On Monday, October 6, 2025, the Nobel Prize in Physiology or Medicine was awarded to Mary E. Brunkow, Fred Ramsdell, and Dr. Shimon Sakaguchi for their groundbreaking discoveries in the field of peripheral immune tolerance. Their work has fundamentally reshaped our understanding of the immune system, particularly how it maintains balance to prevent autoimmune diseases while effectively combating infections and other threats. This prestigious recognition, announced by a panel at the Karolinska Institute in Stockholm, marks the first of the 2025 Nobel Prize announcements and underscores the profound impact of their contributions to immunology and potential therapeutic advancements.
The Laureates: A Trio of Immunology Pioneers
The 2025 Nobel Prize in Medicine celebrates three scientists whose collaborative and individual efforts have unlocked critical insights into the mechanisms that regulate the immune system:
Mary E. Brunkow, 64, is a senior program manager at the Institute for Systems Biology in Seattle, Washington. Her work has been instrumental in identifying genetic mechanisms that control immune responses, particularly through her discovery of the Foxp3 gene's role in immune regulation.
Fred Ramsdell, also 64, serves as a scientific adviser for Sonoma Biotherapeutics in San Francisco, California. His contributions, particularly in collaboration with Brunkow, have been pivotal in linking genetic mutations to immune dysfunction, opening new avenues for research into autoimmune diseases.
Dr. Shimon Sakaguchi, 74, is a distinguished professor at the Immunology Frontier Research Center at Osaka University in Japan. His foundational discovery of regulatory T cells (T-regs) laid the groundwork for understanding how the immune system self-regulates to prevent harmful overreactions.
Together, their discoveries have not only deepened our understanding of immune tolerance but also paved the way for innovative treatments for autoimmune diseases, cancer, and other immune-related disorders.
A Surprising Announcement
The announcement of the Nobel Prize came as a shock to at least one of the laureates. Mary Brunkow, who was at her home in Seattle, initially dismissed an early morning call from the Nobel Committee, mistaking it for spam. “My phone rang, and I saw a number from Sweden and thought: ‘That’s just, that’s spam of some sort,’” she recounted. It wasn’t until an Associated Press photographer arrived at her doorstep that she realized the magnitude of the news. Her husband, Ross Colquhoun, shared her initial disbelief, noting, “When I told Mary she won, she said, ‘don’t be ridiculous.’” The moment was a mix of surprise and joy, marking a milestone in her illustrious career.
Dr. Shimon Sakaguchi, speaking at a press conference at Osaka University, expressed his delight and optimism about the award’s implications. “It was a nice surprise,” he said, adding, “I hope research into this area will further progress so that our findings can be used in treatment, and I hope we can contribute to that as well.” His comments reflect a forward-looking vision for translating their discoveries into clinical applications that could benefit millions worldwide.
Fred Ramsdell, though not quoted directly in initial reports, has been recognized for his critical role in the collaborative efforts that led to these discoveries. His work with Brunkow at a small biotech company in the early 2000s was instrumental in identifying key genetic mechanisms underlying immune regulation.
The Science of Immune Tolerance
The immune system is a complex network of cells, tissues, and organs that work together to protect the body from harmful pathogens such as bacteria, viruses, and other foreign invaders. Central to this system are T cells, a type of white blood cell that plays a critical role in identifying and neutralizing threats. However, T cells must be carefully regulated to prevent them from attacking the body’s own tissues, which can lead to autoimmune diseases such as rheumatoid arthritis, lupus, or type 1 diabetes.
The process of immune regulation begins in the thymus, an organ where T cells are “trained” to distinguish between harmful invaders and the body’s own cells. This training, known as central tolerance, ensures that T cells that might attack healthy tissues are eliminated before they can cause harm. However, central tolerance is not foolproof, and additional mechanisms are needed to keep the immune system in check. This is where the discoveries of Brunkow, Ramsdell, and Sakaguchi come into play, illuminating the concept of peripheral immune tolerance—the body’s secondary line of defense against immune overactivity.
