The Body's Peacekeepers

Introduction

The human immune system is a remarkably complex and sophisticated defence network, an evolutionary marvel honed over millennia to protect the body from a constant barrage of external threats such as viruses, bacteria, and other pathogens. ^{2, 23} Its ability to distinguish between 'self' and 'non-self' is paramount to maintaining health. However, this powerful system carries an inherent risk: if its formidable arsenal is misdirected against the body's own cells and tissues, the consequences can be devastating, leading to a class of debilitating conditions known as autoimmune diseases. ^{8, 25} For decades, a central question in immunology has been how the body maintains a delicate balance, unleashing its full force against invaders while preserving its own integrity. The 2025 Nobel Prize in Physiology or Medicine honours three scientists whose pioneering work has provided a profound answer to this question, revolutionising our understanding of immune regulation. ^{4, 5} Mary E. Brunkow of the Institute for Systems Biology in Seattle, Fred Ramsdell of Sonoma Biotherapeutics in San Francisco, and Shimon Sakaguchi of Osaka University in Japan have been jointly awarded the prestigious prize for their discoveries concerning "peripheral immune tolerance". ^{4, 7, 29} Their research illuminated the existence and function of a crucial population of immune cells, the regulatory T cells (Tregs), which act as the immune system's peacekeepers. ^{2, 3, 37} This work has not only unravelled a fundamental biological mechanism but has also opened up new frontiers for therapeutic intervention in a wide array of human diseases. ^{2, 21, 28}

The Enigma of Self-Tolerance

The concept of the immune system attacking the body it is meant to protect was once considered a biological paradox. ²⁷ In the early 20th century, the German physician and scientist Paul Ehrlich coined the term "horror autotoxicus" to describe this seemingly unnatural state of self-destruction. ^{27, 31} The prevailing view was that a robust mechanism must exist to prevent such self-reactivity. For a long time, the primary explanation for this self-tolerance was believed to lie in a process known as central tolerance. ^{2, 3, 23, 28} This process occurs in the thymus, a small organ located behind the breastbone, where T cells, a critical type of white blood cell, mature. ^{7, 19} Within the thymus, developing T cells that show a strong reactivity to the body's own proteins are eliminated, effectively weeding out potentially harmful cells before they can enter circulation. ^{7, 23, 28}

However, it became increasingly apparent that central tolerance was not the complete story. ⁷ Some self-reactive T cells inevitably escape this thymic censorship and circulate throughout the body. ⁷ This observation posed a significant puzzle: what prevents these escaped cells from wreaking havoc and causing autoimmune disease? This question pointed towards the existence of additional, peripheral mechanisms of tolerance that operate outside the thymus, in the rest of the body. ¹⁹ The search for these peripheral tolerance mechanisms would become a central quest in immunology, a quest in which the 2025 Nobel laureates would play a pivotal role. The historical context of autoimmune research reveals a gradual shift from disbelief to a growing acceptance of the concept of autoimmunity. ^{27, 31} The discovery of autoantibodies in the 1940s provided the first concrete evidence that the immune system could indeed target self-antigens. ³¹ By the mid-20th century, the link between these autoantibodies and diseases like systemic lupus erythematosus and rheumatoid arthritis was becoming clearer. ³¹ Yet, the cellular mechanisms that controlled these self-destructive responses remained largely enigmatic.

Shimon Sakaguchi's Counter-Current Discovery

In the mid-1990s, the field of immunology was still heavily focused on the mechanisms of immune activation. The prevailing dogma held that the immune system's default state was one of rest, and it was only activated in the presence of foreign invaders. The idea of a specialised population of cells dedicated to actively suppressing immune responses was met with considerable scepticism. ²⁰ It was in this climate that Shimon Sakaguchi, then at the Aichi Cancer Center Research Institute in Nagoya, Japan, made a series of observations that would challenge the established view. ³⁶

Sakaguchi was intrigued by earlier experiments where the removal of the thymus from newborn mice led to the development of autoimmune diseases. ³⁶ This suggested that the thymus was not only responsible for generating T cells but also for establishing and maintaining self-tolerance. Building on this, Sakaguchi conducted a series of elegant experiments in the early 1980s. ³⁶ He isolated T cells from healthy mice and injected them into mice that lacked a thymus and were therefore prone to developing autoimmune conditions. ³⁶ The results were striking: the transferred T cells were able to protect the recipient mice from developing these diseases. ³⁶ This strongly indicated the existence of a subset of T cells with a protective, or suppressive, function. ³⁶

The crucial breakthrough came in 1995, when Sakaguchi identified a specific marker on the surface of these suppressive T cells. ^{3, 5, 20} He discovered that a small fraction of a type of T cell known as CD4+ T cells, which were typically considered "helper" cells that activate immune responses, also expressed a protein called CD25. ^{7, 20} When he depleted these CD4+CD25+ T cells from a population of T cells before transferring them into mice, the protective effect was lost, and the mice developed autoimmune diseases. ³⁸ Conversely, transferring the purified CD4+CD25+ T cells alone was sufficient to prevent autoimmunity. ³⁸ This provided compelling evidence for the existence of a distinct lineage of T cells with a dedicated regulatory function, which came to be known as regulatory T cells, or Tregs. ^{7, 20} Sakaguchi's discovery, however, was initially met with resistance from the scientific community, as it ran counter to the prevailing understanding of immune regulation. ^{3, 20}

