Insights Into the 2025 Nobel Prize in Medicine

You’ve just cut your finger. It hurts, but you wash your hands and, since it’s bleeding, you bandage it. You know that by tomorrow, the cut may be a bit red, but it won’t hurt much. After a few days, when you remove the bandage, it will hardly hurt, and after a week or so, it will have healed completely. You have a healthy, balanced immune system. 

Many different cells contribute to wound repair, including the cells of the immune system. The first part of your immune system includes cells that can recognize and kill any microbes that come in through the cut and go on to coordinate the repair of the skin. We now know that the second part of the immune system silences the first part, cell by cell, at the site of the wound, and leaves your immune system ready to work again. 

The 2025 Nobel Prize for Physiology or Medicine recognized the work of three scientists who figured out how the second part of the immune system works.

The prize was awarded to a Japanese scientist, Shimon Sakaguchi, and two Americans, Mary Brunkow and Fred Ramsdell, for their work revealing how the human immune system regulates its own activity by distinguishing friend from foe or foreign from self. They discovered a class of immune cells (called regulatory T-cells or Tregs) that exist to control the T-cells (sometimes called cytotoxic T-cells) mentioned in the cut finger example that can recognize and attack pathogens and help repair damaged tissues. Treg cells are thus the basis for immune tolerance and keep the overall immune system balanced.

We take for granted that our immune system will cope with infections or repair wounds and then disappear, and we will feel healthy again. Normally, an immune response is focused and regulated up and then down. But an overactive immune response can lead to diseases, such as type 1 diabetes, psoriasis, multiple sclerosis, or celiac disease, in which normal tissues are attacked, and a Treg response is missing. Underactive Tregs do not “see” growing tumors and thus fail to activate regular T-cells, an example of inappropriate tolerance.

In the 1980s, immunologists believed that an organ, the thymus, was simply where all T-cells were nurtured. Dr. Sakaguchi discovered, to his surprise, that when he removed the thymus from mice, immune activity was dramatically increased and not decreased as he was expecting. He speculated that Treg cells must exist with the role of teaching other T-cells not to attack host tissues. He confirmed this idea by showing that mice without a thymus could be protected from autoimmune disease by simply injecting them with Treg cells from normal mice. Drs. Brunkow and Ramsdell knew of Sakaguchi’s work and found the responsible gene in the late 1990s.

Drs. Brunkow and Ramsdell studied mice with a severe, lethal autoimmune disease called “scurfy” while working at a biotech company called Celltech in Bothell, where I also worked, although on a different project. They suspected that if there were no Treg cells at all, a runaway immune response could be the problem in these mice. The mice have flaky skin, an oversized spleen and lymph nodes, and a reduced life span. They knew that the mutation resided on the X chromosome and discovered that a mutated form of the gene called Foxp3 caused scurfy in mice and a similar but very rare condition in men called IPEX syndrome. Further work by Drs. Brunkow and Ramsdell, and Dr. Sakaguchi showed that Foxp3 governs the development of Tregs.

The idea for modulating Tregs has spread through the immunology community over the past 20 years, since there is immense potential for drugs or treatments that could rebalance immunity. For autoimmune disorders, more Tregs might represent a therapy to achieve selective tolerance. One path could be to isolate Tregs from a patient, expand them in culture, and then return them to the patient. The possibility of expanding Tregs with particular specificities is tantalizing. Could a therapy be devised to silence or remove the T-cells that destroy the myelin sheath that insulates skeletal nerves in multiple sclerosis or the T-cells that kill the insulin-producing pancreas cells in patients with type 1 diabetes?

We’ve known for years that solid tumors of all sorts are loaded with Tregs, rendering the tumor invisible to the immune system. Could we flag tumor-infiltrating Tregs with antibodies so that they are removed by the immune system, which would then be able to destroy the tumor? Several companies are pursuing approaches like this. There are more than 200 registered clinical trials now that involve Tregs. The 2025 Prize nicely fulfills the stipulations of Alfred Nobel’s will: studies of the physiology of a lethal disease are leading to new medicines.

Richard Gelinas, Ph.D., whose early work earned a Nobel prize, lives in Lakebay.