How a Japanese researcher and laboratory associated with the atomic bomb have contributed to the award -rewarded discovery with the Nobel for Medicine in 2025

The Nobel Prize for Physiology or Medicine, awarded in 2025 to researchers Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi “for their discoveries regarding peripheral immune tolerance, has a fascinating story.

“The immune system is a masterpiece of evolution. Every day, it protects us from thousands of viruses, bacteria and other microbes trying to invade our body. Without a functional immune system, we could not survive. One of the miracles Different appearance. Physiology or medicine from 2025.

For a long time, the researchers believed that they know the answer to these questions: that the immune cells mature by a process called central immune tolerance. However, it has been shown that the immune system is more complex than they thought.

The Nobel laureates for this year's medicine have identified the “guards” of the immune system – the regulatory T cells – thus laying the foundations of a new research area. Before their discoveries, scientists knew about existence:

• helping T cells, which constantly patrol the body. If it detects an invading microbe, it alerts other immune cells, which trigger the attack;
• Tsal cells, which eliminate cells infected by a virus or other pathogens. They can also attack tumor cells;
• Other types of immune cells with different functions, which do not play such an important role in regulating the immune response.

Sensors that detect invaders

All T cells have on their surface special proteins called T cell receptors. These receptors can be compared to some sensors: using them, T cells “scan” other cells to discover if the body is attacked.

The receptors of T cells are unique – like the parts of a puzzle, each has a different shape. They are built from numerous genes that combine randomly. In theory, the body could produce over 10¹⁵ different types of T cell receptors.

The huge number of T cells, each with different receptors, ensures that there is always some capable of detecting the shape of an invading microbe (including new viruses, such as the one that triggered the Covid-19 pandemic in 2019). However, inevitably, the body also creates receptors that can recognize parts of their own tissues. What, then, does T cells react to hostile microbes, but not to their own cells?

T cells that recognize their own tissues are eliminated

In the 1980s, researchers found that when T cells mature in Timus, they go through a test that eliminates those cells that recognize the body's own proteins (called endogenous). This selection process is called central tolerance.

Some researchers have suspected the existence of another type of additional cells, called suppressor T cells, which would manage the T cells that escaped the Timus test. However, some scientists in this field have drawn exaggerated conclusions from their experiments. When it turned out that some evidence was false, the suppressor T cell hypothesis was rejected, and the research area is almost abandoned.

But a researcher went against the current: Shimon Sakaguchi, who worked at Aichi Cancer Research Institute in Nagoya, Japan.

Sakaguchi's intuition: The immune system must have a guard

Sakaguchi was inspired by a previous, contradictory experiment, conducted by his colleagues. In order to understand the role of the thymus in the development of T cells, they had surgically removed the organ from newborn mice.

The hypothesis was that mice will have fewer T cells and a weaker immune system. However, if the operation was done three days after birth, the immune system was crazy – it was hyperactive, and the mice developed a wide range of autoimmune diseases.

In order to understand the phenomenon, in the early 1980s, Sakaguchi isolated T-matured T cells in genetically identical mice and injected them into mice without thymus. The result was interesting: there were T cells that could protect mice from autoimmune diseases.

These results convinced him that the immune system must have a kind of “guardian” that calms other T cells and keeps them under control. But what kind of cell was this?

Sakaguchi discovers a new class of T cells

When researchers differentiate Types of T cells, they use proteins on their surface. Auxiliary T cells are recognized by a protein called CD4, and CD8 is killed.

In the experiment in which Sakaguchi had protected mice from autoimmune diseases, he had used cells that had CD4 on the surface – ie helping cells. They usually activate the immune system. But in his experiment the system was held in the brake. Sakaguchi's conclusion: there must be different types of T cells that carry CD4.

In order to test their hypothesis, he had to find a way to differentiate them. It took more than a decade but in 1995 he presented a new class of T. in the world. In The Journal of ImmunologySakaguchi has shown that these cells – which calm the immune system – are characterized not only by the presence of CD4, but also a protein called CD25.

This new class has been called regulator t cells.

However, many researchers were skeptical and demanded additional evidence. The essential information would come from Mary Brunkow and Fred Ramsdell. This is where the second act of the Nobel 2025 prize begins: the story moves to an American laboratory founded in the 1940s, where some sick male mice were born.

