James' World 2

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In 2006, immunologist and 2025 Nobel prize winner Shimon Sakaguchi co-wrote an article in Scientific American that now feels prophetic. In the story, entitled “Peacekeepers of the Immune System,” Sakaguchi traced a time line of important studies that led to his discovery of an elusive type of immune cell he called regulatory T cells.

In the 1980s, the field had largely dismissed the existence of such a class of cells, but Sakaguchi and other scientists proved that regulatory T cells, or Tregs, are the integral “peacekeepers” that prevent the immune system from overreacting and harming the body itself. That process, known as peripheral immune tolerance, stops the body’s primary defense mechanism from entering self-destruct mode, called autoimmunity.

The experiments Sakaguchi cataloged in Scientific American nearly 20 years ago were recognized last week at the 2025 Nobel award ceremony in Stockholm, where he and immunologists Mary E. Brunkow and Fred Ramsdell shared the prize in physiology or medicine for their discoveries.

“I didn’t expect it, and of course, I was very much pleased,” Sakaguchi says. “I’m happy to have this honor. But at the same time, I really appreciate the community of scientists who have worked together. The progress of this field is really due to the collective effort of many scientists and immunologists.”

In an exclusive interview, Scientific American caught up with Sakaguchi on October 7 EDT, the day after the award announcement. He discussed the crucial findings that led to the discovery of regulatory T cells and clinical trials that harness these cells to potentially treat chronic infections, cancer, and autoimmune diseases.

What was your journey into looking for cells that suppressed the immune system? What drew you to them?

I was very much interested in autoimmune diseases because our immune system normally defends our cells from invading microbes—viruses and bacteria—but sometimes it’s aggressive and destroys our body cells and causes autoimmune diseases such as rheumatoid arthritis and type 1 diabetes. So the immune system has two aspects: good and bad. What’s the mechanism behind this? If we can understand that mechanism, we may be able to treat autoimmune diseases, or the opposite: make the immune system attack abnormal cells, such as cancer cells, arising in our body.

That was my interest when I was a student in medical school, and then I became a researcher to tackle this conundrum. At that time [in the 1980s], the only available approach to study autoimmunity was the mouse model. I happened to find that newborn mice, if you remove the thymus [an organ in the chest that produces various types of T cells], they spontaneously develop autoimmunelike diseases. And then what was interesting was: if you inoculate the thymus-free mice with normal T cells from nonaffected adult mice, you can prevent disease development—meaning that in the normal collection of T cells in the thymus, there must be some cells that can prevent or suppress disease development. That was the start of my research career.

What convinced you that regulatory T cells existed when others abandoned the theory?

I was convinced that autoimmune diseases, similar to [how they can arise] in humans, can be produced in healthy animals by just manipulating the immune system, removing certain T cells. That was always a very solid phenomenon 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 and what [other theories] showed—which one had better explanatory powers. Our results were not so bad—and were even better—so that was the reason that I continued my research on regulatory T cells. It is really a key issue in modern immunology: How can we realize or understand why the immune system does not react with ourselves?

In 2006, you wrote an article for Scientific American entitled “Peacekeepers of the Immune System.” How did you come up with the name “peacekeepers” for the cells?

That was coined by my colleague and co-author of that article, Zoltan Fehervari—he’s now an editor of Nature. At that time, we talked about how we can name them and make them more relatable. And then he came up with that idea: “peacekeeper.” It was a really nice name because, later on, we gradually realized that regulatory T cells not only are immunosuppressive but also have various other functions, such as promoting tissue repair. So they are peacekeepers for many things.

You essentially documented in the article how pivotal this work was nearly two decades ago. Did you think back then that your research would be recognized for a Nobel Prize?

Actually, I didn’t. I really hoped that we could have a better understanding of immunological self-tolerance. It’s a long-standing, important question in immunology. Even the 1960 Nobel awards were awarded to Peter Medawar and Frank Macfarlane Burnet, who showed that immune tolerance is acquired, not innate. Well, that’s really interesting, but how does it happen? There have been several theories, including clonal deletion: deleting the dangerous self-reactive clones [of T cells]. They are eliminated when they are immature and being produced in the immune system. But that couldn’t explain how usual autoimmune diseases happen—for example, type 1 diabetes or rheumatoid arthritis. So it is really a key issue in modern immunology: How can we realize or understand why the immune system does not react with ourselves?

Are there any therapies or applications of your work that are close to making it to the clinic?

What is fascinating about regulatory T cells is that they are specialized for immune suppression, and so this means that if you strengthen their functions or increase their numbers, it could be a good way to treat autoimmunity or allergies, or various diseases. On the other hand, if you reduce the number of these cells or make their function weaker, then the immune response can be enhanced. So it could be good for cancer immunity. We are pursuing both directions, our team and many others. There are many, many trials underway—at the Nobel announcement, the chairperson told us that more than 200 clinical trials are ongoing now.

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Hmmmm… So this is the land of the free!

