Guardians of the Self

Introduction

The immune system is a remarkably complex and sophisticated defence network that protects the body from a constant barrage of pathogens, such as bacteria, viruses, and fungi ^{2, 3, 30}. A key feature of this system is its ability to distinguish between 'self'—the body's own cells and tissues—and 'non-self'—foreign invaders. This capacity for self-recognition is crucial for preventing the immune system from turning against the very organism it is designed to protect. When this fundamental principle of self-tolerance breaks down, the consequences can be severe, leading to a host of debilitating and often life-threatening autoimmune diseases, such as type 1 diabetes, multiple sclerosis, and rheumatoid arthritis ^{1, 4}.

For many years, the prevailing scientific consensus was that the primary mechanism for ensuring self-tolerance occurred in the thymus, a specialised organ located behind the breastbone ^{1, 11, 30}. This process, known as central tolerance, involves the elimination of developing T cells—a critical type of white blood cell—that show the potential to react against the body's own components ^{1, 11, 30, 42}. However, it became increasingly apparent that this could not be the whole story. Some self-reactive T cells inevitably escape this central checkpoint and enter the circulation, posing a potential threat to the body's tissues ^{1, 42}. This raised a fundamental question in immunology: what prevents these escaped, potentially dangerous cells from wreaking havoc?

The groundbreaking work of the 2025 Nobel laureates, Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi, provided the definitive answer to this question ^{1, 2, 3, 4, 6, 7, 8, 11, 12, 15, 19, 21, 25, 26, 27, 28, 30, 31, 35, 36, 42, 45, 46}. Their independent yet interconnected discoveries unveiled a second, crucial layer of immune regulation known as peripheral immune tolerance ^{1, 2, 3, 6, 7, 8, 11, 12, 15, 19, 25, 30, 35, 38, 42, 45}. This mechanism operates outside the thymus, in the peripheral tissues and lymphoid organs, to actively suppress self-reactive immune responses ^{1, 2, 3, 6, 7, 8, 11, 12, 15, 19, 25, 30, 35, 38, 42, 45}. At the heart of this process are the regulatory T cells, or Tregs, a unique population of T cells that act as the immune system's dedicated peacekeepers ^{2, 3, 6, 7, 15, 19, 30, 31}.

The Serendipitous Path to Discovery: Shimon Sakaguchi and the Hunt for Suppressor Cells

The journey to understanding peripheral tolerance began in the early 1980s with the inquisitive mind of Shimon Sakaguchi, then a young researcher at Kyoto University in Japan ^{15, 16, 26, 36}. Sakaguchi was intrigued by a curious phenomenon observed in mice ^{5, 16}. When the thymus was surgically removed from newborn mice, a procedure known as neonatal thymectomy, the animals did not simply become immunodeficient as might be expected ^{2, 5}. Instead, if the operation was performed on the third day after birth, the mice developed a range of severe autoimmune diseases, with their immune systems launching a full-scale assault on their own organs ^{2, 5}. This suggested that the thymus was not only responsible for generating functional T cells but also for producing a population of cells that actively suppressed autoimmunity.

This observation led Sakaguchi to hypothesise the existence of 'suppressor' T cells, a concept that was, at the time, highly contentious and met with considerable scepticism within the immunology community ^{11, 16, 30}. The prevailing view was that central tolerance in the thymus was sufficient to prevent autoimmunity ^{11, 30}. Undeterred, Sakaguchi embarked on a series of elegant experiments to prove his hypothesis ^{5, 16}. He isolated T cells from healthy, genetically identical mice and injected them into the thymectomised mice that were destined to develop autoimmune diseases ^{2, 5}. The results were striking: the injected T cells prevented the onset of autoimmunity, providing compelling evidence for the existence of a protective T cell population ⁵.

The next challenge was to identify and isolate these elusive suppressor cells. Sakaguchi and his team began a meticulous search for a unique molecular marker that could distinguish these protective T cells from their more aggressive counterparts. After years of painstaking work, in 1995, they identified a protein on the surface of a small subset of T cells called CD25 ^{1, 11, 12, 16, 19, 31, 45, 46}. They demonstrated that T cells expressing CD25 were able to suppress autoimmune reactions, while those lacking this marker were not ¹. This was a landmark discovery that provided the first definitive identification of what would later become known as regulatory T cells ^{16, 19, 31}.

The Genetic Key: Mary E. Brunkow, Fred Ramsdell, and the 'Scurfy' Mouse

While Sakaguchi was unravelling the cellular basis of peripheral tolerance in Japan, a parallel line of investigation was unfolding in the United States, focused on a peculiar strain of mice known as 'scurfy' mice ^{3, 6, 42}. These mice were characterised by a severe, multi-organ autoimmune disease that was invariably fatal within the first few weeks of life. The scurfy phenotype was known to be caused by a single gene mutation, but the identity of this gene remained a mystery.

