The separate but related research of Japanese immunologist Shimon Sakaguchi and American immunologists Mary Brunkow and Fred Ramsdell uncovered the complex mechanisms that enable the body to learn internal restraint. Their specific discoveries on peripheral immune tolerance expanded the understanding of how the immune system keeps track of what to attack and what to defend. Hence, for this accomplishment, the Nobel Assembly at the Karolinska Institute awarded them the 2025 Nobel Prize in Physiology or Medicine.
An Overview of Peripheral Immune Tolerance
The immune system knows when to fight and when to hold its fire. It balances fierce defense with careful restraint to protect the body from both external invaders and self-inflicted or autoimmune damage.
Peripheral immune tolerance is a mechanism that enables the immune system to know when to stand down. It ensures that immune cells, trained to detect and destroy invaders or malignant elements, do not mistakenly attack the body itself. This finely tuned restraint prevents unnecessary inflammation and protects vital organs from autoimmune assault.
This is also considered the second branch of immune tolerance. The first branch is called the central immune tolerance. Both function to ensure that the body maintains a state of unresponsiveness to substances or tissues that would otherwise trigger an immune response. Peripheral tolerance takes place in the immune periphery within primary lymphoid organs.
However, unlike central tolerance, which eliminates self-reactive cells during early development within the thymus and bone marrow, peripheral tolerance acts later throughout the body and in lymph nodes. It specifically functions as a crucial second checkpoint by silencing or regulating immune cells that escape initial screening but could still cause harm.
This regulation occurs through several mechanisms. Some self-reactive cells become inactive through a process called anergy. Others are removed through programmed cell death. Note that specialized immune cells called regulatory T cells actively suppress harmful immune reactions to maintain the balance between defense and self-preservation.
From Hypotheses to Nobel Triumph
A once-controversial idea about immune suppression and the overall immune system evolved into groundbreaking and Nobel-celebrated revelations of biological control through the works of modern immunologists.
The modern understanding of immune tolerance can be traced back to the mid-20th century when scientists questioned how the body avoids attacking itself. Pioneers such as Frank Macfarlane Burnet and Peter Medawar proposed that immune cells learn to distinguish self from non-self. This shaped modern immunology and earned them global recognition.
Researchers believed for decades that this process occurred exclusively in central organs like the thymus and bone marrow. However, as experimental models advanced, scientists observed that some self-reactive immune cells escaped early elimination. This made them wonder what prevents these potentially harmful cells from triggering autoimmunity.
New evidence emerged during the 1970s and 1980s. These suggested that suppression rather than deletion could maintain immune balance. Some proposed the existence of special cells that dampen excessive immune activity. This idea was initially controversial, as the immune system was then viewed mainly as an attacking force, not one capable of self-restraint.
The work of Shimon Sakaguchi in the mid-1990s provided a clearer picture. He identified a unique population of CD$+ T cells expressing CD25 surface markers that could prevent autoimmune reactions. His studies found that these cells were essential for keeping immune responses in check. This confirmed that suppression is an active and organized process.
Mary Brunkow and Fred Ramsdell, meanwhile, were investigating an autoimmune disorder in mice known as the scurfy phenotype in the early 2000s. This led to the discovery of the FOXP3 gene. This master regulator was essential for the development and function of regulatory T cells and was later linked to the severe human disease known as IPEX syndrome.
The connection between FOXP3 and the regulatory T cells provided the missing molecular link in understanding peripheral immune tolerance. The findings of Sakaguchi, Brunkow, and Ramsdell established how the immune system maintains balance after its cells mature and leave central organs. These revealed that tolerance is a highly controlled biological program.
In 2025, Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi were awarded the Nobel Prize in Physiology or Medicine for these transformative discoveries. Their combined work redefined the concept of immune self-control, offering new paths for treating autoimmune diseases, improving transplant success, and refining cancer immunotherapies worldwide.
Importance and Implication of the Discoveries
How discoveries in immune restraint transformed the understanding of immune function, while providing clinical applications for dealing with various autoimmune conditions and even certain forms of cancer.
The discovery of peripheral immune tolerance reshaped the scientific understanding of how the body maintains internal harmony. It revealed that the immune system does more than defend against infection; it also moderates its own reactions. This insight bridged decades of unanswered questions about why most people avoid autoimmune diseases.
Moreover, by identifying regulatory T cells and the FOXP3 gene, researchers uncovered the molecular foundation of immune restraint. This knowledge explained why certain genetic defects cause severe autoimmune disorders. It also provided the first blueprint for manipulating immune tolerance in medical treatments for a wide range of human diseases.
The discoveries influence therapies for autoimmune conditions such as type 1 diabetes, rheumatoid arthritis, and multiple sclerosis. Scientists are now exploring how boosting regulatory T cells might reduce inflammation, while selectively limiting them could strengthen anti-tumor immunity in cancer therapy. The possibilities are transformative and far-reaching.
Furthermore, beyond clinical applications, a deeper understanding of immune tolerance indicates that survival depends on balance rather than aggression. The immune system is not a reckless army but a disciplined force governed by internal restraint. Understanding that principle opens the door to designing interventions for maximizing health outcomes.
FURTHER READINGS AND REFERENCES
- Bennett, C. L., Christie, J., Ramsdell, F., Brunkow, M. E., Ferguson, P. J., Whitesell, L., Kelly, T. E., Saulsbury, F. T., Chance, P. F., and Ochs, H. D. 2001. “The immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked Syndrome (IPEX) is Caused by Mutations of FOXP3.” Nature Genetic 27(1): 20-21. DOI: 10.1038/83713
- Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., and Toda, M. (1995). “Immunologic Self-Tolerance Maintained by Activated T cells Expressing IL-2 Receptor Alpha-Chains. Breakdown of a Single Mechanism of Self-tolerance Causes Various Autoimmune Diseases.” The Journal of Immunology. 155(3): 1151-1164. DOI: 4049/jimmunol.155.3.1151