A mutation causes a “rebellion” in the immune system

In a laboratory in the town of Oak Ridge in the US state Tennessee, the researchers studied the effects of radiation-part of the Manhattan project related to the development of the atomic bomb. In a line of mice, an anomaly was produced: some males were born with the skin scaly and cracked, the spleen and the very large lymph nodes, and the specimens lived only a few weeks.

This line of mice was called “shortfy”. Although the molecular genetics was just beginning, the researchers realized that the mutation that caused the disease was on chromosome X. Half of the males were affected, but the females could live with the mutation, because they had two X chromosomes, one of which contained healthy DNA. The females were transmitting the short mutation further.

In the 1990s, when the molecular instruments had become much more efficient, the researchers began to investigate why the Majoi Major Scufy were so serious. It was discovered that their organs were attacked by T cells, which destroyed the tissues. In other words, the mutation causes a “rebellion” of the immune system.

Brunkow and Ramsdell seek explanation of autoimmune diseases

The two American researchers, Mary Brunkow and Fred Ramsdell, were working on the biotechnological company Celltech Chiroscience in Bothell, Washington.

The company was developing drugs for autoimmune diseases, and Brunkow and Ramsdell have realized that Scufy mice could give them important clues. If they managed to understand the molecular mechanism of the disease, they could decipher the origin of the autoimmune diseases. So they made a crucial decision: to look for mutant genes responsible for the disease.

Today, the sequence of a mouse genome takes a few days. In the 1990s, it was as if you were looking for a needle in a hay card: the X chromosome has about 170 million pairs of bases, and identifying a mutation requires time, patience and ingenuity.

Brunkow and Ramsdell find the needle in the DNA hay car

The genetic mapping had shown that the Mutation of the Scufy was somewhere in the middle of the X chromosome. The two researchers managed to restrict the area to about 500,000 nucleotides, then mapped it in detail.

After years of thorough work, they found that the region contained 20 potential mutant genes. They compared them, one by one, between healthy and sick mice. Only in the twentieth gene they could shout “bingo”: they had found the short mutation.

The defective gene was unknown until then, but it resembled a family of genes that regulate the activity of others and influence cell development. Brunkow and Ramsdell called the new Foxp3 gene.

Discovery explains a serious illness to people

During the research, Brunkow and Ramsdell suspected that a rare autoimmune disease in humans, Ipex, also related to the X chromosome, could be the human counterfeit counterphic.

Searching in the genetic databases, they found the human equivalent of the FOXP3 gene. With the help of pediatricians around the world, they collected evidence from boys affected by Ipex. Genetic analysis confirmed: they all had harmful mutations in the Foxp3 gene.

In 2001 in the magazine Nature GeneticsMary Brunkow and Fred Ramsdell have shown that mutations in Foxp3 cause both Ipex's disease and short -faced. Their discovery triggered an effervescence in laboratories around the world. Researchers have understood that FOXP3 plays an essential role in developing regulatory cells discovered by Sakaguchi.

T cells regulating – the guards of the body

Two years later, Shimon Sakaguchi and other researchers convincingly demonstrated that the FOXP3 gene controls the development of regulating T cells. These cells prevent erroneous attacks on their own tissues – a process called peripheral immune tolerance. They also have the role of calming the immune system after eliminating an invader, so that it does not remain in maximum alert.

The fundamental knowledge obtained by discovering regulatory T cells and their role in peripheral immune tolerance have opened the way for new treatments.

Tumor mapping has shown that they can attract a large number of regulating T cells, which protect them from the immune system. The researchers are now trying to remove this “wall” of regulatory cells, so that the immune system can access and destroy tumors.

In the case of autoimmune diseases, the approach is reverse: the researchers try to stimulate the formation of regulating T cells. In pilot studies, patients receive interleukin-2, a substance that helps these cells develop. It is also tested if Interleukin-2 can prevent the rejection of organs after transplant.

There are numerous other examples in which researchers explore the use of T cells for combating diseases.

“Through their revolutionary discoveries, Mary Brunkow, Fred Ramsdell and Shimon Sakaguchi have given humanity a fundamental understanding of how the immune system is regulated and controlled. Thus, they made the greatest possible contribution to the good of humanity,” the Swedish Royal Academy stresses.