2025 Nobel Prize in Medicine

 

On 6^th October, the Noble Assembly at Karolinska Institute has decided to award the 2025 Nobel Prize in Physiology or Medicine to: Mary Brunkow of Institute for Systems Biology, Seattle, USA; Fred Ramsdell of Sonoma Biotherapeutics, San Francisco, USA; and Shimon Sakaguchi of Osaka University, Osaka, Japan “for their discoveries concerning peripheral immune tolerance” that prevents the immune system from harming the body. 

Their work—identification of “immune system’s security guards” that prevent the body from harming itself — laid the foundation for a new field of research to invent potential therapies for cancer and autoimmune diseases. To better appreciate the Nobel Laureates’ contribution, we must first understand what the immune system is all about. 

Our immune system protects us every day from the thousands of different viruses, bacteria and other microbes that attempt to invade our bodies. Suffice it to say that without a functioning immune system, we would not survive.

It is T cells—a type of white blood cell called lymphocytes—that play an essential role in our immune system. They fight germs and protect us from diseases. These T cells have special proteins on their surface that are called T cell receptors. These receptors, acting like sensors, help T cells scan other cells and discover whether the body is under attack. There are two main types of T cells:

Cytotoxic T cells: They are also called CD8+ cells because they have the CD8 receptor (a type of protein) on their membranes. They kill cells infected with viruses and bacteria, and they also destroy tumour cells.

Helper T cells: They are also called CD4+ cells because they have a CD4 receptor (a type of protein) on their membranes. Unlike Cytotoxic cells, these cells don’t kill cells directly. They send signals to other cells in our immune system—Cytotoxic T cells, B cells, and another type of white blood cell called macrophages—as to how to coordinate an attack against invaders.

There is another kind of T cells, though not considered as main type, called T suppressor cells. They play a critical role in our immune system by preventing T cells from attacking our body’s healthy cells.

Interestingly, some of these T cells function as memory T cells. These are not fighters. They remember the intruder and thus enable the immune system to recognise it whenever the virus or bacteria return, and quickly activate our defence system against the invader.

These T cells exist in different places depending on their stage in the cell cycle. They come from stem cells in our bone marrow. Then migrate to the thymus to mature and develop their immune functions. Here in the thymus, the T cells that recognise the body’s own proteins are sorted and removed; otherwise, they may attack the body’s own cells. This process is called ‘central tolerance’. Finally, they relocate to our lymph tissue or bloodstream. They remain in our body as a standby until we need them to protect us.

As mentioned earlier, in our adaptive immune system, T cells are key fighters. They identify invading viruses by recognising viral peptide fragments present on the surface of infected cells within Major Histocompatibility Complex (MHC) molecules. An infected cell processes viral proteins into small peptides and presents them using the MHC proteins. Killer T cells have receptors that bind to these viral peptides bound to MHC molecules, and this process facilitates the identification of an infected cell as abnormal.

Once an intruder is detected, our adaptive immune system builds a customised defence to fight it. Every T cell is unique in that it is designed to fight only one type of intruder. Once our immune system identifies the threat, it picks up the specific T cell designed to defeat the intruder. This T cell copies itself, creating more T cells to defeat the intruder. These T cells that join the battle against the intruder are called effector cells.

T cells continue to protect our body even after the intruder is eliminated. Some of these T cells morph into memory cells. Like effector cells, these memory cells won’t fight against the intruder. Instead, they remember the intruder so that if it revisits, our immune system can identify it and quickly launch defensive action.  

With this understanding, let us now move to examine the research done by the present Laureates. Indeed, the work considered for the award was carried out by these laureates over several decades. Shimon Sakaguchi paved the way with his pioneering research —first published in 1995— that discovered a new class of T cells, called regulatory T cells or Tregs (a previously unknown class of T cells), that help turn the immune response down after it eliminates an invader and thus prevent other T cells from attacking healthy tissues of one’s own body.

Sakaguchi’s discovery fundamentally changed our understanding of immune tolerance. It showed that it is not just due to the elimination of harmful cells in the thymus, but also due to an active suppression by Tregs in peripheral tissues that immune tolerance is ensured. Thus, his work demonstrated that Tregs are crucial for preventing autoimmune diseases such as rheumatoid arthritis, type 1 diabetes, etc. His research also showed how cancer cells can exploit regulatory T cells to evade immune attack, paving the way for new therapeutic avenues. 

Taking forward Sakaguchi’s findings, Brunkow and Ramsdell (2001) found that mutations in the FOXP3 gene lead to the absence or malfunction of regulatory T cells, resulting in severe autoimmune disease. Brunkow and Ramsdell examined the ‘scurfy’ mouse, which exhibited fatal autoimmune symptoms, and using positional cloning, identified a mutation in a then unknown gene on the X-chromosome. They discovered that this gene— named by them as FOXP3—was responsible for the development and function of regulatory T cells (Tregs). Following this, they linked mutations in the human FOXP3 gene to a rare but deadly syndrome in children called IPEX (Immunodysregulation polyendocrinopathy enterotrophy X-linked) syndrome. They thus confirmed the central role of FOXP3 and Tregs in maintaining immune tolerance.

Thus, the research output of Mary Brunkow and Fred Ramsdell formally proved that FOXP3 is a master regulator for Treg cells development and function, offering a mechanistic explanation for immune tolerance and autoimmunity. Their research laid the groundwork for understanding how “peripheral immune tolerance” is established and maintained through regulatory T cells.

Subsequently, in 2003, Sakaguchi and his team demonstrated that the FOXP3 gene was the crucial molecular switch controlling the development of the Tregs that he had discovered earlier.

This collective work demonstrated that self-tolerance is maintained in our body by two processes: i) Central tolerance, in which the thymus eliminates most of the self-reactive T cells, and ii) Peripheral tolerance, in which Tregs, governed by FOXP3, police the body and suppress any remaining self-reactive T cells.

Thus, this year’s Nobel Laureates in Physiology—Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi—provided us critical answers to the marvels of the immune system through a combination of their insightful observations and careful experimentation. This, in turn, opened new paths for treating autoimmune diseases, cancer and improving organ transplant tolerance.

**