The 2025 Nobel Prize in Physiology or Medicine was awarded earlier this month to immunologists Mary E. Brunkow (Institute for Systems Biology, Seattle), Fred Ramsdell (Sonoma Biotherapeutics, San Francisco/Seattle), and Shimon Sakaguchi (Osaka University, Japan) for their discoveries illuminating peripheral immune tolerance, particularly by identifying regulatory T cells (Tregs) and the transcription factor FOXP3, which is essential for their development and function.
Brunkow and Ramsdell carried out their pivotal genetic work at Celltech Chiroscience in Bothell, Washington, while Sakaguchi made his key cellular and functional discoveries at the Aichi Cancer Center Research Institute in Nagoya and later at Osaka. Their work transformed our understanding of how the immune system distinguishes foreign threats from the body’s own systems, allowing the body to protect itself without self-destruction. Their collective work not only redefined immune tolerance but also illustrated the growing interdependence between discovery, technology, and society.
While traditional immunology long emphasized central tolerance, the process by which self-reactive T cells are eliminated in the thymus, the laureates’ discoveries revealed a crucial additional layer: peripheral tolerance. This system operates throughout the body to control any self-reactive T cells that escape deletion in the thymus, preventing them from triggering autoimmune disease.
T cells are continuously generated in the bone marrow and mature in the thymus, a process that begins before birth and continues, though at a declining rate, throughout life. There they undergo rigorous “training” to distinguish self from non-self. Once they exit the thymus, peripheral tolerance mechanisms take over, acting as a secondary safeguard. These mechanisms either silence or suppress potentially self-reactive T cells through the action of regulatory T cells (Tregs).
Most Tregs originate in the thymus (thymic Tregs), but others can arise later in the body’s peripheral tissues and lymph nodes, where certain environmental and inflammatory cues induce ordinary T cells to acquire regulatory functions (peripherally induced Tregs). Together, these systems maintain the body’s internal harmony and allow the immune system to remain vigilant without turning its weapons on itself.
In 1995, Shimon Sakaguchi provided the first definitive evidence for a specialized subset of T cells now known as regulatory T cells (Tregs). He demonstrated that these cells are essential for maintaining immune self-tolerance and for preventing the spontaneous development of autoimmune diseases in experimental mice. This discovery was a pivotal breakthrough, transforming what had long been a controversial notion—the existence of so-called suppressor T cells—into one of the central pillars of modern immunology.
The next breakthrough came from the work of Mary E. Brunkow and Fred Ramsdell, who in 2001 mapped the gene responsible for a fatal autoimmune disorder in the “scurfy” mouse strain. Their research led to the identification of a previously unknown gene, Foxp3 (Forkhead box P3), which functions as a master regulatory switch within the immune system. Foxp3 enables conventional CD4⁺ T cells to acquire suppressive properties, effectively transforming them into regulatory T cells (Tregs). In essence, it activates genes that maintain immune balance and suppresses those that drive excessive immune activation and inflammation.
The human parallel to the “scurfy” mouse condition is IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome), a life-threatening genetic disease marked by severe autoimmunity that targets the gastrointestinal tract, hormone-producing organs such as the pancreas and thyroid, and the skin, often producing chronic eczematous lesions.
Working in close collaboration, Brunkow and Ramsdell demonstrated that mutations in the human FOXP3 gene cause IPEX syndrome in affected boys, establishing the gene’s essential role in immune regulation. Soon after, Sakaguchi’s team confirmed that FOXP3 acts as the master transcription factor governing the development and function of CD4⁺CD25⁺ Tregs. Together, these findings unified the cellular and molecular dimensions of immune tolerance, revealing how the absence of a single cell type, Tregs, controlled by a single gene locus, FOXP3, can unleash catastrophic, multi-organ autoimmunity.
The discoveries surrounding Tregs and FOXP3 have profoundly advanced our understanding of how autoimmune diseases develop and opened a dynamic field of research centered on harnessing immune regulation for therapeutic benefit. Tregs are now recognized as pivotal targets in three major areas of human health: autoimmune disease (including type 1 diabetes and rheumatoid arthritis), organ transplantation, and cancer.
