Dipak Kurmi
The 2025 Nobel Prize in Physiology or Medicine has been awarded to three scientists whose work has fundamentally altered our understanding of the human immune system. Japanese immunologist Shimon Sakaguchi and American researchers Mary E. Brunkow and Frederick Ramsdell were jointly honoured “for their discoveries on peripheral immune tolerance,” a phrase that, in its scientific precision, conceals the profound implications of their work. Their discoveries revealed how the body’s immune system distinguishes between friend and foe — how it can wage war on invading pathogens while maintaining peace with its own cells. The implications of their findings now extend across medicine, from autoimmune disease therapies to organ transplantation and cancer treatment.
The immune system is a paradox of perfection. It can identify and neutralise an astonishing variety of microbial invaders — bacteria, viruses, and parasites — with unmatched precision. Yet, in this power lies danger. An immune system that attacks too aggressively risks destroying the very organism it is meant to protect. For decades, biologists struggled to understand how the body avoided turning its own defences against itself. It was known that within the thymus — a small organ nestled behind the sternum — developing T cells were tested, and those that reacted to the body’s own tissues were eliminated. This process, known as central tolerance, was believed to be the principal safeguard against autoimmunity. But it was an incomplete explanation. Some potentially self-reactive T cells still slipped through this screening, and the question remained: What stopped them from attacking?
It was Shimon Sakaguchi who dared to look beyond the accepted dogma. In the 1980s and 1990s, while many researchers were convinced that immune self-control was entirely dictated within the thymus, Sakaguchi proposed a radical idea — that a separate class of immune cells must exist to regulate and suppress excessive immune reactions. His hypothesis ran counter to prevailing scientific opinion. In 1995, after years of meticulous experimentation, Sakaguchi presented compelling evidence for what he called regulatory T cells — specialised “peacekeeping” T cells that prevent other T cells from launching attacks on the body’s own tissues.
Sakaguchi’s experiments were elegant in their simplicity yet profound in consequence. He removed the thymus from newborn mice, expecting that without it, their immune systems would be weakened. Instead, he observed the opposite: the mice developed severe autoimmune disorders. Their immune systems, unrestrained, began attacking their own organs. When Sakaguchi injected T cells from healthy mice into the afflicted ones, the autoimmune reactions subsided. It was the first clear proof that some T cells act not as attackers but as regulators — guardians that ensure balance within the immune system. He had uncovered the biological basis of what is now called peripheral tolerance — the mechanism by which the immune system maintains peace after its central education in the thymus.
However, the scientific community remained skeptical. Earlier claims about suppressor T cells had collapsed under poor evidence, and many dismissed Sakaguchi’s findings as another false lead. It would take the work of two American researchers, Mary Brunkow and Frederick Ramsdell, to provide the genetic evidence that vindicated Sakaguchi’s theory and completed the picture.
Working in the 1990s at the biotechnology company Celltech Chiroscience, Brunkow and Ramsdell were studying a mysterious strain of mice known as scurfy mice. These animals, with flaky skin and shortened lifespans, suffered from devastating autoimmune diseases that mirrored certain rare human disorders. Scientists had long suspected a genetic defect but had failed to identify its source. Brunkow and Ramsdell undertook a painstaking investigation, narrowing their search through half a million nucleotides of mouse DNA. Eventually, they traced the defect to a single gene — FOXP3. Mutations in this gene were responsible not only for the autoimmune symptoms in scurfy mice but also for a rare human condition called IPEX (Immune Dysregulation, Polyendocrinopathy, and Enteropathy, X-linked syndrome).
Their discovery, published in 2001, proved to be the missing key to Sakaguchi’s puzzle. Within two years, Sakaguchi and others demonstrated that the FOXP3 gene was the master regulator responsible for the development and function of regulatory T cells. It was FOXP3 that endowed these cells with their ability to suppress excessive immune responses. The combined work of these three scientists revealed, at last, the full mechanism of immune self-tolerance — not merely how the body eliminates self-reactive cells but how it keeps them in check throughout life.
