Three winners of the 2025 Nobel Prize in Physiology or Medicine

On October 6, Swedish Caroline School of Medicine announced the awarding of the 2025 Nobel Prize in Physiology or Medicine to scientists Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi, in recognition of their research contributions to outer immunological tolerance.

Their breakthrough research work solved a paradox in the field of immunology: Why doesn't the human body's extremely powerful defense system "defect" to attack itself? According to a press release issued by official website of the Nobel Committee, the collective work of the three winners has identified a special type of immune cells, which are like "peace-keeping forces" in the body and actively suppress autoimmune attacks. Such cells are now called regulatory T cells (Tregs). Their research finally discovered the "master switch" gene that controls the development and function of these key cells-Foxp3.

As Ole Kemp, chairman of the Nobel Prize Committee, said: "Their findings are decisive for our understanding of how the immune system works and why not all of us suffer from serious autoimmune diseases".

A long-standing problem:

Who is constraining the "dangerous molecules" of the immune system?

The human body¡¯s immune system protects us every day from the damage of thousands of microbes trying to invade. In order to this function, the immune system produces a large number of T cells, the receptors of which are randomly combined to identify almost unlimited external threats.

For a long time, the scientific community has believed that the immune system solves this problem mainly through a mechanism called "central tolerance." The theory holds that in the thymus, an organ, T cells that overreact to their own proteins will be screened and eliminated during the maturation process. However, this screening process is not perfect, and there will always be "dangerous elements" who will escape. The work of the three winners revealed a more complex regulatory mechanism of the immune system, a second line of defense that exists outside the thymus, called "peripheral immune tolerance."

Three award-winning scientists discovered that the key perpetrators of this line of defense are a class of previously unknown immune cells, which the Nobel Prize Committee described as the ¡°safe guard¡± of the immune system.The cells, the ¡°regulatory T cells,¡± function to prevent other immune cells from attacking the body¡¯s own tissue, therebyining immune balance.

The first scientific breakthrough:

Ûà¿ÚÖ¾ÎÄ and his reverse exploration.

Japanese scientist Shifumi Sakaguchi was fascinated by the "contradictory nature" of the immune system in his early years: it can both cure and harm. When he returned to Japan from the United States in the early 1990s, he chose a path that directly challenged the scientific consensus of the time. He was attracted by a hypothesis that was "the most unpopular" among immunologists at the time: that dangerous, self-responsive T cells persisted in healthy people, controlled by some inhibitory force.

The Nobel Committee pointed out in the background introduction that Sakaguchi was "reverse up" at the time. An abnormal experimental observation confirmed his belief that when the chest glands of newborn mice were removed, their immune system did not only not weaken, but instead went out of control, triggering a number of serious autoimmune diseases. This convinced him that the chest glands not only produced "warrior" T cells, but also produced some sort of "guard" cells to maintain order.

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After more than a decade of work, Sakamoto Zhiwon published his milestone paper in 1995. He demonstrated by a sophisticated experiment that a small portion of the T cells containing both CD4 and CD25 proteins on the surface were key to immunosuppression. When he removed these cells from the body of healthy mice, mice suffered from severe autoimmune diseases; and when he transferred these cells back into the body of mice, the disease was stopped. He found a ¡°safe guard¡± in his mind and named it ¡°regulatory T cells¡±.

Scientific breakthrough:

Brunko and Ramsder found the "switch"

While Shifumi Sakaguchi is struggling, a different scientific research path is unfolding in the United States. Brenco, a molecular biologist, and Ramsdell, an immunologist, were working to find drug targets for autoimmune diseases.

Their attention was attracted by a strange experimental mouse called ¡°scurfy.¡± The mouse was caused by a gene defect on the X chromosome, which led to massive uncontrolled proliferation of T cells and attacks their own organs. The two realized that this might be the perfect model for studying human own immune disease. They inferred that if the mutant gene that caused the disease could be found, it would provide ¡°decisive insights¡± to understand the cause of the disease.

In 2020, Sakaku Shivun won the Paul Erlich and Ludwig Dammstein Prize

In an era when gene sequencing technology was far less developed than it is today, looking for a gene mutation, as described in Nobel background information, was "like looking for a needle in a huge haystack." They narrowed the location of the mutation to a region on the mouse X chromosome that contains about 500,000 DNA base pairs. Within this region, they identified 20 potential genes. They reportedly discovered the fatal mutation when they examined the 20th and last candidate gene.

In 2001, the two men published this major discovery and named the previously unknown gene Foxp3. Crucially, they linked the discovery to a rare human genetic disease, IPEX syndrome. The symptoms of the disease are strikingly similar to those in scurfy mice and are also associated with the X chromosome. It was finally confirmed that it was a mutation in the human Foxp3 gene that caused IPEX syndrome. They identified a key genetic switch that regulates the immune system.

The third scientific breakthrough:

The two halves of a puzzle merge and the complete picture is finally presented

The two discoveries in 1995 and 2001 seemed to be the same half of a puzzle.Sakata Chvin found a ¡°peacekeeping force¡± cell without knowing the instructions behind it; Blanco and Ramsdale found a ¡°master control switch¡± gene, but did not fully understand its exact role in the immune system.

Eventually, in 2003, Sakamoto Zhiwon linked these two separate discoveries. He proved that the Foxp3 gene discovered by Branko and Ramsdale regulates the ¡°master gene¡± that regulates the development and function of T cells, which he discovered in 1995.

The Nobel Committee said in a statement that ¡°their findings lay the foundation for new fields of research and promoted the development of new therapies for cancers and autoimmune diseases, for example.¡±

Treatment of autoimmune diseases (supporting peacekeeping forces): In diseases such as arthritis, type 1 diabetes, the immune system is overactive. The treatment goal is to increase the emphasis on the strength of the T-cell (Tregs) to restore order. Currently, therapies are available to be treated by extending the patient's own Tregs back into the transistors.

2. Cancer immunotherapy (disarming the guards): Crafty cancer cells use this peacekeeping system to protect themselves. Many tumors actively recruit Tleaves to form a "protective shield" around them, preventing the immune system from attacking. Therefore, the goal of treatment is the opposite of the first: temporarily weaken or remove Trigs around the tumor,"disarming the guards" and allowing the immune system to attack cancer cells.

3. Organ transplantation (strengthening goodwill welcome): By harnessing the power of Tregs, it is expected to "teach" the immune system to tolerate transplanted organs, thereby reducing dependence on potent immunosuppressive drugs.

Currently, a variety of therapies based on the above principles are undergoing clinical trials.

The three winners will be awarded a prize of 11 million Swedish crowns (approximately $1.2 million).Their work has not only changed human perception of the immune system, but also brought new hope for dealing with a variety of immune-related diseases.

Red Star News reporter Deng Shuyi

Edited by Jan.

Inspection is high.