TREGulating the Immune System

Written by Michael Wen

A few weeks ago, I got a cold— a bad one. My body ached, my fever was 38.5°C, and even worse, both of my nostrils were stuffed. It was miserable, but in a strange way, also reassuring: I knew they were signs my body was hard at work attacking the invading microbes. I could only hope the microbes would surrender soon.

I felt better after a week, but one thought lingered: why didn’t my immune system attack me? With nearly 30 trillion human and 38 trillion bacterial cells living in our bodies, how do our immune systems tell human from non-human, friend from foe? ¹ 

Shimon Sakaguchi, Fred Ramsdell, and Mary Brunkow may have an answer.

On October 6, 2025, immunologists Shimon Sakaguchi and Fred Ramsdell, along with molecular biologist Mary Brunkow, received the Nobel Prize in Physiology or Medicine for uncovering how the immune system prevents itself from attacking the body. ² They identified the presence of regulatory T cells, the immune system’s own security guards, opening a new frontier in immunology.³ So what are they? Let’s set the stage. 

Act I. The Breadcrumbs

T cells are key immune fighters, divided into helper and killer types that detect and destroy infected cells.⁴ Each T cell carries unique receptors — like molecular fingerprints — capable of recognizing countless targets, including, by accident, the body’s own tissues. The question underlying this year’s Nobel Prize is then how does our body deal with this?

In the 1960s, Jacques Miller discovered that T cells mature in the thymus, where self-reactive ones are eliminated — a process called central tolerance.⁵ Yet, some still escape. This phenomenon caused researchers to believe in the existence of “suppressor T cells” that catch T cells who slipped through the central tolerance test. However, with a lack of evidence, the idea was discredited—but not for long. 

A decade later, Shimon Sakaguchi at the Aichi Cancer Center Research Institute in Nagoya, Japan revived the dismissed idea: special “suppressor” cells do exist and keep renegade T cells in check.³ He called these cells regulatory T cells or Tregs. It seemed the problem was solved but more pieces of the puzzle were to come from Mary Brunkow and Fred Ramsdell

Act II. The Missing Gene 

At a lab in Oak Ridge, Tennessee, researchers studying radiation (as part of the Manhattan Project) stumbled upon a peculiar mutation: male mice with scaly skin, enlarged organs, and short lifespans. The scientists named them “scurfy” mice, but the cause of their condition remained a mystery.

Years later, Mary Brunkow and Fred Ramsdell took on the puzzle. Tracing the defect to the X chromosome, they eventually identified a faulty gene belonging to the forkhead box (FOX) family, crucial for T cell development.⁶ They named it Foxp3. 

In 2001, their Nature Genetics paper revealed that mutations in FOXP3 cause both the scurfy mouse disorder and the human autoimmune disease IPEX.⁷ This discovery linked FOXP3 to regulatory T cells — the very cells Shimon Sakaguchi had uncovered — uniting the two strands of research.

The pieces were falling in place.

Act III. The Finale

Two years later, the Laureates and researchers worldwide concluded the FOXP3 gene acts as the master switch for the development of Tregs. These cells prevent other T cells from mistakenly attacking the body’s own tissues, maintaining what’s known as peripheral immune tolerance.³ Beyond that, Tregs help calm the immune response once an invader has been eliminated, ensuring the system doesn’t stay in overdrive and damage healthy cells.³ The puzzle is now complete. 

But, what does this mean for us? Lots, actually. This discovery not only deepens our understanding of peripheral immune tolerance, but also opens the door to new medical breakthroughs. For instance, tumor-mapping studies have shown that cancers often recruit large numbers of Tregs to shield themselves from the immune system, suggesting that disrupting this protective “Treg wall” could help the body better attack tumors.^3,8 On the other hand, boosting Treg formation may offer powerful therapies for autoimmune diseases and organ transplant rejection; molecules like interleukin-2, which support Treg growth, are already being explored as potential treatments.³

So the next time you get sick, take a moment to appreciate both the what — the Tregs silently keeping your immune system in check — and the who — the scientists who uncovered the secret. 

References

1. Sender R, Fuchs S, Milo R. Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLOS Biology [Internet]. 2016 Aug 19;14(8):e1002533. Available from: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1002533

2. Physiology in. Nobel Prize in Physiology or Medicine 2025 [Internet]. NobelPrize.org. 2018. Available from: https://www.nobelprize.org/prizes/medicine/2025/press-release/

3. Brunkow M, Ramsdell F, Sakaguchi S. They understood how the immune system is kept in check POPULAR SCIENCE BACKGROUND The Nobel Prize in Physiology or Medicine 2025 “for their discoveries concerning peripheral immune tolerance” [Internet]. Available from: https://www.nobelprize.org/uploads/2025/10/popular-medicineprize2025-2.pdf

4. Cleveland Clinic. T Cells: Types and Function [Internet]. Cleveland Clinic. Cleveland Clinic; 2023. Available from: https://my.clevelandclinic.org/health/body/24630-t-cells

‌5. WEHI History: 1966 Jacques Miller Joins the Institute as Thymus Pioneer [Internet]. WEHI. Available from: https://www.wehi.edu.au/about/history/jacques-miller/

6. Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nature Genetics [Internet]. 2001 Jan;27(1):68–73. Available from: https://www.nature.com/articles/ng0101_68

7. Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nature Genetics. 2001 Jan;27(1):18–20.

‌8.Pan Y, Zhou H, Sun Z, Zhu Y, Zhang Z, Han J, et al. Regulatory T cells in solid tumor immunotherapy: effect, mechanism and clinical application. Cell Death and Disease [Internet]. 2025 Apr 11;16(1). Available from: https://www.nature.com/articles/s41419-025-07544-w