A delicate balance between defense and self-harm
The Nobel Prize in Physiology or Medicine 2025 honors fundamental discoveries about how the body prevents the immune system from doing harm, leading to important medical progress in autoimmune diseases and cancer.
November 21, 2025
Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi have received this year’s Nobel Prize in Medicine for discoveries about peripheral immune tolerance and the identification of its key component, the immune system’s security guards, the regulatory T cells (Tregs).
This discovery has fundamentally reshaped our understanding of immune tolerance and may open new avenues for treating autoimmune diseases.
“Our immune system deals with a delicate balancing act, it must protect us against invading pathogens with full force while avoiding attacking the body’s own tissues. The laureates discovered a fundamental mechanism that limits detrimental immune responses to “self”. Tregs are key to preventing autoimmune reactions in the body’s peripheral tissues,” explains Nils Landegren, Assistant Professor and Group Leader at the department of Medical Biochemistry and Microbiology at Uppsala University and SciLifeLab.
“The importance of this mechanism becomes tragically clear in patients who lack functional Tregs and develop severe, multi-organ autoimmune disease from early childhood. This discovery has fundamentally reshaped our understanding of immune tolerance and may open new avenues for treating autoimmune diseases,” he adds.
A new class of T cells
At the beginning of the 1980s, Professor Shimon Sakaguchi, who at the time worked at the Aichi Cancer Center Research Institute in Nagoya, Japan, set out to understand the role of the thymus in T cell development. During his experiments he found that there appeared to be T cells that could protect the mice he studied from autoimmune diseases. Sakaguchi believed that the immune system must have some form of security guard that calms down other T cells and keeps them in check. About a decade later, in 1995, he presented his results in The Journal of Immunology. The results showed that these cells are characterized by the fact that they carry both CD4 on their surface (like T helper cells), and also a protein called CD25.
“Sakaguchi discovered the suppressor function of a novel subpopulation of CD4+ T cells that suppressed CD8 cytotoxic effector T cells. He found that these interleukin-2 receptor alpha (CD25+) expressing cells prevent CD8+ cells from attacking the body’s own tissue and that they sustain peripheral tolerance,” explains Kjetil Taskén, Professor at the institute of Clinical Medicine at the University of Oslo and Head of the institute for Cancer Research at Oslo University Hospital.
“He found that such tolerance is broken if the CD25+ cells are removed, and in elegant adoptive transfer experiments he found that transferring CD4+CD25+-depleted T cells from wild type mice to mice without T cells led to serious autoimmune manifestations, whereas transfers that also included the CD4+CD25+ cells did not. These cells were named regulatory T cells (Tregs),” explains Taskén.
Scurfy mice
But the scientific community needed more evidence about these new T cells, and this was provided by the other two laureates, Mary E. Brunkow and Fred Ramsdell. It all started with a mouse strain, called scurfy, affected by studies of the consequences of radiation in the 1940s (part of the Manhattan Project and the development of the atomic bomb). Some male mice were unexpectedly born with scaley and flaky skin, and an extremely enlarged spleen and lymph glands, and they lived for just a few weeks, describes the Nobel Assembly at Karolinska Institutet. Scientists found that the mutation that caused this disease was located on the mice’s X chromosome (half of all the male mice were diseased but the females could live with this mutation).
In the 1990s, researchers found that the organs of the diseased male mice were being attacked by T cells that destroyed the tissues. At this time, Mary Brunkow and Fred Ramsdell were working at the biotech company Celltech Chiroscience in Bothell, Washington, US, developing pharmaceuticals for autoimmune diseases. They became very interested in these scurfy mice since they thought they could provide insight into how autoimmune diseases arise. The two colleagues searched for the mutant gene, and in 2001, in Nature Genetics, they were able to show that the “Scurfy” phenotype in mice with serious autoimmune disease is due to mutations in the FoxP3 gene.
“They also showed that the recessive, X-bound IPEX [Immune dysregulation, polyendocrinopathy, enteropathy X-linked] syndrome in humans that affects newborn males who develop fatal multi-organ autoimmune disease within weeks unless they have an allogeneic stem cell transplantation, is due to mutations in the FoxP3 gene,” describes Taskén.
“In 2003 Sakaguchi then showed that FoxP3 is the lineage-defining transcription factor that defines Tregs by turning on a specific gene program. These and later findings have led to the development of a whole field,” he says.
There are several mechanisms in place to maintain peripheral immune tolerance, and the findings made by this year’s laureates clearly showed that the absence of FoxP3+ Tregs is enough to break tolerance in both mouse and man.
“There are several mechanisms in place to maintain peripheral immune tolerance, and the findings made by this year’s laureates clearly showed that the absence of FoxP3+ Tregs is enough to break tolerance in both mouse and man,” adds Leo Holmgren, CEO at the Swedish biotech company TIRmed Pharma.
