The 2025 Nobel Prize in Physiology or Medicine has been awarded to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their groundbreaking discoveries that unveiled how the immune system avoids attacking the body’s own tissues. This is a process known as peripheral immune tolerance. Their work has transformed our understanding of immunity and laid the foundation for new treatments for autoimmune diseases, cancer, and transplant rejection.
Every day, the immune system faces a monumental task: identifying and eliminating countless invading microbes without harming the body’s own cells. But when this finely tuned balance fails, the result can be devastating autoimmune conditions such as type 1 diabetes, lupus, or multiple sclerosis.
Immune tolerance
In the mid-1990s, Professor Shimon Sakaguchi of Osaka University challenged the prevailing scientific view that immune tolerance was established solely in the thymus through a process called central tolerance. In 1995, he discovered an entirely new class of immune cells, regulatory T cells (Tregs, that act as peacekeepers within the immune system, suppressing overactive immune responses and preventing self-destruction.
Eight years later, Mary Brunkow of the Institute for Systems Biology and Fred Ramsdell of Sonoma Biotherapeutics identified the genetic key to these cells. Working with a mouse model prone to autoimmune disease, they found a mutation in the Foxp3 gene, which turned out to be crucial for the development and function of regulatory T cells. Mutations in the human version of this gene cause a rare but severe autoimmune disorder known as IPEX syndrome, confirming its essential role in maintaining immune balance.
Two years later, Sakaguchi connected these findings, demonstrating that Foxp3 controls the development of the regulatory T cells he had identified earlier. This discovery not only clarified a long-standing mystery in immunology but also revealed a powerful new target for medical innovation.
From discovery to therapy
The laureates’ work has since shaped a new field, peripheral tolerance, that explores how immune regulation extends beyond the thymus. These insights have driven major advances in immunotherapy, helping scientists design treatments that fine-tune immune responses instead of simply suppressing them.
In cancer research, therapies are now being developed to block regulatory T cells, allowing the immune system to more effectively attack tumors. In contrast, for autoimmune diseases and transplant medicine, the focus is on enhancing these cells to prevent harmful immune reactions. “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.
A legacy that reshaped modern medicine
Nearly three decades after Sakaguchi’s first experiment, the impact of these discoveries continues to grow. Multiple therapies inspired by the principles of peripheral tolerance are now in clinical trials, aiming to deliver more precise and personalized immune modulation.
By revealing how the body naturally controls its most powerful defense mechanism, Brunkow, Ramsdell, and Sakaguchi have not only solved one of immunology’s greatest puzzles but also opened new frontiers in precision immunotherapy. Thus offering hope for millions living with immune-related diseases worldwide.
