The 2025 Nobel Prize in Physiology or Medicine has been awarded jointly to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their discoveries concerning peripheral immune tolerance, a breakthrough that has transformed understanding of how the immune system avoids attacking the body’s own tissues.
Their pioneering research uncovered the identity and genetic control of regulatory T cells, the so-called “security guards” of the immune system that prevent autoimmune attack.
“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.
The immune system must strike a delicate balance: powerful enough to destroy invading microbes, yet restrained enough to avoid damaging the body itself. Until the 1990s, scientists believed this balance was maintained mainly through a process known as central tolerance, in which self-reactive immune cells are eliminated in the thymus.
However, Shimon Sakaguchi of Osaka University challenged this view. In 1995, he described a previously unknown subset of immune cells, characterised by the surface markers CD4 and CD25, that suppress excessive immune reactions. His findings, published in The Journal of Immunology, revealed that tolerance also operates in the body’s periphery, mediated by what he named regulatory T cells.
Sakaguchi’s discovery faced early scepticism but would later prove foundational. As he continued to explore the mechanisms of immune regulation, others were unravelling the genetic basis of immune dysfunction.
In 2001, Mary E. Brunkow and Fred Ramsdell, then working at Celltech Chiroscience in Bothell, Washington, US, identified a mutation responsible for severe autoimmune disease in a long-studied strain of mice, known as scurfy. Through painstaking genetic mapping, they discovered that these mice carried defects in a previously unknown gene, which they named Foxp3.
Their Nature Genetics paper not only pinpointed the cause of the mice’s immune dysregulation but also linked mutations in the human Foxp3 gene to a rare, often fatal autoimmune disorder called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome).
Two years later, Sakaguchi demonstrated that Foxp3 is the master regulator of the same T cells he had discovered earlier, proving that the gene controls the development of regulatory T cells. This connection completed a central puzzle in immunology and established the concept of peripheral immune tolerance as a fundamental principle of immune regulation.
The Nobel Assembly, which announced this year’s prize on 6 October, noted that the laureates’ discoveries have laid the foundation for a new field of research and spurred the development of new treatments, for example for cancer and autoimmune diseases. Current clinical trials are testing therapies that either boost or suppress regulatory T cell activity. In autoimmune diseases, researchers aim to expand these cells to calm an overactive immune response, while in cancer, the goal is to limit their activity to allow immune attack against tumours.
The implications also extend to transplantation medicine, where regulatory T cells are being explored as a means to prevent organ rejection and graft-versus-host disease.
Mary E. Brunkow earned her PhD from Princeton University and is senior programme manager at the Institute for Systems Biology, Seattle, US. Fred Ramsdell received his PhD from the University of California, Los Angeles, US, and serves as scientific advisor at Sonoma Biotherapeutics, San Francisco, US. Shimon Sakaguchi is Distinguished Professor at the Immunology Frontier Research Center, Osaka University, Japan.
The three laureates will share the Nobel Prize of 11 million Swedish kronor equally.
- By Rosie Bannister, 8 October 2025