Nordic research on Tregs
The Nobel laureates revealed that immune tolerance is not established only in the thymus, where immune cells are first “trained”, but that there is also a crucial second layer of control in the body’s peripheral tissues, describes Landegren further. “We are now beginning to see promising developments where Tregs are being harnessed or boosted to treat autoimmune diseases,” he says.
Tregs have for example been shown to be clearly involved in a number of autoimmune diseases such as Crohn’s disease, Graves’ disease, and diabetes type I.
These findings highlight just how essential Tregs are for maintaining immune balance, particularly in the gut.
Landegren and his colleagues have also studied patients with IPEX syndrome to better understand how Tregs prevent the immune system from attacking the body’s own tissues. “We found that these patients develop strong immune responses against several tissue-specific proteins in the gut, which aligns with their severe autoimmune bowel disease. These findings highlight just how essential Tregs are for maintaining immune balance, particularly in the gut,” he explains.
In Oslo, at Taskén’s lab, work on Tregs started more than 20 years ago, after his former PhD student, Einar Martin Aandahl, did a post-doc at the Gladstone Institute in San Francisco and then came back to continue his work. “Aandahl also specialized in transplantation surgery for which Tregs and tolerance is very relevant [to diminish the risk of transplant rejection] and he later left to start a company,” he describes.
We have also established in vitro methods for how to make peripherally induced Tregs and we are using such methods in a cell-based assay to screen chemical libraries for small molecule Treg inhibitors with potential application in cancer.
Taskén and his colleagues have also discovered that human Tregs need significantly greater activation to be suppressive than mice Tregs. They have also found that activated human Tregs express COX-2 and produce prostaglandin E2 (PGE2), which suppresses effector T cells in a non-contact dependent manner, whereas other modes of suppression are contact dependent, and also that, for example in colorectal cancer, Treg-mediated suppression of anti-tumor immunity occurs with PGE2.
“More recent work has involved peripherally induced Tregs (as opposed to naturally occurring Tregs educated in the thymus) and their role in the tumor micro-environment. We have also established in vitro methods for how to make peripherally induced Tregs and we are using such methods in a cell-based assay to screen chemical libraries for small molecule Treg inhibitors with potential application in cancer,” says Taskén.
A treatment for atopic dermatitis
Although the Nobel discoveries honored this year are basic, fundamental science, there are today over 200 clinical trials involving Tregs, stated Rickard Sandberg, Associate Professor at Karolinska Institutet and Member of the Nobel Assembly at Karolinska Institutet, at the press conference after the Nobel Prize announcement – emphasizing the medical benefits on the horizon.
The drug contains the active substance TIR-01, an immunomodulatory oligonucleotide that helps re-establish immune tolerance in the skin.
One such medical benefit is TIRmed Pharma’s novel topical treatment for atopic dermatitis (eczema), designed to modulate the immune system through the induction of Tregs. The drug contains the active substance TIR-01, an immunomodulatory oligonucleotide that helps re-establish immune tolerance in the skin. The company, founded in 2018, is based on Professor Anna-Lena Spetz’s research at Stockholm University, entailing the discovery of a non-coding oligonucleotide that inhibits TLR3 activation by interfering with the uptake of ligands destined for endosomes.
“Furthermore, her group showed that the non-coding oligonucleotide modulates the differentiation of myeloid antigen-presenting cells to become tolerogenic with the capacity to reduce T helper cell activity and promote the induction of FoxP3+ Tregs,” explains Leo Holmgren, CEO, TIRmed Pharma. The company is currently setting up GMP production and finalizing the GLP toxicity studies with its oligonucleotide treatment, and aims to start phase I/II studies in 2026.
Exciting new treatments
Nils Landegren is hopeful that in the future, therapies that enhance Treg-mediated immune tolerance will become an effective way to treat a wide range of autoimmune diseases.
Both directions are incredibly exciting, and together they show how understanding immune tolerance can lead to better treatments for both autoimmune and cancer patients.
“At the same time, the opposite strategy, to inhibit Treg activity, could make cancer immunotherapies more powerful by allowing the immune system to attack tumors more effectively. Both directions are incredibly exciting, and together they show how understanding immune tolerance can lead to better treatments for both autoimmune and cancer patients,” he says.
I would expect that we will see immune therapies targeting Tregs in the future that will supplement what we have and can be combined with other treatments for immune regulation and to steer immunotherapy optimally.
“In autoimmune diseases work has focused on methods to expand and activate Tregs in vivo (with Il-2) or ex vivo to get better suppression, and genetics modifications are being exposed to correct the FoxP3 mutations that cause IPEX. Tregs may also be genetically modified in cell therapy approaches to target them or to treat rheumatic diseases. In cancer, the focus has been on depleting or inhibiting Tregs to dampen suppression and restore endogenous anti-tumor immunity,” says Kjetil Taskén.
“While no Treg therapies are available today I would expect that we will see immune therapies targeting Tregs in the future that will supplement what we have and can be combined with other treatments for immune regulation and to steer immunotherapy optimally,” he concludes.
Updated: December 7, 2025, 11:02 am
Published: November 21, 2025
