On October 6, 2025, in Stockholm, the Nobel Assembly honored Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi for shedding light on peripheral immune tolerance: the discovery of regulatory T lymphocytes and the key role of the FOXP3/Foxp3 gene. Their work explains how immunity is restrained without self-destruction and opens clinical pathways, from autoimmune diseases to transplants and cancer.
Peripheral Immune Tolerance: What the Nobel Assembly Honored
On October 6, 2025, in Stockholm, the Nobel Assembly of the Karolinska Institutet awarded the 2025 Nobel Prize in Physiology or Medicine to Mary E. Brunkow (Institute for Systems Biology, Seattle), Fred Ramsdell (Sonoma Biotherapeutics, San Francisco), and Shimon Sakaguchi (Osaka University) "for discoveries concerning peripheral immune tolerance." The official announcement specifies that their work revealed regulatory T lymphocytes (Treg), true "guardians" that prevent the immune system from overreacting against our own tissues, and identified the role of the FOXP3 gene as the cornerstone of their development. The gene is spelled Foxp3 in mice and FOXP3 in humans.
The prize (endowed with 11 million Swedish kronor) honors a series of discoveries spread over nearly 30 years: the identification of a T population with a braking power (1995), the identification of a master gene (FOXP3) whose mutation triggers severe autoimmunity (2001), and then the demonstration that this gene governs the formation of Treg (2003).
Treg: How "Guardian" Cells Maintain Balance
To stay healthy, immunity walks a fine line. It must attack microbes and spare the body. For a long time, it was believed that this balance relied mainly on a drastic selection in the thymus (central tolerance). The laureates shed light on the other side, called peripheral tolerance: beyond the thymus, Treg cells patrol and calm excessive responses.
In practice, Treg moderate the activity of other effector T lymphocytes. They use an arsenal of chemical messages and cellular contacts to quell inflammation when it threatens to spiral out of control. Without them, our body could suffer from autoimmune reactions such as type 1 diabetes, arthritis, or lupus. Additionally, there is a risk of graft rejection, complicating transplants. Conversely, in oncology, some tumors use these cells to avoid detection. Consequently, this can lead to undesirable brakes in cancer treatment. Depending on the context, Treg can also limit certain pro-tumoral inflammations.
Simple image: think of the immune system as a car. The defenses are the accelerator; the Treg, the brake. Without a brake, you go off the road; with a stuck brake, you don’t move forward.
FOXP3: The Master Code of Regulatory T Lymphocytes
At the heart of the story, a gene: FOXP3. In 2001, Mary E. Brunkow and Fred Ramsdell showed that a mutation of this gene, identified in a murine line called "scurfy," causes a fulminant autoimmunity. The human equivalent is the IPEX syndrome (Immunodysregulation Polyendocrinopathy Enteropathy X-linked), rare but severe in infants.
FOXP3 encodes a transcription factor: a conductor protein that activates or represses gene batteries. In 2003, Shimon Sakaguchi connected the dots: FOXP3 is essential for the development and functioning of Treg. Without this factor, there is no reliable immune brake.
From the "Scurfy" Mouse to IPEX Syndrome: What Rare Diseases Reveal
Rare diseases play the role of spotlights here. In the "scurfy" mouse, lacking a functional FOXP3, the body self-destructs: dermatitis, visceral involvement, cachexia. In humans, IPEX syndrome – due to X-linked FOXP3 mutations – leads to severe enteropathy, endocrine dysfunctions (neonatal diabetes, thyroiditis), and repeated infections. These extreme cases provided decisive evidence: when FOXP3 is deficient, Treg do not form correctly, and tolerance collapses.
A Scientific Tale: The Close Guard of Immunity
There are scenes of laboratory literature in this story. 1995: in polite indifference, Shimon Sakaguchi describes CD25+ T lymphocytes (CD25, Treg marker) capable of preventing autoimmunity. 2001: two researchers, Brunkow and Ramsdell, dissect a genetic enigma; they named the gene Foxp3. 2003: the loop is closed, the molecular brake joins the cellular population. In the background, a simple idea: immunity is not just an assault army, it’s an expeditionary force with police.
What This Changes for Patients: Today
Do not oversell: clinical immunology advances step by step. Today, the concept of Treg already helps to explain diseases (e.g., IPEX), to better classify certain immunodeficiencies, and to adapt the monitoring of transplants. Teams are exploring markers (including FOXP3) to stratify patients or anticipate graft rejection.
In Treg transfer (cultivated cells then reinjected), trials are evaluating the safety, dose, and persistence of these cells in patients with autoimmune diseases or transplants. Other strategies are testing drugs that increase or direct Treg in vivo (e.g., combinations with low-dose IL-2). Some approaches improve intermediate criteria, but no Treg treatment is yet standard.
Treg and Cancer Immunotherapy: And Tomorrow
Tomorrow, the modulation of Treg could become a therapeutic tool with two-way potential:
- Strengthen the brake to soothe autoimmunities (type 1 diabetes, arthritis, multiple sclerosis), protect organ or marrow transplants.
- Loosen the brake in oncology, in combination with immunotherapies (anti-PD-1, anti-CTLA-4), to amplify the antitumor response when tumors hide behind overly zealous Treg.
Limits and precautions: manipulating Treg is not trivial. These cells are plastic, and their environment (microbiota, cytokines) influences their fate. Protocols must be secured to ensure their effectiveness and avoid shifts towards dangerous pro-inflammatory responses. Additionally, it is essential to monitor the risk of infections that could occur during treatments. Finally, it is important to define precise indications without making promises of cure, to manage expectations.
An Announcement at Dawn… and a Human Wink
On Monday, October 6, the announcement came early in Stockholm… and in the middle of the night on the American West Coast. Fred Ramsdell was unreachable: according to his colleagues, he was probably hiking, phone off. Science sometimes has timelines that do not align with time zones. A wink without mockery: "Fred not aware" – immunity, however, remains vigilant.
Why Now?
Because these discoveries have opened a field. Peripheral tolerance has become a pillar of modern immunology. It feeds clinical programs in autoimmunity, transplantation, and cancer. It reconciles two visions of immunity: selection at the center (thymus) and surveillance at the periphery (Treg). By honoring Brunkow, Ramsdell, and Sakaguchi, the jury also salutes a method: back-and-forth between fundamental/clinical, genetics and physiology, mice and humans.
Chronological Landmarks
- 1995: Shimon Sakaguchi describes a T population (marker CD25, Treg marker) that prevents autoimmunity.
- 2001: Mary E. Brunkow and Fred Ramsdell identify FOXP3 as the cause of severe autoimmunity ("scurfy") and its human equivalent (IPEX).
- 2003: the link is consolidated: FOXP3 governs the development of Treg.
- 2025: the Nobel honors these milestones; clinical trials of Treg modulation are multiplying.
Sources of confirmation: Popular information; Scientific background.
Education for Patients: Simple Questions, Clear Answers
What is a Treg? A specialized T lymphocyte that brakes other immune cells when they risk harming the body.
How is it different from other T cells? Effector T cells attack; Treg soothe. Both are necessary.
What is FOXP3? A gene that programs the birth and function of Treg. When it is mutated, tolerance collapses (e.g., IPEX in children).
Is it a treatment today? Not yet in everyday use. Trials are evaluating Treg transfers or drugs that modulate their number and action. Patients can benefit from a better understanding of diseases and more refined monitoring.
And for cancer? Some tumors hijack Treg to brake immunity. Trials are seeking to reduce this braking, often with other immunotherapies.