On 6 October 2025, the Nobel Assembly at the Karolinska Institutet announced that the Nobel Prize in Physiology or Medicine would be awarded to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi “for their discoveries concerning peripheral immune tolerance.” 

Their collective work has elucidated how the immune system keeps itself in check, identifying regulatory T cells (Tregs) as critical “security guards” that prevent the body’s immune cells from attacking healthy tissues. The challenge of immune regulation is not trivial: the immune system must distinguish friend from foe daily, despite the immense diversity and mimicry of invading pathogens. 

From Discovery to Mechanism: Tracing the Key Milestones

• In the mid-1990s, Sakaguchi challenged prevailing dogma by demonstrating that immune tolerance is not exclusively established in the thymus (central tolerance), but also requires active regulatory mechanisms in the periphery. 

• In 2001, Brunkow and Ramsdell uncovered a mutation in the Foxp3 gene in a mouse strain that was prone to severe autoimmune disease (the “scurfy” phenotype). 

• Subsequent experiments linked these discoveries: Foxp3 was shown to govern the development and function of the regulatory T cells that Sakaguchi had initially characterized. 

In effect, the laureates established that Tregs are indispensable players in peripheral immune tolerance—monitoring potentially harmful immune cell activity and preventing autoimmune reactions. 

Translational Ripples: From Basic Immunology to Therapeutic Frontiers

Their foundational insights have unleashed multiple translational pathways across three major arenas:

1. Cancer Immunotherapy

Tumours are adept at sculpting their microenvironment. Many recruit large numbers of Tregs to create a local immunosuppressive niche, effectively “protecting” themselves from cytotoxic effector cells. Researchers are actively exploring strategies to disrupt or reprogram intratumoral Treg populations, thereby breaching this suppressive barrier. The overarching goal is to restore antitumor immunity without systemic autoimmunity.

2. Autoimmune Disease Modulation

In diseases characterized by hyperactive or misdirected immunity, the therapeutic objective becomes fostering tolerance rather than breaking it. Two major approaches are in development:

• Low-dose IL-2 therapy: This cytokine preferentially supports Treg survival and expansion. Pilot studies are assessing its utility in conditions such as type 1 diabetes, systemic lupus erythematosus, and graft-versus-host disease.

• Adoptive Treg transfer: Autologous Tregs can be expanded ex vivo and reinfused. More advanced iterations involve engineering Tregs with antigen-specific targeting (e.g. by grafting surface antibodies or homing receptors). This may allow the “security guard” cells to traffic selectively to transplanted organs or sites of inflammation.

3. Transplantation Tolerance

One of the most compelling opportunities lies in transplantation: by increasing or directing Tregs to newly grafted tissues (e.g. kidney, liver), researchers aim to prevent organ rejection with less reliance on life-long immunosuppression. The use of engineered Tregs to “guard” grafts could revolutionize transplant medicine.

Looking Ahead: Challenges and Opportunities

While the discoveries of Brunkow, Ramsdell, and Sakaguchi represent a conceptual leap, the translational field is still grappling with critical challenges:

• Treg stability and plasticity: Under inflammatory or cytokine-rich conditions, Tregs may lose their suppressive phenotype or convert into effector-like cells.

• Specificity versus broad immunosuppression: Achieving antigen- or tissue-specific regulation without compromising systemic immune competence is essential.

• Scalability and safety: Manufacturing, quality control, and long-term safety (e.g. risk of opportunistic infection or tumor escape) remain significant hurdles.

• Biomarkers and patient stratification: Identifying which patients will benefit most from Treg-centric therapies is still an evolving endeavor.

 

Nonetheless, the recognition by the Nobel Committee underscores that fundamental immunology remains a fertile ground for paradigm-shifting therapies. By illuminating how tolerance is enforced at the cellular level, these laureates have catalyzed a new generation of immunomodulatory strategies.

 

References

• The Nobel Prize in Physiology or Medicine 2025 – Press Release. Nobel Prize Outreach AB 2025.
  https://www.nobelprize.org/prizes/medicine/2025/press-release/

• Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., & Toda, M. (1995). Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Journal of Immunology, 155(3), 1151–1164.

• Brunkow, M. E., Jeffery, E. W., Hjerrild, K. A., Paeper, B., Clark, L. B., Yasayko, S. A., … & Ramsdell, F. (2001). Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nature Genetics, 27, 68–73.

• Fontenot, J. D., Gavin, M. A., & Rudensky, A. Y. (2003). Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunology, 4, 330–336.

• Sakaguchi, S., Yamaguchi, T., Nomura, T., & Ono, M. (2008). Regulatory T cells and immune tolerance. Cell, 133(5), 775–787.

• Abbas, A. K., & Sharpe, A. H. (2024). Tregs in disease: mechanisms and translational potential. Nature Reviews Immunology, 24, 45–61.

• Tang, Q., & Bluestone, J. A. (2013). Regulatory T-cell therapy in transplantation: moving to the clinic. Cold Spring Harbor Perspectives in Medicine, 3(11), a015552.

• Bettini, M., & Vignali, D. A. A. (2010). Development of thymically derived natural regulatory T cells. Annals of the New York Academy of Sciences, 1183, 1–12.