In 2001, a team of researchers including Mary E. Brunkow and Fred Ramsdell made a pivotal breakthrough ^{3, 11, 12, 19, 30, 31, 42, 45}. Through a series of sophisticated genetic analyses, they identified the mutated gene responsible for the scurfy phenotype ^{3, 11, 30, 31, 42}. They named this gene 'Foxp3' ^{3, 11, 30, 31, 42}. Their research revealed that Foxp3 belonged to a family of proteins known as forkhead box transcription factors, which play a crucial role in regulating the expression of other genes ^{14, 18, 20, 29, 33}.

Crucially, Brunkow and Ramsdell also demonstrated that mutations in the human equivalent of the Foxp3 gene were the cause of a rare and devastating autoimmune disease in humans called IPEX syndrome (Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked) ^{3, 11, 30, 34, 42}. IPEX syndrome, which primarily affects male infants, is characterised by a triad of severe diarrhoea, eczema-like skin rashes, and autoimmune endocrine disorders, most commonly type 1 diabetes ^{23, 34, 37, 39}. The discovery of the link between FOXP3 and IPEX provided the first direct evidence that a single gene was essential for maintaining immune tolerance in humans ^{3, 11, 30, 34, 42}.

The Unification of a Field: Sakaguchi Connects the Dots

The discoveries of Sakaguchi and the team of Brunkow and Ramsdell were initially seen as separate but important advances in the field of immunology. However, the true significance of their work became apparent when, in 2003, Sakaguchi and his group made the crucial connection between the two lines of research ^{3, 11, 12, 19, 30, 31, 45}. They demonstrated that the Foxp3 gene was the master regulator that controlled the development and function of the CD25-expressing regulatory T cells he had identified years earlier ^{3, 11, 19, 30, 31}.

This unifying discovery was a watershed moment in immunology. It established that Tregs are a distinct lineage of T cells, defined by their expression of FOXP3, and that this transcription factor is absolutely essential for their suppressive function ^{14, 18, 20, 29, 33}. The absence or dysfunction of FOXP3, as seen in scurfy mice and IPEX patients, leads to a catastrophic failure of peripheral tolerance and the development of fatal autoimmune disease ^{20, 34}. The work of the three laureates had not only identified the key players in peripheral tolerance but had also elucidated the genetic programme that governs their activity.

The Mechanisms of Treg-Mediated Suppression

Following the seminal discoveries of Brunkow, Ramsdell, and Sakaguchi, a major focus of research has been to understand precisely how Tregs exert their suppressive effects. It is now clear that Tregs employ a variety of mechanisms to keep other immune cells in check and prevent them from attacking the body's own tissues.

One important mechanism involves the production of inhibitory signalling molecules, known as cytokines. Tregs are potent producers of anti-inflammatory cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β) ³². These molecules act directly on other immune cells, including aggressive effector T cells, to dampen their activity and prevent them from causing tissue damage ³².

Tregs can also suppress immune responses through direct cell-to-cell contact. They express high levels of a protein called CTLA-4 on their surface, which can bind to other immune cells and deliver an inhibitory signal, effectively putting the brakes on the immune response ^{18, 29, 32}. Additionally, Tregs can induce the death of other immune cells through the release of cytotoxic molecules like granzymes and perforin ³².

Another fascinating mechanism by which Tregs control immune responses is by acting as a 'sink' for a crucial growth factor called interleukin-2 (IL-2). Effector T cells require IL-2 to proliferate and mount an effective immune response. Tregs express very high levels of the IL-2 receptor on their surface, allowing them to effectively soak up any available IL-2 in their vicinity, thereby starving the effector T cells of this essential growth factor and preventing their expansion ^{18, 29, 32}.

The Clinical Implications of Treg Discovery: A New Era of Immunotherapy

The discovery of Tregs and the FOXP3 gene has had a profound impact on our understanding of a wide range of human diseases and has opened up exciting new avenues for therapeutic intervention ^{2, 8, 12, 15, 21, 31, 35, 38, 45}. The ability to manipulate the number and function of Tregs holds immense promise for the treatment of conditions characterised by either excessive or insufficient immune responses.

In the context of autoimmune diseases, where the immune system is overactive, the goal is to boost the number or function of Tregs to restore immune balance. One approach that is currently being explored in clinical trials is adoptive Treg cell therapy ^{9, 41, 43, 44}. This involves isolating Tregs from a patient's own blood, expanding them to large numbers in the laboratory, and then infusing them back into the patient ^{9, 41, 43, 44}. Early clinical trials of this approach in patients with type 1 diabetes and in the context of organ transplantation have shown promising results, with the therapy being well-tolerated and showing signs of efficacy ^{9, 41, 43}.

