The human immune system is like a powerful army, but how can we distinguish between friend and foe and avoid attacking our own tissues? This puzzle that has plagued the scientific community for decades has been solved by the discovery of three scientists.

On October 6, 2025, Beijing time, the Nobel Prize in Physiology or Medicine was awarded to American scientists Mary Brunko, Fred Lamsdale, and Japanese scientist Shigefumi Sakaguchi for their groundbreaking discoveries in the mechanism of peripheral immune tolerance.

On October 6, 2025 Beijing time, American scientists Mary Brunko and Fred Lamsdale, as well as Japanese scientist Shigefumi Sakaguchi, were awarded the Nobel Prize in Physiology or Medicine for their groundbreaking discoveries in peripheral immune tolerance mechanisms.

01 Immunological Puzzle

The human immune system is a masterpiece of evolution, protecting us from thousands of viruses, bacteria, and other microorganisms every day. Without an immune system, we cannot survive.

One of the miracles of the immune system is its ability to recognize pathogens and distinguish them from its own cells. The microorganisms that threaten our health do not have a unified appearance - they come in various shapes, and some have even evolved to resemble human cells as a disguise.

So, how does the immune system determine what to attack and what to protect? Why doesn't it frequently attack our own bodies?

02 Break the norm

Researchers have long believed that the answer lies in "central immune tolerance": that is, T cells undergo screening during maturation to eliminate cells that recognize their own tissues.

In the 1980s, Shigefumi Sakaguchi from the Aichi Cancer Center in Japan put forward a different view from the mainstream. His inspiration came from an earlier experiment where researchers removed the thymus of newborn mice and found that their immune systems were overactive and out of control.

Subsequently, Sakaguchi injected mature T cells from healthy mice into thymus removed mice and found that the mice's autoimmune diseases were cured. This result convinced him that there must be some kind of "security" role played by the immune system.

03 Discovered 'Security Guard'

It took more than ten years for Sakaguchi Zhiwen to find this' security guard '. In 1995, he introduced a new category of T cells to the world in the Journal of Immunology: cells that can calm the immune system, expressing not only CD4 but also CD25.

This newly discovered type of T cell is named regulatory T cells. However, many researchers at the time were still skeptical of its existence - they hoped to see more conclusive evidence.

The key clues subsequently came from Mary E. Brunko and Fred Ramsdell, and the prologue to this scene began with the birth of a group of frail and sickly male mice in a laboratory in the United States in the 1940s.

04 Gene Key

At Oak Ridge National Laboratory in Tennessee, researchers accidentally discovered during radiation impact studies that some male mice were born with scaly skin, extremely enlarged spleens and lymph nodes, and could only survive for a few weeks.

In the 1990s, with further development of molecular biology tools, Blenko and Ramsdell studied mouse models susceptible to multi organ autoimmune diseases.

After unremitting efforts, they finally found the mutated genes of these diseased mice. Their paper published in the British journal Nature Genetics in 2001 pointed out that mutations in the homologous gene FOXP3 of this gene in the human body can cause a rare autoimmune disease.

05 Perfect Connection

Two years later, Shigefumi Sakaguchi linked these findings and demonstrated that FOXP3 is the main regulatory gene for T cell development and function. Mice lacking Foxp3 are unable to produce functional regulatory T cells and rapidly develop systemic autoimmune responses.

This association study not only establishes the molecular basis of regulatory T cells, but also marks the entry of this field into the stage of functional and mechanistic system analysis.

Nowadays, regulatory T cells have been recognized as the core regulators of immune homeostasis. They are like a "patrol team" in the body, continuously monitoring the activity of other immune cells to ensure accurate and moderate immune responses, avoiding accidental damage to normal tissues.

06 Revolutionary Applications

The discoveries of Brunko, Ramsdell, and Tomonobu Sakaguchi have opened up the important field of "peripheral immune tolerance". The award committee stated that their findings have propelled the development of cancer and autoimmune disease treatments.

Currently, over 200 related studies are in the clinical trial stage. Autoimmune diseases, including type 1 diabetes, rheumatoid arthritis and multiple sclerosis, affect about one tenth of the world's population.

British immunologist Samantha Bucket told Nature that without these preliminary findings and the entire field pioneered by these individuals, 'we would never have come to the point where we can talk about a range of treatments for autoimmune diseases'.

These findings also bring new hope for improving the success rate of organ transplantation. The therapy based on regulatory T cells is being actively explored to treat autoimmune diseases such as type 1 diabetes and rheumatoid arthritis, and is expected to lead to more successful organ transplantation.

The stories of Brunko, Ramsdell, and Tomonobu Sakaguchi remind us that scientific progress often stems from the courage to challenge conventional thinking.

Sakaguchi Zhiwen persisted on a path that no one expected for more than ten years, and eventually discovered the "safety guard" of the immune system.

Brunko and Ramsdell found key genes that cause immune "rebellion" in a group of sick mice.

Regulatory T cells not only explain why humans do not commonly suffer from severe autoimmune diseases, but also open up a new path for future medicine - those autoimmune diseases that were once incurable may usher in new treatment methods in the near future.