Author: Špela Konjar
This year Nobel Prize in Physiology or Medicine was awarded to Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi for their pioneering discoveries explaining how peripheral immune tolerance prevents the immune system from attacking the body. (Figure 1)
Figure 1:
We often think of the immune system primarily as a defense against infections and invading microorganisms. For this to function effectively body´s immune system has to strike a delicate balance — mounting a strong attack against harmful microbes and viruses while simultaneously protecting the body’s own cells from harm. This year’s Nobel Prize honors the discovery of regulatory T cells, a specialized group of immune cells that help maintain this crucial equilibrium. When this regulation fails, the consequences can be severe. The immune system may turn against the body itself, resulting in allergies, autoimmune disorders, and inflammatory diseases — all manifestations of a loss of immune balance and self-tolerance.
In 1995, Shimon Sakaguchi made his first ground-breaking discovery, when most scientist had given up on the idea of the existence of “suppressor T cells”. Most researchers thought that immune tolerance—the body’s ability to avoid attacking its own cells—was achieved solely through the elimination of potentially harmful immune cells in the thymus, a process known as central tolerance. However, experiments in which the thymus was removed from mice revealed that these animals developed severe autoimmune diseases (Figure 2). This finding hinted that another mechanism must be at play. Sakaguchi demonstrated that the immune system is far more complex than previously thought and identified a previously unknown class of immune cells, which he named regulatory T cells (Tregs). These cells play a vital role in preventing autoimmune reactions and maintaining immune balance.
Figure 2:
In 2001, Mary Brunkow and Fred Ramsdell made the second key discovery. They investigated a naturally occurring mutant mouse strain known as scurfy (Figure 3), first described in the 1940s, which exhibited extreme susceptibility to autoimmune disease, the initial symptoms of which have similarities with vitamin C deficiency. Their research revealed that these mice carried a mutation in a gene they named Foxp3 (Figure 3). Furthermore, they showed that mutations in the human equivalent of this gene cause a severe autoimmune condition in humans known as IPEX syndrome. In 2003, Sakaguchi had successfully linked these discoveries. He demonstrated that the Foxp3 gene is essential for the development and function of the regulatory T cells he had identified years earlier.
Figure 3:
Together, the laureates’ discoveries transformed our understanding of immune regulation and launched the field of peripheral tolerance. Their work has inspired new medical strategies for treating autoimmune diseases and cancer, and it also holds promise for improving organ transplantation. Several therapies based on their findings are now progressing through clinical trials.
Figure 2 and 3 attributed to the Nobel Committee for Physiology or Medicine. I11. Mattias Karlén