Another strategy is to develop drugs that can selectively enhance the function of existing Tregs in the body. Researchers are also investigating the potential of gene therapy to correct the faulty FOXP3 gene in patients with IPEX syndrome, which could offer a curative treatment for this devastating disease ^{39, 40}.

Conversely, in the setting of cancer, the presence of a large number of Tregs within the tumour microenvironment can be a major obstacle to effective anti-cancer immunity. Tregs can suppress the activity of cancer-killing immune cells, allowing the tumour to evade destruction. Therefore, a key goal of cancer immunotherapy is to deplete or inactivate Tregs within the tumour, thereby unleashing the full power of the immune system to attack and eliminate cancer cells. Several therapeutic strategies are being developed to achieve this, including antibodies that can specifically target and eliminate Tregs, and drugs that can block their suppressive function.

The discovery of Tregs has also had a significant impact on the field of organ transplantation. One of the major challenges in transplantation is preventing the recipient's immune system from rejecting the transplanted organ. Current anti-rejection therapies rely on broad-acting immunosuppressive drugs that can have serious side effects, including an increased risk of infection and cancer. The use of Treg cell therapy to induce specific tolerance to the transplanted organ is a highly promising strategy that could reduce the need for long-term immunosuppression and improve the long-term outcomes for transplant recipients ^{41, 43}.

The Laureates: A Glimpse into the Lives of Scientific Pioneers

The 2025 Nobel Prize in Physiology or Medicine is shared by three individuals whose dedication and scientific rigour have transformed our understanding of the immune system.

Mary E. Brunkow, born in 1961, is currently a senior programme manager at the Institute for Systems Biology in Seattle, USA ^{4, 12, 15, 36, 45, 46}. She received her PhD from Princeton University in 1991 ^{15, 36, 38}. Her meticulous genetic studies were instrumental in identifying the Foxp3 gene as the critical determinant of the scurfy mouse phenotype and its human equivalent, IPEX syndrome ^{3, 11, 30, 31, 42}.

Fred Ramsdell, born in 1960, is a co-founder and scientific adviser at Sonoma Biotherapeutics in San Francisco, USA ^{1, 4, 12, 15, 36, 45, 46}. He earned his PhD from the University of California, Los Angeles, in 1987 ^{15, 36}. His collaboration with Brunkow on the genetic basis of the scurfy mouse was a pivotal moment in the field of immunology ^{3, 11, 30, 31, 42}.

Shimon Sakaguchi, born in 1951, is a distinguished professor at the Immunology Frontier Research Centre at Osaka University in Japan ^{1, 4, 12, 15, 26, 36, 45, 46}. He obtained his MD in 1976 and his PhD in 1983 from Kyoto University ^{15, 16, 36}. His persistent and visionary research, often in the face of scientific scepticism, led to the discovery of regulatory T cells and their crucial role in maintaining immune homeostasis ^{11, 16, 30}.

The Future of Treg Research: Challenges and Opportunities

While the discoveries of Brunkow, Ramsdell, and Sakaguchi have laid a solid foundation for the field of Treg biology, there are still many unanswered questions and challenges to overcome. A deeper understanding of the different subtypes of Tregs and their specific functions in different tissues and disease contexts is needed. The development of more effective and specific methods for manipulating Treg numbers and function in vivo is a major priority.

Ensuring the long-term stability and safety of Treg-based therapies is another critical area of research. There is a theoretical risk that therapeutic Tregs could lose their suppressive function and convert into pro-inflammatory cells, which could have detrimental consequences. Researchers are actively working on strategies to prevent this from happening, including genetic engineering approaches to lock Tregs into a stable suppressive state ⁴³.

Despite these challenges, the future of Treg research is incredibly bright. The ongoing advancements in our understanding of these fascinating cells, coupled with the development of sophisticated new technologies for cellular and genetic engineering, are paving the way for a new generation of immunotherapies that have the potential to revolutionise the treatment of a wide range of human diseases ^{10, 13, 17, 22, 24}.

Conclusion

The awarding of the 2025 Nobel Prize in Physiology or Medicine to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi is a fitting recognition of their transformative contributions to the field of immunology ^{1, 2, 3, 4, 6, 7, 8, 11, 12, 15, 19, 21, 25, 26, 27, 28, 30, 31, 35, 36, 42, 45, 46}. Their discovery of peripheral immune tolerance, mediated by regulatory T cells and controlled by the master gene FOXP3, has provided a solution to one of the most fundamental puzzles in immunology: how the immune system avoids attacking itself ^{4, 8, 27}. This new understanding has not only rewritten the textbooks but has also provided a powerful new framework for thinking about and treating a vast array of human diseases. The legacy of their work will undoubtedly continue to inspire new discoveries and drive the development of innovative therapies that will benefit humankind for many years to come.