2025 Nobel Prize in Physiology or Medicine — Bruncko, Ramsdell, and Sakaguchi: Unraveling the Immune System’s Self-Tolerance Circuit

What You’ll Learn from This Article

The 2025 Nobel Prize in Physiology or Medicine was awarded to three individuals who elucidated how our immune system avoids attacking its own tissues — the molecular circuit of peripheral immune tolerance. Shimon Sakaguchi of Osaka University, Japan, demonstrated in 1995 the existence of regulatory T cells (Treg), a special type of T cell that suppresses immune attacks against self-antigens. Mary Bruncko and Fred Ramsdell, who collaborated at CellStore in Seattle, USA, identified in 2001 that the FOXP3 gene is the cause of nude mice and human IPEX syndrome, and that this gene is the master regulator of regulatory T cells. These three discoveries, when combined, established the immune system’s whitelist management system, which has become the foundation for understanding and treating autoimmune diseases, transplant rejection, cancer immunotherapy, and fetal tolerance.

Beyond Common Sense — The Immune System Maintains a Whitelist of Self

The common understanding that “the immune system attacks external invaders” obscures the fundamental question of how the immune system distinguishes between self and non-self. Because our T cells randomly generate antigen receptors through genetic recombination, theoretically, there are many T cells that recognize self-antigens. Why don’t these self-reactive T cells attack the body’s own tissues?

The answer in the late 20th century had two components. One was central tolerance — a system that eliminates T cells strongly reactive to self-antigens in the thymus. However, this system alone was not sufficient. A significant number of self-reactive T cells that are not completely eliminated in the thymus enter the periphery, and the question of why these cells do not cause autoimmunity remained unanswered.

The answer to peripheral tolerance was regulatory T cells. Tregs are a special type of T cell that suppresses the activity of other T cells, particularly suppressing the activity of T cells that react to self-antigens, thereby preventing autoimmunity. If Tregs are absent or deficient, autoimmunity occurs, and if Tregs are overactive, the response to pathogens is weakened. This delicate balance is the key to normal immune homeostasis.

If we translate this into a CS framework, Tregs are the whitelist manager. The defense system (the entire immune system) detects danger signals and initiates an attack, but the body’s own tissues are registered on the whitelist and excluded from the attack target. Tregs are the active process that maintains and manages this whitelist, and FOXP3 is the master regulator that acts as the whitelist configuration file. If Tregs fail or FOXP3 is defective, the whitelist is disabled, and the defense system begins to attack the body’s own tissues — this is what happens in autoimmune diseases.

The Era’s Context — A Year of Impeachment Decisions and Trade Wars

In 2025, South Korea began the year in the wake of the December 3rd martial law and the impeachment crisis of the previous year. The Constitutional Court’s decision on the impeachment of the President and the subsequent early presidential election were major events in the first half of the year, leading to a major shift in the political landscape.

Globally, the trade war initiated during the early years of the Trump administration intensified. Tariffs were imposed on several countries, including China, Mexico, Canada, and Europe, fundamentally reshaping the global trade order. The US-China relationship entered a new phase, and this had a significant impact on global supply chains and inflation.

The Ukraine war entered its third year, with attempts at negotiations between Russia and Ukraine taking place in various directions, but a decisive breakthrough proved difficult. The Israel-Gaza war continued, remaining at the center of international humanitarian debate.

The popularization of AI deepened. Several GPT-5-level large language models were released, and code agents began to become the dominant trend in software development. The rapid pace of automation is significantly reshaping the labor market in various industries, and discussions about the social implications of this trend are taking place around the world.

In the scientific community, this award was a step toward a complete understanding of the era of immunotherapy. Following the 2018 Nobel Prize in Physiology or Medicine awarded to Allison and Honjo for their work on immune checkpoint inhibitors, immune regulation has become a major component of cancer treatment, and the Treg story is the fundamental discovery of the opposite side — the maintenance of self-immune tolerance. The two approaches — enhancing T cell activation with immune checkpoint inhibitors and, conversely, enhancing Tregs in autoimmune diseases — are integrated in this narrative.

Personal Stories — Observations from Osaka and Genetics from Seattle

Shimon Sakaguchi (1951– ) was born in Shiga Prefecture, Japan. He received his M.D. and Ph.D. from Kyoto University and held positions at several universities before settling at Osaka University. From the beginning, his research focused on the mechanisms of immune tolerance.

In the 1980s, his laboratory conducted an experiment in which they removed the thymus from newborn mice and made a surprising observation. Mice that had their thymus completely removed developed various autoimmune diseases, despite having very few T cells. This suggested that T cells can both cause autoimmunity and, conversely, contain T cells that suppress autoimmunity. The hypothesis was that these suppressive T cells were also eliminated when the thymus was removed, leading to autoimmunity.

