Taming The Immune System: The Nobel-Winning Story of Regulatory T Cells

The immune system faces a paradox: it must recognize dangerous invaders while carefully sparing the body it protects. This is not an enviable job. Pathogens evolve quickly to hide in plain sight, and the immune system, like an airport security officer on a busy day, must determine who deserves a thorough search and who should simply be allowed to proceed. 

Mistakes either way — attacking the self or missing a threat — come at a steep price. To thrive, the immune system relies on several layers of checks and balances. One of these crucial layers is the regulatory T cell. 

This year’s Nobel Prize in Physiology or Medicine  celebrates not merely a group of scientists’  discovery, but the gene that makes these cells tick. Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi won the prize for their contributions to our understanding of peripheral immune tolerance that prevents the immune system from harming the body. 

“Their discoveries have been decisive for our understanding of how the immune system functions and why we do not all develop serious autoimmune diseases,” said Olle Kämpe, chair of the Nobel Committee, in a press release.

This year’s Nobel Prize honors not just a discovery but a long, winding journey — one with missteps, resilience and, ultimately, a transformation in how we understand the immune system’s most delicate decision: knowing when to act and when to stand down.

It all began in 1945 when Ray Owen, a young postdoctoral researcher at the University of Wisconsin, made a curious observation. Fraternal twin calves, whose blood supplies mixed during gestation, tolerated each other’s blood types without mounting an immune attack. Surprising, since normally a mismatched blood type would invoke a furious immune response. 

Around the same time, Australian immunologist Sir Frank Macfarlane Burnet proposed that anything the body encounters during embryonic development becomes marked as “self,” while anything introduced later is treated as foreign. 

In Production of Antibodies, co-written with Frank Fenner, Burnet predicted that introducing genetically distinct cells in early development might teach lifelong tolerance. This prediction was confirmed by another group of scientists who showed that mice injected with donor spleen cells in utero or shortly after birth later accepted grafts from those donors while rejecting grafts from unrelated mice. 

But the story was not so tidy: not all early-life transplants produced tolerance, leaving scientists with a mix of elegant results and equally elegant confusion.

The discovery of Autoimmune Regulator (AIRE) — a gene and protein crucial for central immune tolerance, specifically in the thymus gland, identified through patients with a rare autoimmune syndrome — deepened scientific understanding. 

AIRE enables specialized thymic epithelial cells to display a broad range of self-antigens. Newly generated T cells encounter this molecular “dress rehearsal,” and those that react strongly are removed. It is a rigorous audition where the thymus rejection rates are higher than NIH study sections. 

Early evidence suggested that some T cells could dampen immune responses, but the field lacked clear markers, and the proposed genetic locus, I-J, stubbornly refused to exist. 

With no molecular handle and results contradicting one another, the idea faded — becoming immunology’s version of a “lost treasure map.” Yet certain experimental findings hinted that something real was hiding in the noise.

That “something” took shape in the hands of Shimon Sakaguchi, then a young immunologist working in Nishizuka’s laboratory. In 1995, Sakaguchi discovered a previously unknown class of immune cells, which protect the body from autoimmune diseases.

The other major chapter of this story begins at Oak Ridge National Laboratory, a facility with roots in the Manhattan Project. There, scientists studying mouse genetics discovered a spontaneous mutation called “scurfy.” 

The name sounds like a minor pirate, but the phenotype was anything but whimsical: affected male mice developed catastrophic autoimmunity. Don’t worry you didn’t miss it, it wasn’t mentioned in Oppenheimer. 

Because the mutation killed males but spared carrier females, it clearly lay on the X chromosome. Mary Brunkow and Fred Ramsdell at Cell Chiroscience in Bothell, Washington, set out to identify the gene. 

Through painstaking positional cloning — they would never describe the process as quick or glamorous — they narrowed the responsible region to a two-base-pair insertion causing premature termination of a gene they named Foxp3.

In 2001, Brunkow and Ramsdell showed the connection between  IPEX syndrome — a devastating autoimmune disease in young boys — and mutations in the human version of FOXP3. 

Two years after this, Sakaguchi was able to link these discoveries. He proved that the Foxp3 gene governs the development of the cells he identified in 1995. These cells, now known as regulatory T cells, monitor other immune cells and ensure that our immune system tolerates our own tissues.

Paul Ehrlich famously described autoimmunity — the immune system attacking its host — as horror autotoxicus. Anyone living with autoimmune disease will confirm that this is no exaggeration. 

Fortunately, regulatory T-cell research is now translating into therapy. Engineered regulatory T cells are being tested for autoimmune diseases, and Sonoma Biotherapeutics, a San Francisco-based company co-founded by Ramsdell, recently reported promising safety data in a trial for rheumatoid arthritis. 

After only a few decades, the field is finally seeing the clinical fruits of its persistence.

At UCSF, work on regulatory T cells continues at full throttle, with the first human clinical trial using regulatory T cells to treat type 1 diabetes among the accomplishments.

Progress in science is rarely linear. The history of regulatory T cells is full of detours, false starts, rediscoveries and moments of deep skepticism. Early work on suppressor cells cast a long shadow; even the editor handling Sakaguchi’s 1995 paper was hesitant, wary of repeating past mistakes. Yet the truth endured, sharpened by evidence from academia and industry alike.