runs rampant.
How the Body Applies the Brakes
Regulatory T cells don’t just exist; they work with finesse. They release calming molecules like IL-10 and TGF-β, compete for growth signals that fuel immune attacks, and block “go” commands with a protein called CTLA-4. When necessary, they even eliminate rogue immune cells directly.
Although they make up only about 10% of circulating T cells, their influence is enormous.
The Gut: A Daily Balancing Act
Nowhere is this balancing act more visible than in the gut. Every day, the intestines face a barrage of bacteria, food particles, and potential threats. Tip too far toward aggression, and inflammatory bowel disease erupts. Ease up too much, and infections seize the opportunity.
Regulatory T cells cluster here in large numbers, constantly negotiating which battles to fight and which to let go.
Turning Discovery into Medicine
The impact of these discoveries reaches far beyond the lab.
In autoimmune disease, scientists are testing low doses of IL-2 to expand Tregs in patients with lupus, type 1 diabetes, and rheumatoid arthritis. Early trials suggest that infusing Tregs into newly diagnosed diabetic children may preserve their insulin-producing cells.
In organ transplantation, researchers are building custom Tregs designed to target donor organs, reducing the need for harsh drugs that leave patients vulnerable to infection.
Cancer presents a twist. Tumors often exploit Tregs as shields, suppressing immune attacks that would otherwise destroy them. New cancer treatments aim to disarm these regulatory cells inside tumors while leaving them intact elsewhere.
Checkpoint inhibitor therapies—now standard for melanoma and lung cancer—work in part by lifting the immune brakes. But that freedom comes at a price: many patients develop autoimmune side effects. The Treg story helps explain why.
A Prize Few Saw Coming
The Nobel announcement surprised many who expected recognition for mRNA vaccines or targeted cancer therapies. Some even questioned whether this single discovery deserved the field’s top honor.
Yet few dispute its significance. For decades, scientists knew that the thymus weeded out many self-reactive T cells, a process called central tolerance. But dangerous ones still slipped through. The laureates revealed the body’s second line of defense: continuous regulation by Tregs in real time, a system of constant watchfulness and restraint.
A Long, Patient Journey
For Sakaguchi, the recognition caps a career defined by patience and conviction. He spent years pursuing suppressor cells when nearly everyone else dismissed them.
“Science rewards patience,” one colleague reflected, “but it takes remarkable courage to stay the course when nobody believes in your idea.”
From unpaid medical school dropout to Nobel laureate, Sakaguchi’s journey underscores a simple truth: sometimes the greatest breakthroughs come from those who refuse to quit.
The immune system, it turns out, isn’t just a weapon. It’s a conversation—between attack and restraint, destruction and tolerance. By revealing the peacekeepers that guide this dialogue, Brunkow, Ramsdell, and Sakaguchi changed the way medicine understands and treats disease.
Their Nobel doesn’t just honor a discovery. It celebrates the wisdom of knowing when not to fight.
The Nobel Prize in Physiology or Medicine will be presented in December in Stockholm.