The average person’s understanding of their immune system often ends at knowing the body’s ability to fight infections such as the common cold. The other side of the same coin –– promoting infection tolerance of one’s own cells –– tends to be neglected. 

This is no longer the case as the 2025 Nobel Prize for Physiology or Medicine was awarded to Mary E. Brunkow and Fred Ramsdell from the United States, as well as Dr. Shimon Sakaguchi from Japan, “for their discoveries concerning peripheral immune tolerance.”

Regulatory T cells: our immune system’s built-in brakes

When our immune system detects invaders, it deploys responders, called ‘T cells,’ that attack these pathogens for removal. Unfortunately, this can result in collateral damage to our own cells. 

To alleviate this, our bodies rely on a separate population called regulatory T cells, called Tregs. True to their name, these Tregs regulate the responder T cells to minimize off-target injuries. In other words, they serve as brakes for our immune response. 

Thanks to this specialized cell group, our bodies can mount efficient attacks against foreign pathogens without incurring excessive damage to our own bodies. 

Like most major scientific discoveries, the road to these regulatory cells was paved by multiple pairs of hands over several years. 

1995: Sakaguchi going against the current 

In 1995, Dr. Sakaguchi, who was working at the Institute of Physical and Chemical Research (Riken) in Japan, reported his findings on a suppressive group of immune cells. He found that by injecting these cells into mice with autoimmune diseases, he was able to alleviate their symptoms. Autoimmune diseases occur when one’s immune cells see one’s own body as foreign and attack it, which can cause eczema, digestive issues, and diabetes.

His paper challenged the scientific consensus at the time, which rejected the existence of said suppressive cells. In fact, these cells were very much a taboo subject. 

“For decades, the prevailing dogma in the immunology community was that suppressor T cells do not exist, and scientists working on this subject were frequently shunned or sidelined,” said Dr. Stephen Juvet in an email to The Varsity. Dr. Juvet is a physician-scientist at U of T, whose research focuses on tolerance in transplantation. 

This was because scientists did not have a reliable marker — like a gene or protein — they could investigate to even identify the cells, let alone study them. Furthermore, although Sakaguchi’s report solved the marker problem, it was still difficult to convince the scientific community since he had yet to show that the same cell type existed in humans with similar biological functions. 

2001: Brunkow and Ramsdell bringing the missing pieces 

All of that changed in 2001 when Brunkow and Ramsdell came along with their work from Celltech in Washington. The two investigated the genetic defect in a strain of lab mice called ‘scurfy,’ which exhibits widespread symptoms of autoimmunity. 

Together, they isolated the responsible gene and called it Foxp3. Most importantly, they discovered that humans with the same mutation suffer a rare condition called immunodysregulation polyendocrinopathy enteropathy X-linked syndrome, or IPEX. 

Individuals with IPEX have a profoundly dysregulated immune system and are plagued with several inflammatory diseases, such as eczema, diabetes, and bowel diseases. 

2003: Sakaguchi completes the puzzle

Everything came full circle when Dr. Sakaguchi connected the puzzles two years later. In another seminal publication, he and his team demonstrated that the same Foxp3 gene was responsible for the development and function of the suppressive cell group that they previously reported on.

Finally, the once-controversial suppressor cells were very much no longer so.  

The work from Sakaguchi, Brunkow, and Ramsdell has provided convincing evidence for the existence and importance of regulatory cells with far-reaching implications. It highlights that a healthy immune system requires a balance of cells that both attack foreign bodies and suppressors that prevent that attack from turning inward.

The finding that keeps on giving 

Over the last three decades, scientists have leveraged this fact to innovate treatments for a multitude of immunological conditions. 

For example, there are several ongoing clinical trials looking at infusing regulatory cells into patients with autoimmune conditions to dampen their excessive immune response. The same strategy is also being employed for those who have undergone transplantation. It’s used to induce lasting tolerance to their new organs, since rejection is still a major issue in the field. 

One of the fields that has benefited greatly from the work of Brunkow, Ramsdell, and Sakaguchi is treatment for cancer patients. Once it was observed that tumour cells can hijack regulatory cells to suppress one’s own immune defence, researchers started to investigate ways to block these biological brakes. 

This led to the discovery of Treg inhibitors that significantly prolong survival in cancer patients. In fact, this work also received its own Nobel Prize in 2018, further illustrating the impact of regulatory cells on the public. 

This is still only the beginning. There is still a lot that is yet to be discovered about Tregs, such as how they develop and the various strategies they use to negatively regulate the immune response –– all of which are potential leads for novel treatments.