The Nobel Prize in Physiology or Medicine 2025

What is the immune system, how does it work, and why is it so important?

The immune system is the body’s defense network that protects us from harmful microorganisms such as bacteria, viruses, and parasites. It includes specialized cells, tissues, and organs that work together to identify and eliminate potential threats.

It functions by distinguishing between the body’s own cells and foreign invaders. Once a pathogen enters the body, immune cells like macrophages and lymphocytes recognize it as foreign and trigger a complex immune response. This process involves producing antibodies, activating T cells, and releasing signalling molecules called cytokines to coordinate the defense.

The immune system is essential for maintaining the body’s internal balance (homeostasis). Without it, even minor infections could become life-threatening. A properly regulated immune system helps fight infections, prevents cancer, repairs damaged tissues, and avoids attacking the body’s own cells.

T cells: The Core of Immune Defense

All T cells have specialized proteins on their surfaces that function as receptors. These receptors act as molecular sensors, enabling the immune system to detect foreign antigens. The T-cell receptor (TCR) recognizes small peptide fragments displayed by other cells through major histocompatibility complex (MHC) molecules. As shown in Figure 2, T cells detect foreign peptides through their unique T-cell receptors presented by MHC molecules.

T cells are classified by the specific surface proteins they express. Helper T cells (CD4⁺ T cells) circulate through the body, and upon encountering a pathogen, alert other immune cells and initiate an immune response. Expression of the CD4 surface protein enables these cells to recognize antigens displayed by MHC class II molecules.

Cytotoxic or killer T cells (CD8⁺ T cells) eliminate virus-infected and malignant cells through direct cell-mediated cytotoxicity. These cells recognize antigens presented by MHC class I molecules.

Every T cell expresses a unique T-cell receptor, formed by random combinations of gene segments. This genetic diversity allows the body to generate more than 10¹⁵ different T-cell receptors. As a result, T cells can detect an extremely wide range of antigens, making it difficult for pathogens to evade immune detection. This remarkable specificity raises an important question: how does the body protect its own cells from being mistakenly targeted by the immune system?

Why does the immune system not attack our bodies more frequently, and how are these mechanisms kept under control?

In the 1980s, scientists suggested that a process called ‘central tolerance’ controls this self-protection mechanism. T cells originate in the bone marrow but undergo maturation in the thymus. This maturation process relies on eliminating T cells that recognize self-derived fragments. Each T cell expresses a unique T-cell receptor (TCR) on its surface, while specialized thymic cells present self-proteins to test the T-cells’ activity. Self-reactive T cells are eliminated during thymic selection, while those that do not respond to self-antigens are released into circulation to defend against pathogens. As illustrated in Figure 3, self-reactive T cells that recognize the body’s own antigens are eliminated during thymic selection, while non-reactive cells are released to patrol the body

In addition, some researchers thought that there was another type of cell that regulates the immune system. They referred to these cells as ‘suppressor T cells’. They believed that this special type of cell inhibited other T cells that had escaped the thymic selection. However, after a series of disappointing results, many researchers rejected the hypothesis and nearly abandoned the field.

“People believed that suppressor T-cell activity had been mapped to a specific genomic region. When that region was sequenced, no gene was found there. Many immunologists walked away at that point — but not Shimon,” said Ramsdell. Shimon Sakaguchi refused to give up and opposed abandoning the entire hypothesis. He and his colleagues continued their experiments at the Aichi Cancer Center Research Institute (Nagoya, Japan).

SAKAGUCHI DISCOVERS A NEW CLASS OF T CELLS: A GROUNDBREAKING DISCOVERY

Sakaguchi and his colleagues removed the thymus from a three-day-old mouse, which caused their immune systems to become hyperactive. Sakaguchi then isolated a group of mature CD4⁺ T cells (helper T cells) from healthy mice and injected them into thymectomized mice. After receiving these T cells, the mice regained normal immune function. As shown in Figure 4, removal of the thymus from three-day-old mice led to immune overactivation and the development of autoimmune symptoms, highlighting the thymus’s crucial role in self-tolerance.

