In 2006, immunologist and 2025 Nobel laureate Shimon Sakaguchi co-authored a paper. Scientific American now it seems prophetic. In a story called “Peacemakers of the immune systemSakaguchi traced the timeline of the important research that led to his discovery of an elusive type of immune cell that he called regulatory T cells.
In the 1980s, the field largely dismissed the existence of this class of cells, but Sakaguchi and others have shown that regulatory T cells, or Tregs, are essential peacekeepers that prevent the immune system from overreacting and causing harm to the body itself. This process, known as peripheral immune tolerance, prevents the body's main defense mechanism from going into self-destruction mode called autoimmunity.
Sakaguchi's experiments, cataloged in Scientific American almost 20 years ago there were recognized last week at the 2025 Nobel Prize ceremony in Stockholm, where he and immunologists Mary E. Brunkow and Fred Ramsdell shared the Physiology or Medicine Prize for their discoveries.
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“I didn’t expect this and, of course, I was very happy,” says Sakaguchi. “I'm delighted to receive this honor. But at the same time, I really appreciate the community of scientists who worked together. Progress in this field is truly the result of the collective efforts of many scientists and immunologists.”
In an exclusive interview Scientific American met with Sakaguchi on October 7 Eastern Time, the day after the award was announced. He discussed the important discoveries that have led to the discovery of regulatory T cells and clinical trials that use these cells to potentially treat chronic infections, cancer, and autoimmune diseases.
[An edited transcript of the interview follows.]
What was your path in finding cells that suppress the immune system? What attracted you to them?
I was very interested autoimmune diseases because our immune system usually protects our cells from invading germs – viruses and bacteria – but sometimes it is aggressive and destroys the cells of our body and causes autoimmune diseases such as rheumatoid arthritis and type 1 diabetes. So the immune system has two aspects: good and bad. What mechanism is behind this? If we can understand this mechanism, we may be able to treat autoimmune diseases – or vice versa: force the immune system to attack abnormal cells, such as cancer cells, that arise in our body.
This was my interest when I was in medical school and then became a researcher solving this mystery. At this time [in the 1980s]the only available approach to study autoimmunity was a mouse model. I discovered that newborn mice, if the thymus gland is removed, [an organ in the chest that produces various types of T cells], they spontaneously develop autoimmune diseases. And here's what was interesting: if you inoculate mice without a thymus with normal T cells from uninfected adult mice, you can prevent the development of the disease – this means that in the normal collection of T cells in the thymus there must be some cells that can prevent or suppress the development of the disease. This was the beginning of my research career.
What convinced you of the existence of regulatory T cells when others rejected the theory?
I was convinced that autoimmune diseases like [how they can arise] in humans, can be produced in healthy animals simply by manipulating the immune system – removing certain T cells. This has always been a very solid thing for me. If other hypotheses or other ideas could explain what we saw, I would follow that concept or idea. I always compared what I believed in and what [other theories] showed which of them had the best explanatory abilities. Our results were not so bad, but even better, and this is the reason why I continued his research on regulatory T cells.
This is really the key question of modern immunology: how can we recognize or understand why the immune system does not respond to ourselves?
In 2006 you wrote an article for Scientific American called “Peacemakers of the Immune System.” How did you come up with the name of the “peacekeepers” cells?
This was invented by my colleague and co-author of this article Zoltan Fehervary – now he is the editor of the magazine. Nature. Then we talked about how we could name them and make them more understandable. And then an idea came to his mind: “peacemaker.” It was a really good name because later we gradually realized that regulatory T cells not only have immunosuppressive effects, but also have various other functions, such as promoting tissue repair. So they are peacemakers in many matters.
Essentially, in the article you documented how important this work was almost two decades ago. Did you think then that your research would be awarded the Nobel Prize?
I didn't actually do that. I really hoped that we could better understand immunological autotolerance. This is a long-standing and important question in immunology. Even the 1960 Nobel Prizes were awarded Peter Medawar And Frank McFarlane Burnetwhich showed that immune tolerance is acquired and not innate. Well, that's really interesting, but how does it happen? There have been several theories, including clonal deletion: removal of dangerous self-reactive clones [of T cells]. They are eliminated when they are immature and produced by the immune system. But this cannot explain how common autoimmune diseases such as type 1 diabetes or rheumatoid arthritis occur. So this is really the key question of modern immunology: how can we recognize or understand why the immune system does not respond to ourselves?
Are there any treatments or applications of your work that are close to making it to the clinic?
What's interesting about regulatory T cells is that they specialize in immune suppression, which means that if you enhance their function or increase their number, it could be a good way to treat autoimmunity, allergies, or various diseases. On the other hand, if the number of these cells is reduced or their function is weakened, the immune response may increase. So it may be beneficial for cancer immunity. We are developing in both directions, our team and many others. There are so many trials going on—at the time of the Nobel Prize announcement, the chairman told us that there are over 200 clinical trials going on.
Our approach is a little complicated. In the area of cancer immunity, we are studying how to improve the effectiveness of current cancer immunotherapies. For example, current immune checkpoint blockade [a type of therapy that uses lab-made antibodies, or inhibitors, that block signals so the immune response can attack cancer cells] may be 20 to 30 percent effective and incurable. So our idea is that regulatory T cells are indeed abundant in cancer tissue and suppress effective antitumor immune responses. How to remove them from tumor tissue? Antibodies can be developed to remove Tregs. We could combine this with current immune checkpoint blockade and perhaps make cancer immunotherapy more effective.
Thinking about the future, we could develop an oral small molecule drug that could have a similar effect to molecular antibodies against Tregs. [molecules that are typically delivered intravenously in most trials]. Then we will be able to improve cancer immunotherapy not only in developed but also in developing countries.
You mentioned that this could be the basis for cancer treatment. What about infections that suppress the immune system, such as HIV/AIDS?
Thus, enhancing the immune response may be beneficial not only in tumor immunity, but also in chronic infection. We still don't know if this will work, but if increasing the immune response can be achieved by reducing the number of Tregs, I think this is one idea for fighting chronic infections.
What advice would you like to give to aspiring scientists?
This may be a common question, but what really matters is this: if you're interested in something, science or anything else, then pursue it and keep working at it. Your interests may change over the course of your studies or through your efforts, but you will find something in the world around you. Someday you will realize that you are now doing something different, more exciting than what you were originally doing. Today you are expected to do something very, very quickly and get results. But it always takes time to achieve something important.
