How Regulatory T Cells Prevent Civil War in Our Bodies
Imagine your body's immune system as an incredibly powerful military, armed to defend against countless invading pathogens. Now imagine if that military suddenly turned its weapons on your own cities—your organs, tissues, and cells. This is precisely what happens in autoimmune diseases like rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. For decades, scientists struggled to understand why these civil wars don't break out more often—what stops our immune systems from attacking our own bodies?
The answer, we now know, lies with a remarkable group of cellular "peacekeepers" called regulatory T cells. The 2025 Nobel Prize in Physiology or Medicine was awarded to three scientists who discovered and decoded these cells: Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi. Their work unveiled one of our immune system's best-kept secrets—a sophisticated system called peripheral immune tolerance that keeps our defenses in check 1 2 .
Immune cells identify and eliminate pathogens like viruses and bacteria.
Regulatory T cells prevent immune attacks on the body's own tissues.
For much of the 20th century, immunologists believed they understood how the body prevented autoimmune attacks. The process was thought to occur primarily in the thymus—a small organ behind the breastbone—where developing T cells that reacted too strongly against the body's own tissues were eliminated before they could enter circulation. This process, called central tolerance, served as the immune system's basic training ground 5 .
However, observations didn't always fit this neat explanation. As early as the 1970s, some researchers proposed the existence of "suppressor T cells" that could rein in wayward immune responses outside the thymus. But the evidence was controversial, and when some studies couldn't be replicated, the entire concept fell out of favor 1 .
It was in this skeptical climate that Shimon Sakaguchi began his pioneering work. Inspired by experiments showing that removing the thymus from newborn mice unexpectedly caused autoimmune diseases, Sakaguchi hypothesized that there must be unknown cells that normally prevent such attacks 5 7 .
Sakaguchi's crucial insight came through a series of elegant experiments in mice. His approach was methodical and clear:
Researchers surgically removed the thymus from newborn mice at different time points 7 .
When the operation occurred exactly three days after birth, the mice developed multiple autoimmune conditions—their immune systems attacked their own tissues 5 7 .
Sakaguchi then injected these mice with mature T cells from genetically identical donors 5 .
The transferred cells prevented autoimmune diseases, but only when they contained a specific subset of helper T cells marked by surface proteins called CD4 and CD25 1 .
This finding was revolutionary. Sakaguchi hadn't just found a way to prevent autoimmune disease in mice—he had identified a completely new class of immune cells. In his 1995 paper in the Journal of Immunology, he named them regulatory T cells (Tregs) 4 . These were the peacekeepers the field had been searching for—cells that could actively suppress immune responses and maintain tolerance to the body's own tissues 1 .
| Surface Protein | Function | Cell Type |
|---|---|---|
| CD4 | Recognizes foreign particles presented by immune cells | Helper T cells, Regulatory T cells |
| CD8 | Binds to molecules on infected cells | Killer T cells |
| CD25 | Receptor for interleukin-2 (IL-2), a growth factor | Regulatory T cells (identified by Sakaguchi) |
| T-cell Receptor | Scans other cells for signs of infection | All T cells |
While Sakaguchi had identified the peacekeeper cells, fundamental questions remained. Were these a stable cell type, or just temporary states of ordinary T cells? The answer would come from an unexpected source—a strain of mice with crusty, scaly skin.
In the 1940s, researchers working on the Manhattan Project in Oak Ridge, Tennessee noticed that some male mice were born with a severe condition: flaky skin, enlarged lymph nodes, and death within weeks of birth. They named these mice "scurfy" 5 7 . Decades later, Mary Brunkow and Fred Ramsdell, then working at the biotech company Celltech Chiroscience, recognized that the scurfy mice held clues to autoimmunity. These mice suffered from exactly the kind of civil war that regulatory T cells were supposed to prevent 1 .
In the 1990s, finding a single mutated gene was a monumental task. Brunkow and Ramsdell embarked on what they called "looking for a needle in a DNA haystack" 5 . The process involved:
They first narrowed the mutation to the middle of the X chromosome, then to a region of about 500,000 nucleotides 5 .
This region contained 20 potential genes. They examined them one by one 5 .
The very last gene they checked was the culprit—a previously unknown gene that belonged to the forkhead box (FOX) family of genetic regulators. They named it Foxp3 5 .
