T cells and a breakthrough that reshaped immunology

The 2025 Nobel Prize in Physiology or Medicine recognises findings that redefine immunity as a dynamic balance between attack and restraint.

The immune system is a marvel. It recognises and destroys an almost infinite range of foreign and dangerous agents while sparing the body’s own cells and tissues. Failure of either task leads to disease or death. It is no wonder that more than ten Nobel Prizes in Physiology or Medicine have been awarded for discoveries in immunology.

In 1960, Sir Frank Macfarlane Burnet and Peter Brian Medawar received the prize for their discovery of acquired immunological tolerance. They showed that during embryonic life, the immune system learns to tolerate “self” – the molecules present on host cells – including any foreign cells introduced at that stage. This process, called central tolerance, occurs in the thymus, a small organ behind the breastbone that trains immune cells. It was believed to be complete within a few days of birth. Autoimmune diseases, where the immune system attacks host tissues, were therefore thought to result from an unfortunate failure of this early deletion process.

As a young researcher, Shimon Sakaguchi was fascinated by the thymus. In the 1970s, he became interested in what happened when scientists removed the thymus from newborn mice within a few days after birth. By all logic, nothing dramatic should have occurred. The thymus was assumed to have finished its work by that time. Yet the removal of the thymus in newborn mice led to a devastating autoimmune disease, with the immune system turning against host organs.

Puzzled, Sakaguchi spent years chasing the answer. Eventually, he realised the thymus did more than just eliminate harmful cells – it also produced a special group of “peacekeeper” cells that actively prevented such attacks. These regulatory T cells, or Tregs, became the focus of intense debate. The cells he described had no clear molecular identity, other than CD4 and CD25 surface markers shared with other T cells. Many immunologists dismissed them as simply activated effector T cells, not a distinct regulatory lineage.

Several senior scientists, influenced by the Nobel Prize-winning work on central tolerance, rejected the notion of active “peripheral suppression,” maintaining that immune tolerance arose solely from the deletion or inactivation of self-reactive cells. Without a defining molecular marker of Tregs, replication of research findings was difficult, and skepticism persisted for years about the existence of this new T cell population.

The missing link in Sakaguchi’s mystery came from another direction – a rare and fatal human disorder known as IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked). Infants with IPEX develop uncontrolled autoimmune inflammation that destroys the intestines, pancreas, and skin within months of birth. Their immune systems clearly lacked a vital braking mechanism, but no one knew what it was.

The answer to this puzzle came from Dr Mary Brunkow and Dr Fred Ramsdell, then working at Celltech Chiroscience, a biotechnology company near Seattle. They were studying a peculiar strain of mice that developed a similarly violent autoimmune disorder – the “scurfy” mice – whose immune systems attacked their own tissues so severely that they survived only a few weeks.

After years of painstaking work, Brunkow and Ramsdell identified the missing gene: FOXP3, a transcription factor that switches on the genetic programme for regulatory T cells. Without it, Tregs never develop. The disease in their mice turned out to be the counterpart of human IPEX syndrome, both caused by FOXP3 mutations. This discovery, published in 2001, provided the long-sought molecular proof that the cells Sakaguchi had described were indeed a distinct lineage – the body’s own peacekeeping force. FOXP3 became the defining marker of regulatory T cells and the master regulator of immune tolerance.

The implications were profound. In autoimmune disease, defective or depleted Tregs unleash the immune attack. In cancer, tumours exploit Tregs to suppress anti-tumour immunity. Understanding FOXP3 has since enabled efforts to design therapies
that either boost Tregs to restore tolerance or inhibit them to enhance tumour immunity.

A prize for inquiry,
perseverance

When the 2025 Nobel Prize in Physiology or Medicine honoured Sakaguchi, Brunkow, and Ramsdell for these discoveries, it recognised not just the solution to a decades-old mystery but also a shift in how we view immunity itself. The immune system is no longer seen as a simple on-off switch. It is a finely tuned thermostat, balancing attack and restraint every moment of life.

The story of regulatory T cells is also a lesson in scientific perseverance. For almost two decades, Sakaguchi’s findings were met with skepticism. Yet he persisted, guided by careful observation, elegant experiments, and quiet conviction. His journey reminds us that breakthroughs often emerge not from new technology alone but from challenging accepted wisdom and asking uncomfortable questions.

The field continues to advance rapidly. Researchers are now exploring how Tregs could be harnessed to treat autoimmune diseases, transplant rejection, allergies, and neuroinflammation, while others seek to block them in cancer therapy to strengthen the immune attack on tumours.

In the end, the discovery of Tregs stands as a tribute to both the elegance of the immune system and the tenacity of scientific inquiry. It shows that even the body’s fiercest defences depend on restraint and that in science, as in life, progress often begins with the courage to see what others overlook.

(The writer is Dean, BioSciences and Health Research, Trivedi School of Biosciences, Ashoka University, and Head, Koita Centre for Digital Health at Ashoka)

Disclaimer: The views expressed above are the author's own. They do not necessarily reflect the views of DH.