The 2025 Nobel Prize in Physiology or Medicine recognised discoveries on regulatory T-cells (Tregs) and FOXP3, transforming understanding of autoimmune regulation and self-tolerance.

• Mary Brunkow, Fred Ramsdell and Shimon Sakaguchi have been honoured for their work on deciphering the intricacies of the immune system.

Understanding the Immune System

• The human body has a powerful and complex immune system, which not just fights off various bacteria and viruses, but also knows what cells should not be attacked.
• Immune Defence Mechanism: The human immune system fights thousands of microbes daily using specialized cells like T cells, which detect and destroy pathogens.

• Challenge of Self-Tolerance: The immune system must also recognise the body’s own cells and prevent attacking them. 
  • Failure of this mechanism leads to autoimmune diseases, where immune cells mistakenly destroy healthy tissues.
• Role of the Thymus (Central Tolerance): For decades, scientists believed that the thymus gland ensured immune self-tolerance by eliminating harmful T cells during maturation — a process called central tolerance.
  • However, this could not explain why some self-reactive immune cells still circulate in healthy individuals.

Shimon Sakaguchi’s Contribution (1990s)

• In the mid-1990s, Japanese immunologist Shimon Sakaguchi challenged existing understanding by showing that a special class of T cells acts as “security guards” of the immune system.
• Through experiments in mice, he demonstrated that when these cells were removed, animals developed severe autoimmune disorders, while restoring them prevented disease.
• He named them Regulatory T cells (Tregs) — immune cells that suppress excessive immune reactions and maintain peripheral tolerance.
• His work laid the foundation for the concept of peripheral immune tolerance, ensuring the immune system remains balanced.

Brunkow and Ramsdell’s Contribution

• Around the same time, American scientists Mary Brunkow and Fred Ramsdell were studying sick male mice that developed fatal autoimmune disorders. Their genetic analysis revealed a mutation on the X chromosome in a gene they identified and named FOXP3.
• Human Link – IPEX Syndrome: The same mutation was later found in boys suffering from a rare human autoimmune disease, IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked) Syndrome. This proved that FOXP3 is critical for immune regulation.

Connecting the Two Discoveries

• A few years later, Sakaguchi demonstrated that the FOXP3 gene controls the development and function of regulatory T cells. 
• Together, these findings provided the molecular and cellular basis for immune self-tolerance.

Medical and Scientific Significance

• The discoveries explain how the immune system distinguishes between self and non-self, preventing autoimmune disorders.
• New Field of Research: Their work launched the field of immune-regulation biology, leading to research on how to control or modulate immune responses in various diseases.
• Therapeutic Implications:
• • Autoimmune Diseases: Treatments now focus on boosting regulatory T cells to prevent the immune system from attacking healthy tissues.
  • Cancer: Tumours often exploit Tregs as a protective shield to evade immune attack. Research is exploring ways to inhibit Tregs around tumours to enhance immune destruction of cancer cells.
  • Organ and Stem Cell Transplants: Understanding Tregs helps in developing therapies to prevent graft rejection and improve transplant success rates.

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