2025 Nobel Prize in Physiology or Medicine: Pioneering Discoveries in Immune Tolerance and Regulatory T Cells

Award Recipients and Their Research

The Nobel Prize in Physiology or Medicine 2025 was awarded jointly to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their pioneering discoveries concerning peripheral immune tolerance, specifically the identification and understanding of regulatory T cells and their role in preventing the immune system from attacking the body’s own tissues. This breakthrough fundamentally reshaped immunology and opened new avenues for treating autoimmune diseases, cancer, and improving transplantation outcomes.

Brief Background of Each Laureate

• Mary E. Brunkow is an American molecular biologist and immunologist at the Institute for Systems Biology in Seattle. She co-identified the FOXP3 gene’s role in immune tolerance, an essential contribution to regulatory T cell biology.
• Fred Ramsdell, also American, works at Sonoma Bio therapeutics in San Francisco. His research further elucidated the genetic mechanisms underlying peripheral immune tolerance alongside Brunkow.
• Shimon Sakaguchi, a distinguished Japanese immunologist and professor affiliated with Osaka University, made the seminal discovery of regulatory T cells, fundamentally changing the understanding of immune tolerance.

Basic Idea: Immune Tolerance

Our immune system is designed to attack harmful invaders like viruses and bacteria. But it must avoid attacking the body’s own cells a concept known as immune tolerance. Failure of this leads to autoimmune diseases.

Before Their Work

Scientists knew the immune system destroys dangerous or malfunctioning immune cells during development (in the thymus), but they noticed that it wasn’t enough to explain how self-tolerance is maintained in the body’s periphery (outside the thymus).

Sakaguchi’s Discovery (1995)

In 1995, while working at the Aichi Cancer Center Research Institute in Nagoya, Japan, Shimon Sakaguchi made a landmark discovery. His research identified a previously unknown subtype of T cells, now called regulatory T cells (Tregs) that play a crucial role in preventing the immune system from attacking the body’s own tissues.

During the early 1980s, scientists observed that removing the thymus gland from newborn mice led to unexpected autoimmune diseases, with the immune system attacking multiple organs. This phenomenon puzzled researchers because the thymus was believed to mainly produce T cells but not regulate immune tolerance beyond eliminating self-reactive T cells (a process called central tolerance).

Sakaguchi was inspired by these findings and hypothesized that the immune system must have an additional mechanism beyond central tolerance that actively suppresses autoimmune reactions. This would require a specialized class of T cells acting as “security guards” to keep immune responses in check.

Experimental Approach

To test this idea, Sakaguchi isolated T cells from genetically identical (syngeneic) mice and transferred them into thymectomized mice lacking a thymus. He observed that transferring a particular subset of T cells could prevent the development of autoimmune diseases in those thymectomized mice. This indicated that some T cells suppress the autoimmune reactions.

Using cell surface markers, he focused on CD4+ T cells (helper T cells) and discovered that within this population, the subset expressing an additional marker called CD25 could prevent autoimmune disease development. This was a critical breakthrough because it identified a distinct immunosuppressive T cell type characterized by CD4 and CD25 markers.

Key Findings Published in 1995

Sakaguchi published his findings in The Journal of Immunology in 1995, demonstrating that:

CD4+CD25+ T cells actively suppress other immune cells that cause autoimmune disease.

Mice deprived of CD25+ T cells develop severe autoimmune disorders.

This discovery re-established the concept of suppressor (regulatory) T cells, which had been previously controversial and nearly abandoned.

Genetic Basis by Brunkow and Ramsdell

Mary Brunkow and Fred Ramsdell made critical advances in understanding the molecular basis of regulatory T cell (Treg) development and function by identifying the key role of the FOXP3 gene. FOXP3 encodes a transcription factor that acts as a “master switch” for Tregs, crucial for their formation and immune-regulating activity.

Discovery of FOXP3’s Role

Brunkow and Ramsdell discovered that mutations in the FOXP3 gene lead to a failure in Treg development, causing severe autoimmune diseases in both mice (scurfy phenotype) and humans (IPEX syndrome). This showed that without FOXP3, Tregs cannot develop properly or maintain their suppressive functions, leading to unchecked immune attacks on the body’s own tissues.

Implications of the Research

These discoveries explained why our immune system usually does not attack the body’s own tissues, solving a fundamental question about immune function and tolerance. The identification of regulatory T cells and the FOXP3 gene opened new fields in immunology, aiding the development of therapies for autoimmune diseases, cancer immunotherapy, and strategies to reduce transplantation rejection. Clinical trials are underway for treatments inspired by these findings, aiming to cure or alleviate conditions caused by immune dysregulation.

Summary

The 2025 Nobel Prize in Physiology or Medicine celebrates groundbreaking discoveries central to our understanding of how the immune system protects the body while preventing self-harm. These findings have revolutionized immunology, promising transformative advances in the treatment of autoimmune disorders, cancer, and transplant medicine, marking a major stride in medical science and patient care.