Discovering the Immune System’s Balancing Act

The laureates Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi uncovered a crucial process in our immune system: it’s not only actively fighting infections but also features a suppressive side to prevent overreactions.

This discovery answered one of immunology’s most persistent questions: How does the immune system kill without destroying us?

This question is important because about 5–8% of the world’s population is assumed to suffer from autoimmune diseases.

It was known that autoreactive immune cells are eliminated right after generation. However, it was unclear how the rest of our immune system would be tamed – especially after an infection was over, or when immune cells encountered the ever-present bacteria inside us.

> The recipients found that specialized cells, called regulatory T cells (Tregs), actively suppress immune activation.

However, the path to this discovery led through irradiated animals, extensive genetic mapping, and even the pursuit of cells that turned out not to exist.

Here is why this discovery is so special and how it was made:

A Shift in How We Saw the Immune System

For decades, immunology emphasized attack – antibodies, immune cells, and inflammatory signaling.

Especially antibodies received a lot of attention.

They became the central focus of immunology in the 20th century because they were detectable, measurable in blood, and could be directly applied in medicine – from transfusions to organ transplants and later diagnostics and therapies.

The B-cell puzzle

After several genetic studies, it became clear that B cells generate countless different antibodies through a genetic process called V(D)J recombination, which mixes and matches gene segments to create millions of unique antibody receptors.

This randomness explained how our immune system could recognize virtually any pathogen – but it also raised a paradox:

If this process is random, why doesn’t it constantly produce antibodies that attack our own tissues?

Central vs. Unknown Tolerance

What scientists soon discovered was what we now call central tolerance.

This mechanism operates primarily in the thymus, where newly formed T cells are tested against the body’s own antigens. If they recognize these “self” molecules too strongly, they are destroyed – a process called negative selection.

But this system isn’t perfect – and that’s where the problem begins.

Some potentially self-reactive T cells escape deletion in the thymus and circulate in the bloodstream. Moreover, why was it that some patients had overshooting immune responses while others didn’t?

A Wrong Idea

In the 1970s, scientists proposed the existence of “suppressor T cells,” based on experiments showing that certain immune cells could inhibit immune responses.

But the evidence was inconsistent, the methods were unreliable, and researchers lacked molecular markers to distinguish these cells from other T-cell types.

Even worse, genetic studies later revealed that the supposed mouse gene linked to suppression (the “I-J locus”) didn’t actually exist.

As a result, the concept of suppressor T cells was abandoned, and the field of immune suppression fell into scientific disrepute for nearly two decades.

The First Nobel Breakthrough

It wasn’t until Shimon Sakaguchi advanced how we think about immune regulation in 1995.

He identified a distinct population of CD4⁺ T cells expressing CD25, the α-chain of the IL-2 receptor.

When these CD25⁺ cells were removed from mice, the animals developed multiple autoimmune diseases affecting organs like the thyroid, pancreas, and stomach.

When the same cells were reintroduced, autoimmunity was prevented.

This provided clear evidence that suppressive T cells existed – and that they were essential for preventing self-destruction.

A Rodent’s Contribution

The next breakthrough came from an unexpected source – a mouse first observed in the 1940s at the U.S. Department of Energy’s Oak Ridge National Laboratory, during radiation studies from the Manhattan Project.

This mutant, nicknamed the scurfy mouse, developed a severe, systemic autoimmune disease that proved fatal in males.

Decades later, in the late 1990s, Mary Brunkow and Fred Ramsdell decided to uncover the genetic cause behind this strange immune malfunction.

After genetic mapping, they discovered a two-base-pair insertion mutation in a previously unknown gene on the X chromosome. They named it Forkhead box P3 (FOXP3) because it resembled other transcription factors with “forkhead” DNA-binding domains.

The Molecular Key

They could also show that patients suffering from a rare, often fatal autoimmune disorder known as IPEX syndrome had mutations in the human FOXP3 gene – mirroring the scurfy mouse’s disease.

