Nobel Prize 2025: How Immune “Security Guards” Stop Autoimmune Disease

Nobel Prize in Medicine 2025: Awarded to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi for discovering how the immune system prevents attacking its own body ^[1]. The trio’s work uncovered a mechanism of peripheral immune tolerance – the body’s way of keeping the immune system in check.
Immune System “Security Guards”: The laureates identified special immune cells called regulatory T cells (Tregs) that act as the immune system’s “security guards”, suppressing overactive immune responses ^[2]. These Tregs prevent immune cells from mistakenly attacking our own organs and tissues, thereby averting autoimmune disease.
Key Genetic Breakthrough (FOXP3): In 2001, Brunkow and Ramsdell discovered a mutation in a gene they named FOXP3 that caused mice to suffer rampant autoimmunity ^[3]. They linked FOXP3 mutations in humans to a rare, deadly autoimmune disorder (IPEX syndrome), revealing this gene as a master switch required for developing the protective regulatory T cells ^[4].
New Treatments on the Horizon: By uncovering immune “self-control” mechanisms, the winners launched a new field of research in immunology ^[5]. Their discoveries have already spurred development of therapies – now in clinical trials – aiming to treat or even cure autoimmune diseases, improve cancer immunotherapies, and promote tolerance in organ transplants ^[6].
Expert Praise: “Their discoveries have been decisive for our understanding of how the immune system functions and why we do not all develop serious autoimmune diseases,” said Olle Kämpe, chair of the Nobel Committee, in the prize announcement ^[7]. The Nobel Assembly noted that the trio’s work “laid the foundation for a new field of research” and has inspired new treatments for cancer and autoimmune illness ^[8].

A Breakthrough in Immune Self-Control

In a landmark recognition for immunology, the 2025 Nobel Prize in Physiology or Medicine has been awarded to three scientists who unlocked how the immune system keeps itself from going rogue. Mary E. Brunkow (Institute for Systems Biology, Seattle), Fred Ramsdell (Sonoma Biotherapeutics, San Francisco), and Shimon Sakaguchi (Osaka University, Japan) earned the prize “for their discoveries concerning peripheral immune tolerance that prevents the immune system from harming the body” ^[9]. In essence, they found the body’s own “off-switch”: a mechanism that stops immune cells from attacking healthy tissues. Their work solved a medical mystery – why most of us don’t suffer autoimmune disease – and opened new avenues to treat illnesses ranging from diabetes to cancer. As Nobel Committee chair Olle Kämpe explained, the trio’s insights have been “decisive for our understanding of how the immune system functions and why we do not all develop serious autoimmune diseases” ^[10].

The human immune system is a double-edged sword. It must fiercely attack invading viruses and bacteria, yet somehow restrain itself from attacking the body’s own cells. This balance is called immune tolerance. For decades, scientists thought immune tolerance was achieved solely in the thymus – an organ where maturing immune cells that recognize “self” are eliminated in a process known as central tolerance ^[11]. Essentially, any T cells (a type of white blood cell) that could target the body’s own proteins were believed to be weeded out in the thymus “school,” leaving only safe, self-tolerant cells. But this theory left puzzles: Some self-reactive immune cells escape the thymus, yet healthy people typically don’t suffer constant autoimmunity. How was the immune system restraining those stray attackers? The 2025 laureates uncovered the answer by proving an additional safeguard exists outside the thymus – a peripheral immune tolerance system made up of specialized suppressor cells.

The Discovery of the Immune System’s “Peacekeepers”

In the mid-1990s, Shimon Sakaguchi challenged the prevailing dogma that the thymus was the immune system’s sole safety check ^[12]. “Swimming against the tide” of scientific opinion ^[13], Sakaguchi hypothesized that the immune system must have active “peacekeepers” patrolling the body to prevent friendly-fire attacks on healthy tissues. In 1995, working at Kyoto University, he identified a small subset of T cells that did something extraordinary – instead of triggering immune attacks, these cells suppressed immune responses. Sakaguchi had discovered a previously unknown class of T cells that could act as a brake on the immune system ^[14]. He later coined these cells regulatory T cells, or Tregs, often described as the immune system’s “security guards” or “peacekeepers.” They function essentially as immune police, monitoring and calming down other T cells to prevent misguided assaults on the body’s own organs ^[15].

