Nobel Prize in Physiology or Medicine 2025: Guardians of Immunity

The 2025 Nobel Prize in Physiology or Medicine: Decoding Immune Regulation

The immune system, a remarkable defense network, safeguards the body against countless pathogens like viruses and bacteria. However, without precise control, it risks attacking the body’s own tissues. The 2025 Nobel Prize in Physiology or Medicine honors Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their pioneering discoveries in peripheral immune tolerance, a mechanism that prevents the immune system from harming the body. Their work has established a new field of immunology and fueled innovative treatments for conditions like cancer and autoimmune diseases.

The Immune System: A Balancing Act

The immune system is a biological marvel, capable of distinguishing harmful invaders from the body’s own cells. Pathogens vary widely in structure, and some mimic human cells to evade detection. How does the immune system differentiate friend from foe, and why doesn’t it attack healthy tissues more often?

Historically, scientists attributed immune regulation to central immune tolerance, a process where T cells, critical immune players, are screened in the thymus to eliminate those that target the body’s own proteins. However, this mechanism alone proved insufficient to explain the immune system’s complexity. The 2025 Nobel laureates revealed a complementary process peripheral immune tolerance driven by regulatory T cells (Tregs), which act as the immune system’s peacekeepers.

T Cells: The Immune System’s Guardians

T cells are central to immune defense:

Helper T cells (marked by CD4 proteins) detect invaders and signal other immune cells to respond.

Killer T cells (marked by CD8 proteins) destroy infected or cancerous cells.

T cells use T-cell receptors, diverse proteins shaped by random gene combinations, potentially forming over 10^15 unique receptors. This diversity ensures T cells can recognize virtually any pathogen, including novel threats like the COVID-19 virus. However, some T cells mistakenly target the body’s own tissues, necessitating mechanisms to keep them in check.

Central vs. Peripheral Tolerance

In the 1980s, central tolerance was understood as a thymic “test” that eliminates self-reactive T cells. Some researchers hypothesized the existence of suppressor T cells to handle self-reactive T cells that escaped this filter, but flawed experiments led to skepticism, and the concept was largely abandoned.

Shimon Sakaguchi’s Breakthrough

Shimon Sakaguchi, working at the Aichi Cancer Center Research Institute in Nagoya, Japan, challenged this skepticism. Inspired by experiments showing that thymus removal in newborn mice triggered autoimmune diseases, Sakaguchi hypothesized the existence of a regulatory cell type. In the 1980s, he injected T cells from healthy mice into thymus-less mice, preventing autoimmune conditions. By 1995, in The Journal of Immunology, he identified regulatory T cells (Tregs), characterized by CD4 and CD25 proteins, which suppress harmful immune responses.

The Scurfy Mutation: A Genetic Clue

In the 1940s, researchers at Oak Ridge, Tennessee, studying radiation effects, discovered a mouse strain called scurfy. Male scurfy mice, carrying an X-chromosome mutation, suffered severe autoimmunity, with scaly skin, enlarged spleens, and early death. Females, with a second healthy X chromosome, were unaffected but passed the mutation to offspring.

In the 1990s, Mary E. Brunkow and Fred Ramsdell, at Celltech Chiroscience in Bothell, Washington, investigated this mutation to understand autoimmune diseases. Mapping the mouse X chromosome’s 170 million nucleotides, they narrowed the mutation to a 500,000-nucleotide region containing 20 genes. After meticulous analysis, they identified the defective gene, naming it Foxp3, a member of the forkhead box (FOX) gene family that regulates cell development.

Linking Foxp3 to Human Disease

Brunkow and Ramsdell suspected that the scurfy mutation mirrored IPEX syndrome, a rare human autoimmune disorder affecting boys. Analyzing patient samples, they confirmed that mutations in the human FOXP3 gene caused IPEX, paralleling the scurfy phenotype. Their 2001 Nature Genetics paper established FOXP3 as critical for immune regulation.

Regulatory T Cells and FOXP3: The Full Picture

By 2003, Sakaguchi and others demonstrated that FOXP3 governs Treg development. Tregs prevent self-reactive T cells from attacking healthy tissues and calm the immune system after eliminating pathogens. This process, peripheral immune tolerance, complements central tolerance, ensuring immune balance.

Impact on Medicine

The laureates’ discoveries have transformed medical research:

Cancer: Tumors recruit Tregs to shield themselves from immune attack. Disabling Tregs could enhance therapies like checkpoint inhibitors.

Autoimmune Diseases: Boosting Tregs with interleukin-2 or lab-multiplied Tregs is being tested for conditions like lupus and rheumatoid arthritis.

Transplantation: Modified Tregs, tagged with antibodies, could protect transplanted organs from rejection.

These advancements, inspired by over 10,000 research papers, are driving clinical trials and new biotech therapies.

Conclusion

Through their groundbreaking work, Brunkow, Ramsdell, and Sakaguchi have illuminated how regulatory T cells and the FOXP3 gene maintain immune harmony. Their discoveries, recognized by the 2025 Nobel Prize in Physiology or Medicine, have laid the foundation for transformative treatments, offering hope for millions with autoimmune diseases, cancer, and transplant challenges.