2025 Nobel Prize in Medicine: Keeping the Immune System in Check

Mary E. Brunkow (U.S.)

Fred Ramsdell (U.S.)

Shimon Sakaguchi (Japan)

The immune system constantly defends against invading pathogens (bacteria, viruses, etc.).

However, it must differentiate between “self” and “non-self” - an imbalance causes autoimmune diseases (like lupus, type 1 diabetes, rheumatoid arthritis).

The 2025 Nobel laureates discovered the mechanism that prevents the immune system from attacking its own tissues, explaining how immune tolerance is maintained.

In the 1980s, experiments showed that removing the thymus (where T cells mature) in newborn mice caused severe autoimmune reactions — their immune systems attacked their own organs.

This suggested the existence of a “suppressor” or “regulatory” mechanism within the immune system.

Shimon Sakaguchi discovered a new class of T cells carrying an extra surface protein CD25.

These were named Regulatory T cells (Tregs).

Function: Suppress overactive immune responses and prevent autoimmune attacks.

He hypothesized that these “security guard” cells kept other immune cells (especially effector T cells) in check.

Working independently in the U.S., Mary Brunkow and Fred Ramsdell studied a mouse strain where males died young due to immune attacks on their organs.

They identified a mutant gene — Foxp3 - responsible for the defective immune regulation.

Foxp3 was found to be the master control gene for the development and function of regulatory T cells.

In humans, mutations in Foxp3 cause a fatal autoimmune disorder known as IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome).

Even after central selection in the thymus (central tolerance), some self-reactive T cells escape into circulation.

Regulatory T cells maintain peripheral immune tolerance by:

• Suppressing self-reactive immune cells outside the thymus.

• Ensuring the immune system “stands down” after fighting infections.

• Preventing chronic inflammation and autoimmunity.

Express CD25 (IL-2 receptor alpha chain) and Foxp3 transcription factor.

Function through:

• Cytokine release (IL-10, TGF-β) to suppress immune activation.

• Cell–cell contact inhibition of effector T cells.

• Metabolic control — depriving other T cells of growth factors like IL-2.

Maintain immune homeostasis after infection clearance.

Over 200 ongoing trials globally on Treg-based therapies.

In Cancer:

• Strategy: Dismantle or inhibit Tregs → immune system attacks tumors more effectively.

In Autoimmune Diseases:

• Strategy: Enhance or expand Tregs → reduce self-attack (in diabetes, multiple sclerosis).

In Transplants:

• Tregs could be cultured and infused to promote tolerance and avoid organ rejection.

The discoveries bridged immunology, genetics, and clinical medicine.

Marked a shift from viewing the immune system as purely defensive to one requiring regulatory balance.

Opened pathways for precision immunotherapy and tolerance-inducing medicine.