He hypothesized that different subsets of T cells might carry distinct surface markers. A decade later, Sakaguchi identified a new class of T cells that expressed not only CD4 but also CD25. He termed these T cells regulatory T cells (Tregs). Following this discovery, many researchers remained skeptical and demanded further evidence to validate his findings. A decade later, Sakaguchi identified a distinct subset of T cells expressing both CD4 and CD25, which he termed regulatory T cells(Tregs) (Figure 5).The supporting evidence came from Mary Brunkow and Fred Ramsdell, who later confirmed Sakaguchi’s results.

Brunkow and Ramsdell Findings

At the Oak Ridge National Laboratory in Tennessee, researchers working on the Manhattan Project unexpectedly observed that some male mice were born with severe immune abnormalities. These mice developed scaly skin, enlarged spleens and lymph nodes, and survived only a few weeks. The mutation responsible for these symptoms was later named scurfy. At the time, molecular genetics was still emerging, but researchers were able to trace the mutation to the X chromosome. Since female mice have two X chromosomes—one carrying a normal allele–they were unaffected and passed the mutation on to their offspring.

Decades later, Mary Brunkow and Fred Ramsdell, working at Celltech Chiroscience in Washington, became interested in the scurfy mutation due to its potential to elucidate the mechanisms underlying autoimmune diseases. They hypothesized that identifying the defective gene could provide valuable insights into immune regulation.

After years of detailed mapping and analysis, they localized the mutation to a specific region in the middle of the X chromosome, which contained about twenty candidate genes. By examining these genes individually, they ultimately identified the defective one and named it Foxp3. This discovery revealed that mutations in Foxp3 caused the scurfy condition in mice.(Figure 6).

Further collaboration with pediatric researchers revealed that mutations in the same gene led to a rare human disease called IPEX (Immunodysregulation Polyendocrinopathy Enteropathy X-linked syndrome). Their findings established FOXP3 as a key regulator of immune tolerance, directly linking it to autoimmune pathology. Soon after, Shimon Sakaguchi discovered that FOXP3 controls the development and function of regulatory T cells (Tregs), connecting this gene directly to immune tolerance.

Regulatory T cells- Tregs

Regulatory T cells express both CD25 and CD4 surface markers. The FOXP3 gene regulates Tregs’ development and functional activity. Tregs suppress autoactive T cells and prevent them from attacking the body’s own tissues. This mechanism, known as peripheral immune tolerance, is essential for maintaining self-tolerance and preventing autoimmune damage.

Another critical function of regulatory T cells is to help the immune system return to its resting state after eliminating an invader, thereby preventing excessive immune activation and autoimmunity. (Figure 7).

What potential applications and future developments can we expect from these discoveries?

Thanks to the discoveries of the Nobel laureates, a new field of immunological research and potential medical therapies has emerged. Tumor cells can manipulate regulatory T cells to suppress immune responses, allowing them to evade immune surveillance.

Researchers are now investigating how to reverse this suppression, aiming to reactivate the immune system to fight cancer. Another promising line of research focuses on modulating regulatory T-cell activity in autoimmune disorders.

Scientists are also exploring ways to expand or enhance regulatory T cells to restore immune tolerance in autoimmune diseases. One promising therapeutic approach involves isolating a patient’s Tregs, expanding them under controlled laboratory conditions, and reintroducing them into the patient to strengthen immune regulation.

Additionally, advances in gene-editing and cell-targeting techniques now allow researchers to modify T cells by adding molecular “address tags” that guide them to specific tissues or organs, such as transplanted livers or kidneys. This targeted approach helps prevent graft rejection and graft-versus-host disease, thereby protecting the transplanted organ from immune attack.

These advances mark the beginning of a new era in immunotherapy, where a deeper understanding of immune regulation may lead to treatments once considered impossible.

Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi’s pioneering discoveries have greatly expanded our knowledge of immune regulation and its therapeutic applications. Their groundbreaking work continues to inspire innovative medical strategies and guide new directions for future research.