Sakaguchi’s Groundbreaking Discovery of Regulatory T Cells
The story begins with Dr. Shimon Sakaguchi’s seminal discovery in 1995. At the time, Sakaguchi was investigating how the immune system maintains balance to prevent autoimmune diseases. His research led to the identification of a previously unknown subtype of T cells, now known as regulatory T cells, or T-regs. These cells act as the immune system’s “security guards,” patrolling the body to suppress overactive immune responses that could lead to self-harm.
T-regs are unique in their ability to modulate the activity of other T cells, ensuring that the immune system does not spiral out of control. By dampening excessive immune responses, T-regs play a critical role in preventing autoimmune diseases, where the immune system mistakenly attacks healthy tissues, and in maintaining immune homeostasis. Sakaguchi’s discovery was a paradigm shift in immunology, revealing a new layer of regulation that had previously been overlooked.
Brunkow and Ramsdell’s Genetic Breakthrough
Building on Sakaguchi’s work, Mary Brunkow and Fred Ramsdell made a critical discovery in 2001 while working together at a small biotech company. Their research focused on a strain of mice with an overactive immune system, which exhibited symptoms resembling autoimmune diseases in humans. Using cutting-edge genetic techniques, they identified a mutation in a gene called Foxp3 as the culprit behind the mice’s immune dysfunction.
The Foxp3 gene, they found, was essential for the development and function of T-regs. A small alteration in the DNA sequence of this gene led to a dramatic disruption in immune regulation, causing the immune system to attack the body’s own tissues. “From a DNA level, it was a really small alteration that caused this massive change to how the immune system works,” Brunkow explained. This discovery was particularly significant because the Foxp3 gene was also implicated in a rare human autoimmune disorder known as IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome, highlighting its relevance to human health.
Connecting the Dots: Sakaguchi’s Synthesis
In 2003, Sakaguchi brought these discoveries together, demonstrating that the Foxp3 gene is a master regulator of T-reg development. His work showed that Foxp3 controls the differentiation and function of T-regs, enabling them to act as gatekeepers that prevent other T cells from mounting harmful immune responses. This finding linked the genetic insights from Brunkow and Ramsdell’s research with the cellular mechanisms identified by Sakaguchi, creating a comprehensive picture of how peripheral immune tolerance operates.
The interplay between these discoveries revealed a sophisticated system of checks and balances within the immune system. T-regs, under the control of Foxp3, act as a fail-safe mechanism to prevent autoimmune diseases by suppressing aberrant T cell activity. This mechanism of peripheral tolerance complements central tolerance, providing an additional layer of protection against immune dysregulation.
Implications for Medicine
The discoveries of Brunkow, Ramsdell, and Sakaguchi have had far-reaching implications for the field of immunology. Their work has opened a new frontier in understanding how the immune system maintains balance and has sparked a global effort to harness T-regs for therapeutic purposes. As noted by Karolinska Institute rheumatology professor Marie Wahren-Herlenius, their findings have “been decisive for our understanding of how the immune system functions and why we do not all develop serious autoimmune diseases.”
Researchers worldwide are now exploring ways to manipulate T-regs to treat a wide range of conditions, including autoimmune diseases, cancer, and organ transplant rejection. For example, boosting T-reg activity could help calm the immune system in autoimmune disorders, while inhibiting T-regs could enhance immune responses against cancer cells. These approaches hold promise for developing novel therapies that are more targeted and effective than current treatments.
In autoimmune diseases, where the immune system attacks healthy tissues, therapies that enhance T-reg function could restore immune balance and alleviate symptoms. Conversely, in cancer, where the immune system often fails to recognize and destroy tumor cells, strategies to temporarily reduce T-reg activity could unleash a more robust immune response against malignancies. Additionally, in organ transplantation, T-reg-based therapies could help prevent rejection by promoting tolerance to the transplanted tissue.