In 1995, Sakaguchi’s team published a pivotal paper that confirmed this hypothesis. They isolated a subset of CD4+ T cells that express CD25 (the α chain of the IL-2 receptor) from mice and demonstrated that this subset has autoimmune-suppressive activity. When these CD25+ cells were removed and the remaining T cells were transplanted into mice, autoimmunity developed, whereas when the CD25+ cells were co-transplanted, autoimmunity was suppressed. This was the moment when CD4+CD25+ regulatory T cells were clearly established as a distinct entity.

In the years that followed, this discovery was gradually recognized by the academic community, but the identity of CD4+CD25+ cells and the master regulatory gene remained unresolved.

Mary Bruncko (1961– ) and Fred Ramsdell (1960– ) were two researchers who led genetic research at CellStore (which later changed its name to several companies) in Seattle, USA. Their interest was in a naturally occurring mutant mouse strain called nude mice. These mice have a peculiar phenotype in which they develop severe autoimmune reactions and die within a few weeks of birth, and the causative gene was unknown.

In 2001, the Bruncko-Ramsdell team identified the causative gene in nude mice. This was a novel transcription factor gene, which they named FOXP3 (Forkhead Box P3). Surprisingly, it was soon confirmed that the human equivalent of this gene is also the cause of IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome) — a severe autoimmune syndrome that occurs only in males.

The moment when these three discoveries came together was a few years later. Through collaborative experiments with several laboratories, it was confirmed that FOXP3 is the master regulatory transcription factor for CD4+CD25+ Tregs discovered by Sakaguchi. Tregs are FOXP3-expressing cells, and when FOXP3 is expressed, these T cells acquire suppressive function. Nude mice and IPEX patients develop autoimmunity because FOXP3 is defective, and Tregs are not produced.

These three discoveries — Sakaguchi’s Tregs, Bruncko and Ramsdell’s FOXP3 gene — together established the molecular circuit of peripheral tolerance. The 2025 Nobel Prize recognized this integration.

Key Achievements — The Whitelist Management System in a CS Framework

If we depict the pipeline of peripheral immune tolerance, it would look like this:

• Treg generation (Treg differentiation): In the thymus, some of the T cells that react with moderate intensity to self-antigens express FOXP3 and differentiate into regulatory T cells. These Tregs are called thymus-derived Tregs (tTregs).
• Peripheral expansion: In the periphery, CD4+ T cells can also be induced to become Tregs by expressing FOXP3 under certain conditions (TGF-β, IL-2, exposure to specific antigens). These are called peripherally derived Tregs (pTregs).
• Surveillance: Tregs monitor the activity of other T cells throughout the body. When they detect T cells that react to self-antigens, they suppress them through various mechanisms.
• Suppression mechanisms: Tregs use various mechanisms to suppress other T cells:
  • Inhibition of antigen-presenting cell co-stimulation by expressing CTLA-4 (CTLA-4, which was awarded the 2018 Nobel Prize, also appears here).
  • Secretion of suppressive cytokines such as IL-10 and TGF-β.
  • Inhibition of the activity of other T cells by consuming IL-2.
  • Direct cytotoxic suppression, and so on.
• Prevention of autoimmunity: This suppression controls T cell responses against self-tissues, preventing autoimmunity.

The essence of this system is active whitelist management. The defense system (the entire immune system) responds to danger signals and prepares to attack, but Tregs continuously suppress reactions to self-tissues, maintaining the whitelist. FOXP3 is the master configuration file that defines the identity of Tregs, and if this configuration is damaged, the entire whitelist is disabled.

The failure of this system in disease states occurs in two directions:

• Treg deficiency/dysfunction: The whitelist is disabled, leading to autoimmunity. Treg dysfunction is one of the factors in the pathogenesis of various autoimmune diseases, such as type 1 diabetes, multiple sclerosis, lupus, and rheumatoid arthritis.
• Treg overactivity/dysfunction: The whitelist becomes too broad, suppressing normal responses to pathogens and tumors. Chronic infections, immunodeficiencies, and immune evasion in the tumor microenvironment are examples of this. A typical example is tumors recruiting Tregs into their microenvironment to suppress T cell attacks.

It should also be noted that the Treg is not a completely stable state. Under certain conditions, Tregs can lose their suppressive function or transform into other T cell states, and this flexibility is involved in both pathological and normal regulation. Unlike a static whitelist, it is a dynamic regulatory system, which is a limitation of the pure configuration file analogy.

Why It Matters: Autoimmunity, Transplantation, Cancer, and Fetal Tolerance

First, it offers new therapeutic approaches for autoimmune diseases. Strategies to enhance Treg function are being developed in several directions. Low-dose IL-2—an approach that leverages the property of IL-2 to preferentially stimulate Tregs at low concentrations—has entered clinical trials, and Treg cell therapy—an approach in which a patient's Tregs are expanded ex vivo and then reinfused—is being tested in conditions such as type 1 diabetes and Crohn's disease.