The translational impact of this research is already evident. Clinical trials are exploring Treg-based cell therapies designed to restore immune balance, either by expanding functional Tregs to treat autoimmune disorders and promote transplant tolerance, or by blocking or depleting Tregs to prevent them from suppressing anti-tumor immune responses in cancer therapy. These dual strategies exemplify the immune system’s remarkable balance between protection and restraint, and how understanding that balance can be translated into life-saving interventions. Ironically, the same suppressive mechanisms that protect us from autoimmunity must be dismantled to fight cancer.
The historical roots of immunology
The origins of immunology reach back more than two millennia, to the simple yet profound observation that people who survived a devastating epidemic were somehow protected or exempted from contracting it again. The first known written account of this phenomenon comes from 430 BCE, when the historian Thucydides described how survivors of the Plague of Athens could tend to the sick without being reinfected. This early empirical insight laid the conceptual groundwork for later efforts to induce protection deliberately, what we now understand as immunization. Over the centuries, the hidden mechanisms that defend the body from disease were gradually revealed through successive scientific revolutions, each building on the observations of those who came before.
The first major step toward deliberate immune control came in 1796, when Edward Jenner performed the first scientific vaccination by using material from cowpox lesions to protect against smallpox. His pioneering experiment established the principle of cross-protective immunity where exposure to a benign agent could confer protection against a deadly one. This laid the foundation for the scientific prevention and management of infectious diseases.
A century later, the Germ Theory of Disease, developed by Louis Pasteur and Robert Koch, proved that specific microorganisms cause specific illnesses. Pasteur went on to devise systematic methods for producing vaccines by attenuating pathogens, creating effective immunizations against diseases such as anthrax and rabies.
These advances ignited a vigorous scientific debate over how the body defends itself, dividing researchers into two schools of thought. The humoralists, led by Paul Ehrlich (Nobel Prize, 1908), emphasized the role of soluble factors, particularly antibodies, in the blood. The cellularists, led by Élie Metchnikoff (Nobel Prize, 1908), championed specialized immune cells known as phagocytes or “devouring cells” as the first line of defense. This conceptual tension between humoral and cellular immunity ultimately shaped the birth of modern immunology.
By the mid-20th century, immunology achieved conceptual clarity with the Clonal Selection Theory, which explained how the body prepares for an almost limitless array of threats by randomly generating millions of lymphocytes (white blood cells), each bearing a unique antigen receptor created through genetic recombination. When one of these receptors encounters its matching foreign molecule, that specific lymphocyte is selected and multiplied, producing a targeted immune response.
This elegant mechanism raised an immediate paradox that Paul Ehrlich had recognized decades earlier and termed “horror autotoxicus”: if receptors are produced randomly, what prevents the immune system from turning its weapons against the body itself?
Frank Macfarlane Burnet and Peter Medawar (Nobel Prize, 1960) resolved this mystery with their discovery of acquired immunological tolerance, showing that the immune system learns to distinguish “self” from “non-self” during early development. Subsequent breakthroughs revealed how this recognition is encoded at the molecular level by the Major Histocompatibility Complex (MHC) (Nobel Prize, 1980), a system of self-identifying molecular “tags” displayed on every cell. Later, the discovery of MHC restriction (Nobel Prize, 1996) demonstrated that T cells must recognize foreign material only when it is presented together with these self-markers safeguards that allows immune precision while maintaining tolerance. In essence, every cell in the body carries its own cellular passport, a molecular identification tag issued by the MHC that tells the immune system, “I belong here.”
Although the mechanisms of central tolerance—the elimination of self-reactive, immature T cells in the thymus—were well understood, the persistence of debilitating autoimmune diseases revealed that this system alone could not fully explain how the body maintains immune tolerance.
The discovery recognized by the 2025 Nobel Prize resolved this mystery by defining peripheral immune tolerance, a complementary layer of active immune control that operates outside the central lymphoid organs. After decades of controversy surrounding the idea of “suppressor T cells,” Sakaguchi provided the first definitive cellular evidence in 1995, demonstrating that a distinct population of Tregs actively suppresses inflammation and prevents autoimmunity. Only a few years later, in 2001, Brunkow and Ramsdell identified the genetic basis of this regulation in the FOXP3 gene, which governs the development and function of Tregs. Together, these discoveries established the dual architecture of immune tolerance—central and peripheral—that preserves the body’s integrity against both external and internal threats.
A new era in clinical medicine is underway
The insights gained from FOXP3 and Tregs have opened vast new therapeutic frontiers in medicine. For patients with IPEX syndrome, the only curative treatment remains hematopoietic stem cell transplantation (HSCT), which replaces the defective immune system entirely.