At first, Sakaguchi’s findings were met with skepticism – the idea that the immune system actively restrains itself “ran counter to decades of dogma” in immunology ^[16]. Earlier attempts to find so-called “suppressor T cells” in the 1970s had been fraught with controversy and unreliable results, so many experts had dismissed the concept. But Sakaguchi’s experiments in mice provided compelling evidence: When he removed this special T cell subset, mice developed severe autoimmune diseases, whereas transferring these cells could protect animals from autoimmunity ^[17] ^[18]. Over time, his work convinced the scientific community that Tregs were real and crucial. “This and other similar results convinced Sakaguchi that the immune system must have some form of security guard, one that calms down other T cells and keeps them in check,” the Nobel Committee’s background report notes ^[19]. By introducing the world to regulatory T cells, Sakaguchi fundamentally reshaped immunology, revealing that the immune system has built-in self-control mechanisms beyond the thymus.

The Genetic Key: FOXP3 and Fatal Autoimmunity

While Sakaguchi was illuminating the cells behind immune tolerance, Mary Brunkow and Fred Ramsdell were probing a genetic puzzle that would prove to be the missing piece. In 2001, Brunkow (then a researcher who earned her Ph.D. at Princeton) and Ramsdell investigated why a certain mutant mouse strain – known for decades as the “scurfy” mouse – suffered a devastating syndrome of multi-organ autoimmune disease ^[20]. These mice lacked the immune system’s restraint and attacked their own organs, much like unchecked autoimmunity in humans. Brunkow and Ramsdell discovered the cause: a mutation in a previously unknown gene, which they named FOXP3 ^[21]. This single genetic defect meant the mice could not produce functional regulatory T cells, leaving their immune system without “brakes.” As a result, the mice’s immune cells aggressively targeted the body itself – a striking demonstration of what happens when immune tolerance fails.

Crucially, the researchers also linked FOXP3 to human disease. They showed that mutations in the human version of FOXP3 are responsible for a rare but severe disorder called IPEX syndrome ^[22]. Infants born with IPEX (short for Immunodysregulation Polyendocrinopathy Enteropathy X-linked) develop overwhelming autoimmune attacks against their own tissues from infancy, resulting in life-threatening illness. The discovery that both mice and humans develop catastrophic autoimmunity without a working FOXP3 gene was a eureka moment – it revealed FOXP3 as the master switch that generates the regulatory T cells Sakaguchi had found. In other words, FOXP3 is the gene that programs the immune system’s “security guard” cells, enabling them to develop and function. Without FOXP3, the body has no Tregs and thus no way to rein in destructive self-attacks ^[23].

Brunkow and Ramsdell’s 2001 breakthrough provided molecular proof of the genetic basis for peripheral immune tolerance. Their findings, published in seminal papers, explained on a genetic level what Sakaguchi’s work hinted biologically – that a dedicated mechanism exists to prevent autoimmune disease. “Their findings revealed that the FOXP3 gene acted as a master switch, the key to generating regulatory T cells,” as one account summarized ^[24]. This set the stage for the final piece of the puzzle.

Completing the Puzzle: Linking FOXP3 and Tregs

Just two years later, in 2003, Shimon Sakaguchi and colleagues brought the pieces together. Sakaguchi demonstrated conclusively that FOXP3 is the crucial controller of the regulatory T cells he had discovered in 1995 ^[25]. In experiments reported in Science, he showed that FOXP3 is expressed in those suppressive T cells and is required for their development and function ^[26]. By either adding or knocking out FOXP3, researchers could create or eliminate regulatory T cells – and correspondingly turn peripheral immune tolerance on or off ^[27]. This was the smoking gun that connected Brunkow and Ramsdell’s genetic discovery with Sakaguchi’s cellular discovery. “Two years later, Sakaguchi linked it all. He proved that the FOXP3 gene governed the development of the same regulatory T cells he had discovered in 1995. The puzzle was complete: Brunkow and Ramsdell had found the gene; Sakaguchi had revealed the cells it controlled,” one report explained ^[28].