The Genetic Key: Brunkow and Ramsdell's Crucial Finding

While Sakaguchi had identified the cellular player in peripheral tolerance, the genetic and molecular mechanisms governing the development and function of these regulatory T cells remained unknown. The next critical piece of the puzzle would emerge from the work of two American scientists, Mary E. Brunkow and Fred Ramsdell, who were working at the biotech company Celltech Chiroscience in Bothell, Washington. ² Their research focused on a particular strain of mice known as "scurfy" mice. ^{2, 7} These mice suffered from a severe and fatal autoimmune-like disorder characterised by an overactive immune system, leading to widespread inflammation and tissue damage. ⁹

Brunkow and Ramsdell hypothesised that the scurfy phenotype was caused by a mutation in a single gene. ² Given that the disorder was inherited in an X-linked manner, they knew the responsible gene was located on the X chromosome. ^{4, 7} Using the genetic technologies available in the late 1990s, they embarked on a painstaking search for this elusive gene. ⁴ In 2001, their perseverance paid off. They identified a previously unknown gene that was mutated in the scurfy mice. ^{3, 4, 5, 23} They named the gene Foxp3, as it belonged to a family of transcription factors known as the forkhead box, or FOX, proteins. ^{4, 36} Transcription factors are proteins that control the expression of other genes, essentially acting as master switches for cellular development and function. ^{15, 17}

Their discovery did not stop there. Brunkow and Ramsdell also recognised the striking similarities between the symptoms of the scurfy mice and a rare and severe human autoimmune disease called IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked). ^{2, 4, 12} Collaborating with paediatricians, they obtained samples from boys affected by IPEX and found that they too had mutations in the human equivalent of the Foxp3 gene. ^{2, 4} This was a landmark finding, directly linking a single gene to a devastating human autoimmune disease and providing a powerful new tool for understanding the genetic basis of immune regulation. ^{2, 4, 11}

Connecting the Dots: The Unification of a New Field

The discoveries by Sakaguchi and the team of Brunkow and Ramsdell were initially independent lines of investigation. However, it soon became clear that their findings were two sides of the same coin. The scurfy mice, lacking a functional Foxp3 gene, were essentially a naturally occurring model of what happens in the absence of regulatory T cells. The scientific community quickly began to connect the dots.

In 2003, Shimon Sakaguchi provided the definitive link. ^{3, 5, 20} He demonstrated that the Foxp3 gene is the master regulator for the development and function of the CD4+CD25+ regulatory T cells he had identified years earlier. ^{3, 4, 36} The expression of Foxp3 is both necessary and sufficient to endow T cells with their suppressive capabilities. ^{12, 17} This discovery unified the field of peripheral tolerance, providing a clear molecular basis for the existence and function of regulatory T cells. ^{3, 20} The identification of Foxp3 as the key transcription factor for Tregs was a watershed moment in immunology. ⁹ It provided a specific and reliable marker for these cells, which had previously been difficult to distinguish from other T cell populations. ⁶ This enabled researchers around the world to study Tregs in much greater detail, leading to an explosion of research into their biology and their role in a wide range of diseases.

The Intricate Workings of Regulatory T Cells

Regulatory T cells are now understood to be a critical component of a healthy immune system, acting as a crucial "self-check" to prevent excessive or misdirected immune responses. ^{6, 13} They are a subpopulation of T cells that actively suppress the activation and proliferation of other immune cells, including the effector T cells that are responsible for attacking pathogens and infected cells. ^{6, 10, 12} This suppressive function is essential for maintaining immune homeostasis, the steady state of the immune system. ^{10, 13}

Tregs employ a variety of mechanisms to exert their suppressive effects. ¹³ They can produce inhibitory signalling molecules, known as cytokines, such as transforming growth factor-beta (TGF-β) and interleukin-10 (IL-10). ^{6, 12} These cytokines can directly inhibit the activity of other immune cells. Tregs can also act through cell-to-cell contact, interacting directly with effector T cells and dendritic cells, which are key activators of the immune response. ⁶ Furthermore, they can compete with other T cells for essential growth factors, effectively starving them of the signals they need to proliferate. ¹²

There are different types of regulatory T cells. Those that develop in the thymus are known as natural Tregs (nTregs), and they are crucial for maintaining tolerance to the body's own tissues from birth. ^{12, 13} Other Tregs, known as adaptive or induced Tregs (iTregs), can develop outside the thymus in the peripheral tissues. ¹² These cells are thought to play a role in controlling immune responses to foreign but harmless substances, such as commensal bacteria in the gut and certain food antigens. The discovery of Foxp3 provided a molecular handle to dissect these intricate mechanisms. ¹⁵ It is now known that Foxp3 controls a whole network of genes that are essential for the suppressive function of Tregs. ¹⁵