More broadly, the expanding understanding of Tregs is driving a new generation of cell-based therapies, collectively known as adoptive cell transfer (ACT). These approaches involve isolating a patient’s functional Tregs, expanding them in the laboratory, and reinfusing them to restore immune balance. Clinical trials are testing this strategy to suppress inappropriate immune attacks in autoimmune diseases and to prevent organ transplant rejection, potentially freeing patients from the toxic, lifelong use of generalized immunosuppressive drugs.
Building on these advances, researchers are developing highly specific chimeric antigen receptor (CAR)-Tregs, which can be engineered to direct their suppressive activity toward a defined tissue or antigen. This precision targeting aims to maximize therapeutic efficacy while minimizing systemic side effects.
In contrast, the goal in cancer immunotherapy is often the opposite: to disable Tregs. Within tumors, Tregs act as cellular shields that protect cancer cells by dampening the anti-tumor immune response. Depleting or blocking these cells has become a major therapeutic strategy, complementing modern approaches such as immune-checkpoint blockade. Ironically, the same immune restraint that safeguards self-tolerance must be lifted to unleash the body’s natural defense against cancer.
Systems immunology and computational sciences merge
Despite this revolutionary progress, immunology remains a field of staggering complexity. Human immunology continues to face challenges because much of the discipline is still largely descriptive, struggling to capture the vast diversity and dynamism of the human immune system. To address these limitations, researchers are rapidly shifting to systems immunology, which integrate experimental biology with computational science. Using powerful new technologies such as single-cell multiomics, which can analyze the molecular contents of individual cells one by one, researchers can now generate unprecedented details about immune activity in dynamic terms. High-throughput sequencing, advanced computational modeling, and artificial intelligence make it possible to merge and interpret these massive datasets, reconstructing how immune cells interact across multiple biological layers.
As our capacity to decode the immune system expands, so too does the moral question of who will benefit from that knowledge. Systems immunology offers a dynamic window into the body’s cellular microcosm. By collecting and integrating molecular data directly from human patients during key clinical events like after a vaccination, infection, or during disease progression, it promises to accelerate discovery and bridge the gap between fundamental knowledge and precise, personalized immunotherapy for the future.
Science and inequality
The immune system lies at the very center of human health, intricately intertwined with nearly every physiological process. Far from being an isolated organ, it communicates continuously with the nervous, endocrine, and metabolic systems, coordinating the body’s defense not only against external pathogens but also against internal dysregulation.
This fundamental importance underscores the 2025 Nobel Prize, awarded to Brunkow, Ramsdell, and Sakaguchi for defining the Treg lineage and the FOXP3 gene that governs it. The scientific merit of their discovery is indisputable, extending the Nobel tradition of honoring breakthroughs that advance knowledge for the “benefit of humankind.”
Yet the economic reality surrounding how such discoveries are translated into practice exposes a deep tension between human need and commercial imperatives. The medical revolution sparked by the discovery of Tregs is now deeply entwined with costly, biotechnology-driven medicine. For instance, Dr. Ramsdell’s leadership at Sonoma Biotherapeutics, which is advancing Treg cell therapies into clinical trials for conditions such as rheumatoid arthritis and autoimmune liver disease, represents the direct transformation of Nobel-winning insight into commercial enterprise.
Furthermore, the latest advances in personalized immunotherapies, such as mRNA-based cancer vaccines, come with formidable financial costs, often exceeding $100,000 per patient. While these treatments hold transformative promise for aggressive diseases like melanoma and pancreatic cancer, their high cost and the technical complexity of manufacturing patient-specific T-cell products through adoptive cell transfer (ACT) mean that access to the true benefit of these discoveries remains sharply constrained. Scalability, patent exclusivity, and profit-driven pricing frequently determine who can receive these therapies, rather than the scope of their medical potential.
The modern frontier of medicine is therefore dual in nature. On one side, scientists continue to unravel intricate biological puzzles, as exemplified by the 2025 Nobel recognition of peripheral immune tolerance. On the other, the realization of these discoveries depends on overcoming the economic, manufacturing, and policy obstacles that govern access to innovation. Whether these therapies become universally accessible instruments of health or remain prohibitively expensive commodities benefiting a privileged few (both medically and financially) will depend not only on scientific ingenuity, but on the struggle to overturn a profit-driven medical order and establish a public health system based on providing access to therapies to all who need them, regardless of wealth and income.