With this knowledge, the scientists had uncovered a fundamental truth: the immune system possesses an active, gene-driven system of peripheral tolerance that operates throughout life to prevent self-destruction. They had identified both the key players (regulatory T cells) and the genetic instructions (FOXP3) that together serve as the body’s internal immune self-regulation system. The Nobel Prize press release hailed these “groundbreaking discoveries concerning peripheral immune tolerance” as launching an entirely new field of medical research ^[29] ^[30]. Immunologists everywhere now had a concrete framework to understand and investigate autoimmune diseases through the lens of Tregs and FOXP3.

Impact on Medicine: Autoimmune Diseases, Cancer, and More

By revealing how the body normally prevents autoimmune disease, the 2025 Nobel laureates also opened the door to new therapies for a wide range of illnesses. Their discoveries “have laid the foundation for a new field of research and spurred the development of new treatments, for example for cancer and autoimmune diseases,” the Nobel Assembly noted in its announcement ^[31]. In the two decades since the identification of regulatory T cells and FOXP3, researchers have raced to translate this knowledge into medical advances. Several experimental treatments inspired by this work are now in clinical trials ^[32]:

Autoimmune disease therapy: Scientists are exploring ways to boost or replace regulatory T cells in patients with autoimmune conditions like type 1 diabetes, rheumatoid arthritis, lupus, and multiple sclerosis. The idea is to restore the missing “brakes” in the immune system of these patients. For instance, early trials are testing infusions of lab-grown Tregs or drugs that enhance Treg activity, aiming to suppress the inappropriate immune attacks on the patient’s own tissues. The Nobel Committee highlighted hope that such approaches could “treat or cure autoimmune diseases” by reinstating tolerance ^[33].
Transplant tolerance: One of the holy grails in transplant medicine is achieving immune acceptance of a transplanted organ without long-term suppression of the entire immune system. The insights from Tregs offer a strategy: by increasing regulatory T cells targeted to the transplanted organ, doctors might induce the immune system to tolerate the foreign organ as if it were the body’s own. This could prevent rejection episodes and reduce the need for toxic immunosuppressant drugs. The Nobel press release noted that leveraging peripheral tolerance mechanisms “may lead to more successful transplantations” in the future ^[34], and indeed clinical studies are underway to see if Treg cell therapies can promote organ transplant tolerance.
Cancer immunotherapy: Interestingly, the same “peacekeeper” cells that protect us from autoimmunity can sometimes hinder the fight against cancer. Tumors often co-opt regulatory T cells to shield themselves from attack by the immune system. Knowing this, cancer researchers have developed strategies to overcome the Treg shield in cancers – for example, drugs or antibodies that deplete Tregs in tumor sites, aiming to unleash the immune response against cancer cells. Conversely, in certain contexts boosting Tregs might alleviate harmful inflammation associated with cancer treatments. The Nobel-winning discoveries therefore also inform the booming field of cancer immunotherapy. As the Nobel Committee noted, the balance between activating the immune system (useful in infections and cancer) and restraining it (needed to prevent autoimmunity) is a powerful lever for multiple medical applications ^[35].

The concept of peripheral immune tolerance has become a cornerstone of modern immunology and medicine. It bridges fundamental biology and clinical application, illustrating how a basic discovery about “how the immune system is kept in check” can have far-reaching benefits ^[36]. “Their discoveries have laid the foundation for a new field… now being evaluated in clinical trials,” the Nobel Assembly emphasized ^[37]. Indeed, pharmaceutical companies and research institutions are actively pursuing treatments that modulate regulatory T cells or FOXP3 pathways – essentially, Nobel-inspired therapies that could transform care for autoimmune disorders, improve outcomes in transplantation, and fine-tune cancer treatments.