A New Field of Immunology
The work of Brunkow, Ramsdell, and Sakaguchi has given rise to a new field of immunology focused on regulatory T cells and their role in immune tolerance. This field has attracted significant attention from researchers, clinicians, and biotech companies, all eager to translate these discoveries into clinical applications. The potential to develop treatments that modulate T-reg activity represents a major leap forward in precision medicine, offering hope for patients with conditions that have been difficult to treat with conventional therapies.
Olle Kämpe, chair of the Nobel Committee, emphasized the transformative impact of their work, stating, “Their discoveries have been decisive for our understanding of how the immune system functions and why we do not all develop serious autoimmune diseases.” This recognition underscores the significance of their contributions not only to basic science but also to the potential for improving human health.
The Journey to Discovery
The path to these discoveries was not without challenges. Brunkow and Ramsdell, working at a small biotech company, had to rely on innovative techniques to pinpoint the Foxp3 mutation in mice. At the time, genetic sequencing and analysis tools were far less advanced than they are today, making their achievement all the more remarkable. Their ability to identify a single gene mutation with such profound effects on the immune system required both technical skill and scientific intuition.
Sakaguchi’s discovery of T-regs was equally groundbreaking, as it challenged existing paradigms in immunology. His work required meticulous experimentation to demonstrate that T-regs were a distinct subset of T cells with unique regulatory functions. By persevering through these challenges, the trio laid the foundation for a new understanding of immune regulation.
The Nobel Prize and Its Significance
The Nobel Prize in Physiology or Medicine is one of the most prestigious awards in science, recognizing individuals whose discoveries have had a transformative impact on human health. The 2025 award to Brunkow, Ramsdell, and Sakaguchi highlights the importance of basic research in uncovering fundamental biological processes that can lead to medical breakthroughs. Their work exemplifies how curiosity-driven science can yield insights that reverberate across disciplines and open new possibilities for treatment.
The announcement of the Nobel Prize on October 6, 2025, marks the beginning of the Nobel season, with awards in physics, chemistry, literature, peace, and economic sciences to follow. The Karolinska Institute, which oversees the selection of the medicine prize, has a long history of recognizing discoveries that have reshaped our understanding of biology and medicine. This year’s award is a testament to the power of collaboration and interdisciplinary research in addressing some of the most pressing challenges in human health.
Looking to the Future
As the scientific community celebrates the achievements of Brunkow, Ramsdell, and Sakaguchi, the focus now shifts to the future. The field of T-reg research is poised for significant advancements, with ongoing studies exploring how to manipulate these cells for therapeutic benefit. Clinical trials are already underway to test T-reg-based therapies in conditions such as type 1 diabetes, multiple sclerosis, and inflammatory bowel disease. These efforts hold the promise of transforming the treatment landscape for millions of patients worldwide.
Moreover, the discoveries recognized by this Nobel Prize have implications beyond medicine. Understanding how the immune system maintains tolerance could shed light on other biological processes, such as tissue repair, aging, and even neuroimmune interactions. The interplay between genetics, cellular function, and immune regulation is a rich area for future exploration, with the potential to uncover new insights into human biology.
Conclusion
The 2025 Nobel Prize in Physiology or Medicine awarded to Mary E. Brunkow, Fred Ramsdell, and Dr. Shimon Sakaguchi is a celebration of their pioneering contributions to the field of immunology. Their discoveries of regulatory T cells and the Foxp3 gene have revolutionized our understanding of peripheral immune tolerance, revealing how the immune system maintains balance to prevent autoimmune diseases. By identifying the mechanisms that govern T-reg function, they have opened new avenues for research and therapy, with the potential to transform the treatment of autoimmune disorders, cancer, and other immune-related conditions.
Their work serves as a reminder of the importance of basic science in driving medical progress. From Sakaguchi’s discovery of T-regs to Brunkow and Ramsdell’s identification of the Foxp3 mutation, their contributions have created a new field of immunology that continues to inspire researchers worldwide. As the scientific community builds on their findings, the legacy of this Nobel Prize will be felt for generations, offering hope for new treatments and a deeper understanding of the intricate workings of the immune system.