Therapeutic Horizons: Harnessing the Power of Tregs

The fundamental knowledge gained from the discoveries of Brunkow, Ramsdell, and Sakaguchi has profound implications for medicine. ² Their work has opened up entirely new avenues for the treatment of a wide range of diseases where the immune system plays a central role. ^{2, 5, 22, 28} The ability to manipulate the number and function of regulatory T cells offers the potential to either boost or dampen immune responses, depending on the clinical need. ¹

In the context of autoimmune diseases, where the immune system is overactive and attacks the body's own tissues, the goal is to enhance the function of Tregs. ^{1, 2} Researchers are exploring several strategies to achieve this. One approach involves the administration of low doses of interleukin-2 (IL-2), a cytokine that promotes the growth and survival of Tregs. ³⁶ Another promising strategy is adoptive cell therapy, where Tregs are isolated from a patient's blood, expanded to large numbers in the laboratory, and then re-infused back into the patient. ^{16, 33, 41} This approach has shown promise in early clinical trials for conditions such as type 1 diabetes, lupus, and in preventing the rejection of transplanted organs. ^{1, 16, 33}

Conversely, in the treatment of cancer, the aim is often to reduce the number or suppressive activity of Tregs. ^{2, 26} Tumours can attract and accumulate large numbers of Tregs, which create an immunosuppressive microenvironment that shields the cancer cells from attack by the immune system. ^{2, 6, 36} By depleting or inhibiting Tregs within the tumour, it may be possible to unleash the body's own anti-tumour immune response. ^{2, 36} Several therapeutic agents that target Tregs are currently being investigated in clinical trials for various types of cancer. ²

The field of organ transplantation also stands to benefit significantly from a deeper understanding of Tregs. ^{1, 33} One of the major challenges in transplantation is preventing the recipient's immune system from rejecting the foreign organ. Current treatments rely on broad-spectrum immunosuppressive drugs, which can have serious side effects, including an increased risk of infections and cancer. ^{8, 33} Therapies that specifically enhance the function of Tregs could offer a more targeted and safer way to induce tolerance to the transplanted organ, potentially reducing or even eliminating the need for long-term immunosuppression. ^{33, 41}

The Laureates and Their Enduring Legacy

The 2025 Nobel Prize in Physiology or Medicine recognises the distinct yet complementary contributions of three scientists whose work converged to create a new paradigm in immunology. Shimon Sakaguchi, born in 1951 in Japan, earned his M.D. and Ph.D. from Kyoto University and is currently a Distinguished Professor at the Immunology Frontier Research Center at Osaka University. ^{2, 22, 29, 37} His persistent and insightful research laid the cellular foundation for the field of peripheral tolerance. ^{3, 5}

Mary E. Brunkow, born in 1961 in the United States, received her Ph.D. from Princeton University and is a Senior Program Manager at the Institute for Systems Biology in Seattle. ^{2, 9, 19, 22} Fred Ramsdell, born in 1960 in the United States, obtained his Ph.D. from the University of California, Los Angeles, and is a Scientific Advisor at Sonoma Biotherapeutics in San Francisco. ^{2, 4, 11, 19, 22, 34} Their collaborative work provided the crucial genetic link that unlocked the molecular secrets of regulatory T cells. ^{4, 11, 14}

The discoveries of Brunkow, Ramsdell, and Sakaguchi have not only answered a fundamental question about how the immune system maintains its delicate balance but have also provided a powerful conceptual framework for understanding and treating a vast array of human diseases. Their work has spawned a vibrant and rapidly evolving field of research, with scientists around the world now working to translate these fundamental insights into new and effective therapies. ^{2, 4, 5, 28} The hope is that in the coming years, the ability to precisely modulate the activity of regulatory T cells will lead to cures or long-term remission for many debilitating conditions that currently have limited treatment options. ^{2, 21}

Conclusion

The awarding of the 2025 Nobel Prize in Physiology or Medicine to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi is a testament to the power of fundamental, curiosity-driven research to transform our understanding of human biology and open up new avenues for improving human health. Their collective discoveries have unravelled the intricate mechanisms of peripheral immune tolerance, revealing the critical role of regulatory T cells and the master gene, Foxp3, that controls them. This work has not only solved a long-standing immunological puzzle but has also laid the scientific groundwork for a new generation of immunotherapies. As clinical trials based on their discoveries continue to progress, the legacy of these three laureates will undoubtedly be felt by patients for many years to come, offering new hope for the treatment of autoimmune diseases, cancer, and a host of other conditions where the immune system plays a pivotal role. Their research has fundamentally changed the way we view the immune system, not just as a weapon against disease, but as a finely tuned orchestra that requires skilled conductors to maintain harmony within the body.