A Collaborative Triumph and Ongoing Research

It’s notable that this Nobel Prize honors a trio of scientists whose work converged from different directions. Sakaguchi, now a distinguished professor in Osaka, was the pioneering immunologist who identified the elusive cell type that provides immune restraint ^[38] ^[39]. Brunkow and Ramsdell, working in the U.S., provided the genetic evidence and molecular handle (FOXP3) that validated and extended Sakaguchi’s theory ^[40]. Together, their contributions over the late 20th and early 21st century solved a critical puzzle of human biology. The result was “groundbreaking discoveries concerning peripheral immune tolerance” that the Nobel committee deemed worthy of the highest honor in science ^[41].

This 2025 award also highlights the importance of immune regulation in maintaining health. Autoimmune diseases affect millions worldwide – conditions like type 1 diabetes, multiple sclerosis, and Hashimoto’s thyroiditis occur when immune tolerance breaks down and the body erroneously attacks itself. Thanks to the work of Sakaguchi, Brunkow, and Ramsdell, we now understand that our immune system is actively patrolled by its own regulators to prevent such scenarios. When that system fails (for example, due to FOXP3 gene mutations or other disruptions), the consequences are severe, but knowing the cause offers a path to intervention. As researchers build on the laureates’ discoveries, there is new optimism that conditions once deemed incurable might be managed by restoring immune self-control.

Looking ahead, the field of peripheral tolerance continues to expand. Scientists are investigating how regulatory T cells develop and function in finer detail, how they might be selectively harnessed or reprogrammed, and how other cells or signals might cooperate in the tolerance network. The principles discovered by the 2025 Nobel winners have broad implications, even in areas like allergy (over-reactive immunity) and chronic inflammatory diseases. In the words of the Nobel Assembly, the laureates “have provided fundamental knowledge of how the immune system is regulated and kept in check. They have thus conferred the greatest benefit to humankind.” ^[42] ^[43]

A Nobel Celebration

The three new Nobel laureates will formally receive their award – a gold medal and a diploma – at the Nobel Prize ceremony in Stockholm on December 10, 2025, the anniversary of Alfred Nobel’s death. They will share the prize money of 11 million Swedish kronor (around US$1.2 million) equally ^[44]. This honor places Brunkow, Ramsdell, and Sakaguchi among the historic ranks of Nobel-winning scientists who have advanced humanity’s understanding of life and disease. Last year’s Medicine Nobel recognized the discovery of microRNAs (gene-silencing molecules); this year, the spotlight shifts to the immune system’s internal balance ^[45].

As the world celebrates these achievements, experts note that the impact of the trio’s work is already being felt in clinics and labs. “Their discoveries have been decisive,” the Nobel Committee remarked, underscoring how a basic biological insight can revolutionize medicine ^[46]. The story of immune “security guard” cells – from skeptical beginnings to Nobel-worthy vindication – exemplifies the unpredictable journey of scientific discovery. What once was “unimaginable” in immunology is now foundational: our immune system’s ability to police itself is real, crucial, and exploitable for better health ^[47]. In honoring Brunkow, Ramsdell, and Sakaguchi, the Nobel Prize 2025 not only recognizes past discoveries but also shines a light on a future where diseases of immune imbalance might be reined in by the very mechanisms these scientists uncovered.

Sources: Nobel Prize Press Release ^[48] ^[49] ^[50] ^[51]; Nobel Assembly Statement ^[52]; Reuters ^[53]; Nobel “Popular Information” Background ^[54] ^[55]; Economic Times ^[56] ^[57] ^[58]; Princeton University News ^[59]; Euronews ^[60].

Announcement of the 2025 Nobel Prize in Physiology or Medicine

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