The implications of these discoveries have been revolutionary. In autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, and multiple sclerosis, the body’s immune system mistakenly turns its weaponry inward. Understanding how regulatory T cells function has opened up possibilities for treatments that could restore balance to these overactive immune systems. Researchers are now exploring ways to boost or introduce regulatory T cells to calm such autoimmune attacks. Early trials are examining whether engineering a patient’s own T cells to become regulatory can prevent organ rejection after transplantation — a long-standing medical challenge.
But the same mechanism that protects the body from self-attack can also become a shield for its enemies. In the context of cancer, many tumours attract regulatory T cells to their surroundings. These cells, doing what they were designed to do, suppress immune activity in the tumour’s vicinity, effectively protecting cancerous cells from being destroyed. As Dr. Hasmukh Jain of Tata Memorial Hospital explains, tumours “use these regulatory T cells as bodyguards” against the immune system’s assault. Modern cancer immunotherapies, such as checkpoint inhibitors and CAR-T cell therapies, aim to overcome this problem by dampening the influence of regulatory T cells or reprogramming them. By understanding the dual nature of these cells — both protective and potentially obstructive — scientists can design therapies that strike the right balance between immunity and tolerance.
In this way, the discoveries of Sakaguchi, Brunkow, and Ramsdell have bridged two previously disconnected medical frontiers: autoimmunity and oncology. Their work explains why therapies that unleash the immune system to fight cancer sometimes cause dangerous autoimmune side effects. It has also offered a roadmap for designing safer, more effective treatments that respect the immune system’s delicate equilibrium.
The Nobel Committee’s recognition of this research carries symbolic weight beyond its scientific importance. It represents a triumph of perseverance and collaboration across continents and decades. Sakaguchi’s initial discovery in Japan, met with skepticism and isolation, found its vindication in the genetic laboratories of American scientists who had never set out to confirm his work. Yet, through independent lines of inquiry, their findings converged — a testament to how science advances not through isolated brilliance but through shared pursuit.
Today, Shimon Sakaguchi continues his work at Osaka University, still probing the mysteries of immune regulation. Mary Brunkow, now at the Institute for Systems Biology in Seattle, and Frederick Ramsdell, working with Sonoma Biotherapeutics in San Francisco, are leaders in translating immunological insights into therapeutic realities. Their careers have not merely added to our understanding of biology; they have reshaped the very foundations of modern medicine.
The 2025 Nobel Prize also arrives at a poignant moment in scientific history. It marks a century of immunology’s evolution from an observational science into a precise and programmable field. The discovery of regulatory T cells and the FOXP3 gene reflects a broader shift toward understanding the immune system not just as a weapon but as a network of negotiations — one where peacekeeping is as vital as combat. This perspective is already changing how researchers think about everything from vaccine development to allergy treatment and organ transplantation.
In clinical practice, the principles of immune tolerance are beginning to shape therapies in tangible ways. Trials are underway to harness regulatory T cells to prevent graft-versus-host disease in bone marrow transplants, and to treat conditions like lupus and multiple sclerosis by rebalancing the immune system rather than simply suppressing it. The dream of precision immunotherapy — where doctors can dial immune responses up or down as needed — owes much to the discoveries honoured by this year’s Nobel Prize.
When Alfred Nobel envisioned his prizes as rewards for discoveries that “confer the greatest benefit to humankind,” he could scarcely have imagined how aptly this year’s laureates would embody that spirit. Their work touches the very core of what makes us resilient: the capacity of our bodies to defend without self-destruction, to remember without misfiring, to fight and yet to heal.
The story of Sakaguchi, Brunkow, and Ramsdell is, ultimately, a story about balance — not only within the immune system but within science itself. It is about persistence in the face of doubt, about the merging of molecular biology with human health, and about how the smallest cellular mechanisms can have the largest consequences for life.
In a world still reeling from pandemics and autoimmune crises, their discoveries remind us that the answers to the most profound medical challenges often lie within our own bodies, waiting to be understood. The immune system, once viewed as a chaotic army of microscopic soldiers, now appears as an orchestra guided by intricate harmonies and quiet regulators. And thanks to these three scientists — the guardians of balance within us all — humanity has learned to listen to the symphony with new understanding.
(the writer can be reached at dipakkurmiglpltd@gmail.com)