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As the agents left, they released tear gas, apparently without warning, sending people coughing and running for cover. Among those affected by the gas were 13 Chicago Police Department officers, the police department said, and at least one officer was seen rinsing his eyes out with water from a neighbor’s garden hose.

A spokeswoman for the Department of Homeland Security said that the federal agents were conducting an immigration enforcement operation when two people tried to flee and hit the agents’ vehicle.

“This incident is not isolated and reflects a growing and dangerous trend of illegal aliens violently resisting arrest and agitators and criminals ramming cars into our law enforcement officers,” the D.H.S. said in a statement. The statement said that federal agents used “crowd control measures” after a group of people gathered and turned hostile.

It was one of many turbulent episodes to erupt in Chicago in recent days. Federal agents from Immigration and Customs Enforcement and the Border Patrol have roamed the city and suburbs, making arrests, often pulling up to people walking along sidewalks, stopping them, and questioning them.

The agents repeatedly have been observed releasing smoke bombs, tear gas, and pepper balls to disperse residents who gather or capture videos on cellphones, including when the agents were making arrests in densely populated neighborhoods. Chicago police officers, who have been called to the scenes of some clashes, have been exposed to tear gas from federal agents twice in the last two weeks.

As the intensity of the Trump administration’s immigration crackdown has risen, residents of Chicago are increasingly pushing back with fury.

In the last several weeks, Chicagoans have formed volunteer groups to monitor their neighborhoods for federal immigration agents, posting alerts on Facebook and in Signal group chats when agents are seen.

If agents are spotted on the street, motorists lean on their horns as a warning and sometimes give chase. Around the city last weekend, pairs of volunteers were seen with orange whistles around their necks, blowing the whistles at the first sight of immigration agents.

One Chicago resident, Chris Molitor, stationed himself on a street corner on the North Side on Tuesday, holding a sign denouncing President Trump and wearing a shirt critical of ICE.

“We’re seeing videos of people being abused,” said Mr. Molitor, 64, who works in hospitality, nodding in the direction of a local taqueria whose owners were questioned by ICE. “There’s got to be a pushback of some kind.”

Smoke filled the air after federal agents used tear gas during a clash with community members on the far South Side.

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The idea that a single-celled bacterium can defend itself against viruses in a similar way as the 1.8-trillion-cell human immune system is still “mind-blowing” for molecular biologist Joshua Modell of Johns Hopkins University.

Scientists discovered 20 years ago that bacteria use an adaptive defense system called CRISPR that allows microbes to recognize and destroy viral invaders on repeat encounters. In a recent study published in Cell Host & Microbe, Modell and his team have deepened our understanding of how bacteria use this system to “vaccinate” themselves against phages, the viruses that try to kill them. The findings could help the development of treatments to fight antimicrobial resistance, which contributes to millions of deaths annually.

The CRISPR system allows bacteria to edit their own genome. After being exposed to a virus, bacteria can use a special enzyme to insert small pieces of the virus’s DNA, called spacers, into their genome, which helps them recognize and fight off the virus next time. Scientists now use this enzyme as a pair of “genetic scissors” to tweak DNA in everything from lab experiments to gene therapies, but researchers still knew little about how this process plays out in bacteria. “We called it the CRISPR mystery because we didn’t really understand what was happening inside,” Modell says.

To understand how bacteria manage to grab the DNA of invading viruses, the researchers ran controlled lab experiments using Streptococcus pyogenes bacteria and the phages that infect it. During the infectious phase, most phages rupture the cell immediately, a process known as lysis. On rare occasions, they can instead hide inside the bacterial DNA and become dormant, a state called lysogeny. This state is notoriously difficult to study.

In the lab, Modell’s team infected bacteria with phages that could go dormant as well as genetically engineered phages locked in an active state. The researchers then collected surviving cells and checked their genetic code to see if they had added new spacers taken from the viruses’ DNA.

They found that bacteria only added spacers from phages that could go dormant. During this lull, Modell explains, the bacteria have time to grab tiny pieces of viral DNA and store them in their genome. “The CRISPR system makes memories against an inactivated form of the virus just like a vaccine,” Modell says. To confirm their results, Modell and his team exposed spacer-carrying bacteria to the same phages again to observe whether the new genetic memories protected them from infection. The researchers observed that the bacterium can recognize the phages using those stored fragments and fight them off.

The findings are “pretty remarkable,” says molecular biologist Stan Brouns of Delft University of Technology in the Netherlands, who was not involved in the study. Understanding the interactions between phages and bacteria is key to improving phage therapies, an approach where scientists use viruses to treat infections caused by bacteria that have developed resistance to antibiotics.

This new understanding could also help researchers design phages that more types of infection-causing bacteria will be susceptible to, says North Carolina State University molecular biologist Rodolphe Barrangou, who co-founded Locus Biosciences, a biotech company that develops antibacterial products, and who also was not involved in the study. Various bacteria can have any of more than 150 antiphage defense mechanisms that treatments have to dodge; understanding how this one works is “going to inspire people who work on [bacteria] to think about phage therapies on a broader range of infectious diseases.”

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Thomas Fuchs

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