Even more significant was their next discovery. Brunkow and Ramsdell learned of a rare but devastating autoimmune disease in humans called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) that primarily affected young boys. When they analyzed samples from these patients, they found mutations in the human version of Foxp3 1 7 . This was the smoking gun—the same gene that caused autoimmunity in scurfy mice was responsible for a human autoimmune disease.
| Feature | Scurfy Mice | IPEX Patients |
|---|---|---|
| Genetic Cause | Mutation in Foxp3 gene | Mutation in FOXP3 gene |
| Inheritance | X-linked | X-linked |
| Symptoms | Scaly skin, enlarged lymph organs, multi-organ inflammation | Severe diarrhea, diabetes, eczema, multi-organ inflammation |
| Lifespan | 3-4 weeks | Often fatal in early childhood without treatment |
The stage was now set for the final breakthrough. In 2003, Sakaguchi and other researchers made the critical connection: the Foxp3 gene served as the master regulator for the development and function of regulatory T cells 1 . Without a properly functioning Foxp3 gene, the peacekeeper cells couldn't do their job, and the immune system descended into civil war.
This connection transformed immunology. As Jeffrey Bluestone, an immunologist who co-founded a company with Ramsdell, noted: "The identification of this gene, Foxp3, was the discovery that changed the field, because now there was a molecular basis for immune regulation by T regulatory cells and immune tolerance. That was the defining moment in the early 2000s when all of a sudden, this became real" 1 .
Master regulator for regulatory T cell development and function.
Foxp3 ensures proper function of peacekeeper cells to maintain immune tolerance.
The discoveries honored by the 2025 Nobel Prize depended on sophisticated research tools and reagents. Here are some of the essential components that enabled this groundbreaking work:
| Tool/Reagent | Function | Role in Treg Research |
|---|---|---|
| Animal Models | Provide experimental systems for studying immune processes | Scurfy mice and thymectomized mice were crucial for discovering Tregs and Foxp3 |
| Flow Cytometry | Identifies and sorts cells based on surface proteins | Enabled isolation of T cells with CD4 and CD25 markers |
| Genetic Sequencing | Determines the DNA sequence of genes | Allowed Brunkow and Ramsdell to identify Foxp3 mutations |
| Antibodies | Binds to specific proteins for detection and isolation | Anti-CD4 and anti-CD25 antibodies helped define Treg population |
| Cell Culture Systems | Allows growth of cells outside the body | Enabled functional tests of Treg suppression capabilities |
Initial proposal of "suppressor T cells" concept
Sakaguchi identifies CD4+CD25+ regulatory T cells
Brunkow and Ramsdell identify Foxp3 as the gene mutated in scurfy mice
Foxp3 established as master regulator of Treg development and function
Nobel Prize awarded for Treg discoveries
The discovery of regulatory T cells has spawned an entire field of medical research focused on harnessing these cells for therapy. More than 200 clinical trials are currently underway exploring Treg-based treatments 1 . These approaches include:
For patients with autoimmune diseases or those receiving organ transplants, researchers are developing ways to expand populations of regulatory T cells. One approach involves taking a patient's own Tregs, growing them in large numbers in the laboratory, and reinfusing them to suppress unwanted immune responses 1 .
Scientists are creating "designer" Tregs using chimeric antigen receptor (CAR) technology—the same approach used in revolutionary cancer treatments. These CAR-Tregs can be engineered to specifically target tissues that need protection, such as transplanted organs or joints affected by rheumatoid arthritis 1 .
In cancer, the problem is sometimes too much suppression. Tumors often surround themselves with regulatory T cells that protect them from immune attack. Researchers are developing treatments to temporarily disable Tregs in cancer patients, allowing the immune system to attack the tumor 1 .
The work of Brunkow, Ramsdell, and Sakaguchi has fundamentally changed how we view the immune system. We now understand that immunity isn't just about unleashing powerful attacks against invaders—it's about maintaining a delicate balance between defense and self-tolerance.
As Adrian Liston, an immunologist at the University of Cambridge, explains: "It has one key brake, which is the regulatory T cell, and that means that we can shut the immune system down much faster than we would otherwise. It's quite a profound conceptual shift" 4 .
The discovery of regulatory T cells represents one of those rare scientific advances that simultaneously answers fundamental biological questions while opening new therapeutic pathways. From explaining why we don't all develop autoimmune diseases to offering new hope for treating conditions ranging from diabetes to cancer, these cellular peacekeepers have truly revolutionized our understanding of health and disease.