Second, it addresses the management of rejection in organ transplantation. Immunosuppressants (e.g., cyclosporine) have long been used to suppress the immune attack against transplanted tissues, but these drugs suppress the entire immune system, significantly increasing the risk of infection. Using Tregs to induce antigen-specific tolerance has emerged as a promising solution to this problem, and several clinical trials are underway. Success in this area would greatly improve the quality of life for transplant recipients.

Third, it enhances our understanding of the tumor microenvironment and offers new approaches to cancer therapy. Tumors use a strategy to attract Tregs to their microenvironment, thereby evading T cell attack. Several approaches are being explored to specifically inhibit tumor Tregs, and combination therapies with checkpoint inhibitors are being developed. Interestingly, some of the mechanisms of action of CTLA-4 inhibitors (ipilimumab, a key drug in the 2018 Nobel Prize) are explained by the reduction of Tregs in the tumor microenvironment.

Fourth, it provides insight into fetal tolerance. During pregnancy, the mother's immune system does not reject the fetus, even though it recognizes the fetus as a semi-allogeneic graft. It has been established that Tregs expand in the placenta and maintain this tolerance, creating a new framework for understanding pregnancy-related pathologies such as recurrent miscarriage and preeclampsia.

Fifth, it offers new treatments for allergies and asthma. It has been found that impaired Treg function is involved in allergies and chronic inflammation, and approaches to enhance Tregs are being studied as new directions for allergen immunotherapy.

Sixth, it enables precise diagnosis and treatment of IPEX syndrome and rare genetic diseases. Early diagnosis and hematopoietic stem cell transplantation can treat IPEX patients with FOXP3 gene mutations, and recently, attempts have been made to restore FOXP3 using gene therapy.

Seventh, it provides a comprehensive understanding of immunotherapy. The immunological discoveries from the late 20th to the early 21st centuries—innate immunity (2011), checkpoint inhibitors (2018), and Tregs (2025)—together complete an integrated map of the human immune system. On this map, the development of precise immunotherapies specific to each disease will become a major focus of medicine in the latter half of the 21st century.

Eighth, it represents a continued achievement in Japanese immunology. Sakaguchi's Nobel Prize is part of the ongoing Nobel Prize trend in Japanese immunology and basic biology, following Omura (2015), Osawa (2016), and Honjo (2018). The accumulated strength of Japanese immunology, centered in Osaka and Kyoto, has been reconfirmed internationally.

Ninth, it tells the story of the 25-year journey from discovery to the Nobel Prize. Sakaguchi demonstrated the existence of Tregs in 1995, and Bronchoud and Lambe identified FOXP3 in 2001. It took 20 to 30 years for these discoveries to be recognized with the Nobel Prize. During that time, the understanding of autoimmunity and its clinical applications gradually matured, and with the success of checkpoint inhibitors, immune regulation became a standard for cancer treatment, which in turn highlighted the importance of the opposing system of tolerance.

There was a reason why our bodies do not attack themselves. The core of this story is that the reason is an active whitelist management system—regulatory T cells and FOXP3. The 25th Nobel Prize in Physiology or Medicine of the new century named this system, and on this basis, the understanding of autoimmunity, transplantation, cancer, and pregnancy will continue in the latter half of the 21st century.

Batch 9 Completed: A 25-Year Nobel Story of the New Century

The series of Nobel Prizes in Physiology or Medicine of the new century, which began in 2001 with the cell cycle, reaches its 25th installment in 2025. The list of major stories that humanity has uncovered over the past 25 years is as follows:

• Cellular Basic Programs: Cell cycle (2001), apoptosis (2002), autophagy (2016), vesicular transport (2013), cellular reprogramming (2012)
• Physical Layers of Sensation: MRI (2003), olfactory combination code (2004), temperature and touch (2021), brain GPS (2014), circadian clock (2017)
• Infection and Immunity: Helicobacter (2005), HPV and HIV (2008), innate immunity and dendritic cells (2011), hepatitis C (2020)
• Cancer and Immunotherapy: Checkpoint inhibitors (2018), regulatory T cells (2025)
• Genetics and Evolution: Knockout mice (2007), telomeres (2009), human genomics (2022), miRNA (2024), RNAi (2006)
• Regeneration and Therapy: IVF (2010), mRNA vaccines (2023), hypoxia sensing (2019)
• Infectious Diseases in Developing Countries: Ivermectin and artemisinin (2015)

These 25 discoveries have redrawn the map of human understanding in the early 21st century. Each piece is connected to the next, and when viewed as a single, large story, the direction of the 25-year trend becomes clear: from observation to manipulation, from organism to cell, from cell to molecule, and from molecule to personalized treatment.

The 25-year Nobel story of the new century is completed here. The story of the next 25 years will continue, and on this basis, humanity will continue to understand itself.

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