Every day, the immune system performs a delicate balancing act, defending you from thousands of disease-causing pathogens and preserving your body’s own healthy cells. This careful balance is so perfect that most people don’t think about it until something goes wrong.
Autoimmune diseases like type 1 diabetes, lupus, and rheumatoid arthritis are harsh reminders of what happens when the immune system mistakes its own cells for threats it needs to attack. But how does your immune system distinguish between “me” and “not me”?
The 2025 Nobel Prize in Physiology or Medicine honors three scientists, Shimon Sakaguchi, Mary Brunkow and Fred Ramsdell, whose groundbreaking discoveries revealed how your immune system maintains this delicate balance. His work on two key components of immune tolerance, regulatory T cells and the FOXP3 gene, transformed the way researchers like me understand the immune system, opening new doors for the treatment of autoimmune diseases and cancer.
How immune tolerance works
While the immune system is designed to recognize and eliminate foreign invaders such as viruses and bacteria, it must also avoid attacking the body’s own tissues. This concept is called self-tolerance.
For decades, scientists thought that self-tolerance was established primarily in parts of the body that produce immune cells, such as the thymus for T cells and the bone marrow for B cells. There, newly created immune cells that attack the “self” are eliminated during development through a process called central tolerance.
However, some of these self-reactive immune cells escape this elimination process and are released to the rest of the body. Sakaguchi’s 1995 discovery of a new class of immune cells, called regulatory T cells, or Tregs, revealed another layer of protection: peripheral tolerance. These cells act as security guards for the immune system, patrolling the body and suppressing rogue immune responses that could lead to autoimmunity.
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While Sakaguchi identified the cells, Brunkow and Ramsdell discovered the molecular key that controls them in 2001. They found that mutations in a gene called FOXP3 caused a fatal autoimmune disorder in mice. They later showed that similar mutations in humans lead to immune dysregulation and a rare and severe autoimmune disease called IPEX syndrome, short for immunodysregulation polyendocrinopathy enteropathy X-linked syndrome. This disease is the result of a lack or malfunction of regulatory T cells.
In 2003, Sakaguchi confirmed that FOXP3 is essential for the development of regulatory T cells. FOXP3 encodes a type of protein called a transcription factor, which means it helps activate the genes needed for regulatory T cells to develop and function. Without this protein, these cells do not form or suppress harmful immune responses.
Harnessing the immune system for medicine
Regulatory T cells can be heroes or villains, depending on the context. When regulatory T cells don’t work, it can lead to disease. A failure in immune tolerance can result in autoimmune diseases, where the immune system attacks healthy tissues. By contrast, in cancer, regulatory T cells may be too effective at suppressing immune responses that might otherwise destroy tumors.
Understanding how FOXP3 and regulatory T cells work launched a new era in immunotherapies that harness the immune system to treat autoimmune diseases and cancer. For autoimmune diseases such as rheumatoid arthritis and type 1 diabetes, researchers are exploring ways to increase the function of Tregs. For cancer, the goal is to inhibit Tregs, allowing the immune system to target tumors more aggressively.
Beyond disease treatment, this research may also improve organ transplantation, where immunological tolerance is crucial to preventing rejection. Scientists are exploring how to engineer or expand Tregs to help the body accept transplanted tissues long-term.
Continuing to uncover the secrets of immune regulation may help lead to a future where the immune system can be fine-tuned like a thermostat, whether to slow it down in autoimmunity or rev it up against cancer.
The 2025 Nobel Prize reminds us that science, at its best, not only explains the world, but changes lives.
*Aimee Pugh Bernard is an associate professor of Immunology and Microbiology at the University of Colorado Anschutz Medical Campus.
This article was originally published on The Conversation/Reuters
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