Nobel Prize for regulatory T cells
Monday, October 6, 2025 at 1:50PM A small primer on the Nobel Prize awarded to Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi today. This prize was for combining two separate fields of immunology research - genetic research on IPEX and immunology research of regulatory T cells (Tregs), with enormous impact on biology/medicine.
First, let's talk about IPEX. It is short for "Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome", which is a bit of a mouth-full. Essentially, it is a severe autoimmune disease, impacting boys (inherited only from the mother), which is fatal in early childhood unless treated. By coincidence, there was a mouse strain with the same disease and inheritance pattern called “Scurfy”, allowing it to be studied in mice.
IPEX/Scurfy was rather mysterious, but because of the inheritance pattern it was quickly mapped to the X chromosome. Several teams of scientists worked on mapping this disorder down to the gene level, with Brunkow and Ramsdell leading the teams that identified FOXP3 as the causative gene in both humans and mice, with major papers in 2001.
Completely independent of this, we had the field of regulatory T cells. There were some misleading experiments on "suppressive T cells" early on, a field which rapidly built and then collapsed in the 80s. Few of those experiments had lasting impact in the field of immunology, but an exception were the papers of Nicole Le Douarin in 1987/1988. She grafted the wing buds of quail onto embryonic chickens, which developed into chickens with quail wings, which were then rapidly rejected by the immune system. The key finding, however, was that if the proto-thymus was also transplanted the chickens kept their wings long term. Here it was quite important that the chicken was used, as it has 10-16 anatomically-separated thymic lobes and you only need to transplant one to get transplant acceptance. This means that the chicken developed a form of tolerance mediated by T cells educated in the thymus but effective in the periphery.
It was a hard and unpopular field for decades, however, with the key pioneers being Fiona Powrie and Shimon Sakaguchi. They chased up independent sets of T cells with immunosuppressive properties, using different markers on what were ultimately the same cells – regulatory T cells, potent at shutting down immune responses in multiple different assays.
It wasn’t until 2003 that regulatory T cells gained wide uptake by the immunology community. This key breakthrough happened by the linking of FOXP3, the IPEX/Scurfy gene, and regulatory T cells. Three groups, lead by Sakaguchi, Ramsdell and Sasha Rudensky, all demonstrated that FOXP3 was acting as the master transcription factor that converted regular T cells into the immunosuppressive regulatory T cells. Suddenly everyone could study Tregs and manipulate their genetics, with tool after tool coming online (such as Foxp3GFP, Foxp3Cre, Foxp3DTR – Rudensky, Tim Spawasser and Jeff Bluestone, among others). It triggered an exponential increase in papers on regulatory T cells, linking them to disease after disease.
The impact has been enormous, with regulatory T cells going from being a niche frowned-upon subset of immunology, to underpinning our entire understanding of how the immune system works. This is obvious important for diseases where we want to shut down the immune system, such as autoimmunity, allergy, transplantation and inflammatory diseases. There anything to boost the number or function of regulatory T cells could be clinically beneficial, with the therapeutic interleukin 2 (IL2) being the prototype therapy and still in clinical use today. It was also a key discovery for contexts where we want to activate the immune system, in particular in cancers, which locally recruit regulatory T cells to protect themselves from immune clearance. Treatments such as anti-CTLA4 essentially allow inflammatory T cells to bypass suppression by regulatory T cells, and have transformed the oncology space. The pre-clinical pipeline is even richer, so we can expect many more regulatory T cell-based therapies to enter the market soon!
Huge congratulations not only to the team leaders who won this prize, but all the students, technicians and expert scientists who did the work that underpins this discovery. Their work, and the work of those following in their footsteps, is changing the future for patients!
Also see a few articles where I was quoted in the Guardian and Science.
immunology 
