Nobel Prize in Physiology/Medicine 2025: Peripheral Immune Tolerance

The immune system is one of the more complex systems of the human body, consisting of organs, such as the spleen and thymus, numerous types of cells and over 1,500 proteins. What differentiates the immune system from other systems is that it has to decide what is a foreign body and what is not – in other words, what is “self” and what is “non-self”.

Attacking the Wrong Target

For decades, scientists have known that this delicate balancing act can sometimes malfunction and attack the body’s own cells, giving rise to autoimmune diseases. In the 1970s, Richard K. Gershon and his team demonstrated that suppressor T cells can control immune responses, and may sometimes tolerate particular antigens, such as viruses or tumors.

Breakthroughs After a Quiet Phase

Despite these advances, the field entered a quiet phase, waiting for the important developments in molecular biology techniques to move forward. In 1995, Shimon Sakaguchi at the Tsukuba Life Science Center in Japan, found that T cells with the activation marker CD25+ protected mice from autoimmune diseases, down-regulating the immune response.

Over time, suppressor T cells became known as regulatory T cells (Tregs). Some of these cells develop in the thymus, where central immune tolerance takes place. Other T cells originate in secondary lymphoid organs, such as lymph nodes and the spleen, which constitute peripheral immune tolerance.

Several years after Sakaguchi’s discovery, Fred Ramsdell and Mary E. Brunkow, both working in the biotherapeutics industry, proved that scurfy, a lethal autoimmune disease in mice, is caused by a mutation in the Foxp3 gene. Afterwards, they found that IPEX syndrome, a human genetic disease of the immune system, is also caused by this mutation. Foxp3 is now known to be the main regulatory gene that controls the development of Tregs.

“We must continue working on our research with the hope that it can be applied in the clinic,” said Sakaguchi soon after learning he had won the Nobel Prize. Fred Ramsdell echoed this thought: “Now, you can turn this discovery from the year 2000 into an actual drug.”

This Nobel Prize emphasizes that Nobel Prize-worthy work flourishes in both academia and biotech companies. “Biotech brings together people from different skillsets who are incredibly good at what they do,” said Ramsdell.

“It’s amazing how much the science has changed,” said Brunkow, highlighting the work-intensive quest to find the exact mouse mutation responsible for the immune defect.

The discoveries are decades old, and the Nobel Prize winners were taken completely by surprise when they learned that they were this year’s recipients. They did the research “thinking it was important, but not knowing exactly how,” said Ramsdell. Yet another example of the value of basic science.