Soon thereafter, Sakaguchi’s team made the connection: FOXP3 is the master transcription factor that defines and controls regulatory T cells. When they introduced FOXP3 into normal T cells, those cells acquired suppressive functions – they had become Tregs.

This was the final piece of the puzzle.

Peripheral tolerance, the counterpart to central tolerance and broader immune regulation in processes such as microbe elimination or wound healing, depends on FOXP3+ regulatory T cells.

The Mechanism of Control

Regulatory T cells act as the immune system’s “brakes” through several complementary mechanisms:

• Release of inhibitory cytokines like IL-10, TGF-β, and IL-35.
• Induction of cytolysis in other cells.

• Starving effector T cells by consuming IL-2, depriving them of a growth signal.

Several other mechanisms, such as cell–cell contact with dendritic cells or the release of adenosine, might contribute to their functions as well.

Why the Discovery Was Nobel-Worthy

The combined discoveries provided the missing molecular and cellular foundation for understanding immune self-control.

This work didn’t just explain immune tolerance – it redefined it. It connected basic immunology, genetic discovery, and clinical pathology into a unified framework that now drives new therapeutic strategies.

Ever since then, Tregs have become fundamental in immunological research and teaching.

Today, more than 200 clinical trials are exploring ways to modulate Tregs – from expanding them to treat autoimmune diseases, to selectively disabling them in cancer therapy.

Why Did the Nobel Prize Go To…

Building Truly Versatile Materials

The 2025 Nobel Prize in Chemistry was awarded to Susumu Kitagawa, Richard Robson, and Omar M. Yaghi for developing metal–organic frameworks (MOFs) – materials that combine metals and organic molecules into highly ordered, porous structures.

MOFs are like molecular scaffolds: they have rigid frameworks with vast internal surface areas where gases such as carbon dioxide or hydrogen but also ions, and larger molecules can be stored or react.

Roald Hoffmann once said, “In two or three dimensions, it’s a synthetic wasteland.” The laureates changed that. Here is how:

The Birth of Predictable Frameworks

Richard Robson was among the first to show that one could build extended crystalline networks with precision rather than luck.

In 1989, he assembled copper ions and rigid organic molecules into a diamond-like 3D structure with open cavities – a feat previously deemed impossible by many scientists.

From Fragile to Functional

Susumu Kitagawa advanced this concept in the 1990s by creating frameworks that could adsorb and release gases like oxygen, nitrogen, and methane without losing structure.

Kitagawa also introduced the idea of “soft porous crystals” – frameworks that can shift their shape in response to temperature, pressure, or guest molecules.

This concept redefined solids as dynamic, responsive materials rather than fixed lattices.

The Game Changer: MOF-5

Meanwhile, Omar Yaghi took the field to new heights. In 1999, his group created MOF-5, a zinc-based framework with enormous pores and record-breaking surface area – almost 3,000 m² per gram.

Yaghi then formalized the field through the concept of reticular chemistry – the deliberate linking of building blocks into predesigned networks.

This systematic approach allowed chemists to vary linkers, pore sizes, and functions, leading to families of “isoreticular” MOFs with shared structures but different properties.

Why MOFs Matter

MOFs are now central to materials chemistry because of their unparalleled tunability:

• Their internal surface areas can exceed 10,000 m² per gram.
• Their pore sizes can be customized to trap specific molecules – from hydrogen to greenhouse gases to toxins.
• They can act as catalysts, filters, gas reservoirs, or drug carriers.

Today, MOFs are being developed for carbon capture, clean hydrogen storage, pollutant removal, and even water harvesting in deserts. More than 90,000 MOF structures are now known, and industrial-scale production is already underway.

By making it possible to predict, design, and build porous crystalline materials atom by atom, Kitagawa, Robson, and Yaghi changed how chemists think about matter itself, revealing that even solids can breathe, flex, and adapt.

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Written by Patrick Penndorf
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