2025 Nobel Prize in Medicine Awarded for Groundbreaking Discoveries on Immune System Balance

This Monday, the Nobel Committee at the Karolinska Institute in Stockholm opened the 2025 Nobel Prize season. This year’s Nobel Prize in Physiology or Medicine was awarded to Dr Mary E. Brunkow (USA), Dr Fred J. Ramsdell (USA), and Prof. Shimon Sakaguchi (Japan) for their groundbreaking discoveries revealing how the immune system learns not to attack itself. Their pioneering work on regulatory T lymphocytes (Tregs) and the FOXP3 gene has clarified how the immune system maintains balance and protects against autoimmune diseases, allergies, and harmful chronic inflammation.

According to Prof. Laura Malinauskienė, a researcher at the Institute of Clinical Medicine of the Faculty of Medicine at Vilnius University (VU), these discoveries have fundamentally reshaped our understanding of how the immune system maintains equilibrium between defence and self-preservation, thus paving the way for new therapies from allergy treatment to cancer immunotherapy.

Immune tolerance – a balance between defence and self-preservation

Immunologist Prof. Sakaguchi was the first to describe regulatory T lymphocytes (Tregs) – immune cells that suppress excessive immune responses and prevent the body from attacking its own tissues. Later, Dr Brunkow and Dr Ramsdell discovered that the FOXP3 gene is essential for the development and function of these cells. Together, their findings revealed how the immune system maintains a delicate balance between attacking invaders and protecting itself.

‘This year’s Nobel Prize honours discoveries that explain how the immune system learns when to attack and when to hold back. Immune tolerance is the immune system’s ability to refrain from attacking one’s own cells and to ignore harmless substances such as food or pollen, while remaining ready to fight infections and cancer cells – a wise balance between defence and self-preservation,’ said Prof. Malinauskienė.

According to her, immune tolerance begins in the ‘factory’ – the thymus and bone marrow – where overly self-reactive cells are eliminated, and some develop into protective regulatory T cells (Tregs). After birth, the immune system continues to be ‘educated’ by the environment: the microbiota, nutrition, vaccines, and contact with external factors.

‘Every day, peripheral brakes – Tregs, tolerogenic dendritic cells, and other mechanisms – help maintain peace in our body. They ensure that we respond only when our body’s integrity is truly threatened. When this balance is disturbed, the risk of allergies and autoimmune diseases increases, and malignant tumours may begin to develop,’ explained the researcher.

Regulatory T cells as the immune system’s ‘peacekeepers’

To put it simply, Prof. Malinauskienė suggests imagining the immune system as a school’s security team: ‘They have to catch intruders – viruses or bacteria – but might sometimes detain their own ‘students’ by mistake. Regulatory T cells act as supervisors who step in to say, ‘these are ours – don’t touch them’. The FOXP3 protein is like their ID badge: without it, there are no supervisors, and order breaks down.’

According to Prof. Malinauskienė, without such control, the immune system could turn against the body – ‘swatting flies with a sledgehammer’ – and rather than providing protection, it would begin damaging healthy tissues, leading to autoimmune diseases, chronic inflammation, and tissue injury: ‘When mutations affect the FOXP3 gene and disrupt Treg function, the immune system loses balance and begins attacking the body’s own tissues. This causes IPEX syndrome, a rare genetic disorder leading to severe early-onset immune dysfunction.’

‘FOXP3 acts like a switch in the cell’s nucleus, turning on the genetic programme that allows regulatory T cells to form and function properly. Without this switch, they either fail to develop or cannot work effectively, and the immune system loses self-control. FOXP3 helps maintain harmony, enabling the immune system to fight real threats without endangering the body itself,’ noted the immunologist.

Peripheral tolerance – a new direction for research and treatment

‘Until the late 1980s, scientists believed that immune tolerance mechanisms developed exclusively before birth – during the central selection processes in the thymus. The work of Dr Brunkow, Dr Ramsdell, and Prof. Sakaguchi demonstrated that this balance is actively maintained throughout life, creating an entirely new field of study – the biology of peripheral tolerance. The scientists’ discoveries also paved the way for targeted therapies, where treatment involves not just attacking, but also precisely regulating the immune system’s brakes,’ said the researcher.

As Prof. Malinauskienė notes, these findings explain why some individuals’ immune systems overreact to harmless allergens: ‘When Treg cells are weak, instead of maintaining tolerance, we get allergic inflammation: rhinitis, asthma, or anaphylaxis. Here, Tregs act as a switch determining whether the immune system will remain tolerant or trigger an allergy.’

The Professor emphasises that these discoveries already have practical applications in medicine: ‘Allergen-specific immunotherapy promotes Treg formation and helps restore tolerance. In oncology, understanding that tumours hide behind a Treg ‘shield’ has led to therapies designed to dismantle that barrier. In transplantation, patient-derived Tregs are being expanded and reinfused to reduce the risk of organ rejection. In autoimmune diseases, low-dose IL-2 therapy, which stimulates Treg growth, and Treg-based treatments are under active investigation.’

‘The next major step is to fine-tune Treg activity precisely, keeping the immune system balanced – neither too weak nor too aggressive. Scientists are now exploring antigen-specific Tregs, novel IL-2 delivery methods, and strategies that ‘release the brakes’ only within tumour environments. All of this builds on the discoveries of this year’s Nobel laureates, who revealed how the immune system maintains balance and protects us not only from infections but also from its own mistakes. Once we learn how to reliably switch peripheral tolerance on where it is lacking, and off where it is excessive, we will move from a ‘one-size-fits-all’ model to true precision immunomedicine,’ concluded Prof. Malinauskienė
The laureates will receive their award comprising a diploma, a gold medal, and 11 million Swedish kronor (approximately €950,000) at the official ceremony to be held on 10 December.
Last year’s Nobel Prize in Physiology or Medicine was awarded jointly to Prof. Victor Ambros and Prof. Gary Ruvkun for their discovery of microRNA and its role in post-transcriptional gene regulation.

The Nobel Prize in Physics was announced on Tuesday, followed by the Chemistry Prize on Wednesday; the Literature and Peace Prizes will be revealed on Thursday and Friday, respectively, while the Nobel Prize season will conclude next Monday with the announcement of the Award for Economic Sciences.