Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi won this year’s Physiology or Medicine Nobel Prize.
Mary Brunkow, a molecular biologist at the Institute for Systems Biology, Fred Ramsdell, an immunologist at Sonoma Biotherapeutics, and Shimon Sakaguchi, an immunologist at Osaka University won this year’s Nobel Prize in Physiology or Medicine for their discoveries concerning how immune tolerance prevents the immune system from attacking the body, the Nobel Assembly at the Karolinska Institute announced today (October 6).
“Sakaguchi was quite taken with the news,” said Thomas Perlmann, a developmental biologist at the Karolinska Institute and member of the Nobel Committee. “He sounded incredibly grateful and expressed that it was quite an honor.”
Their discoveries lay the foundation for new and improved treatments for autoimmune disorders, such as type 1 diabetes and multiple sclerosis, and cancers.
“Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi have provided fundamental knowledge for how the immune system is regulated,” said Marie Wahren-Herlenius, a rheumatologist at the Karolinska Institute and member of the Nobel Committee. “[This research] relates to how we keep our immune system under control, so we can fight all imaginable microbes and still avoid autoimmune disease.”
From the moment a human is born, the immune system starts learning the differences between harmful invaders and the body’s own tissues. T cells generated in the bone marrow travel to the thymus, a lymphoid organ wedged between the lungs, where they are presented with a variety of foreign and self-proteins. During this crucial period, any rogue T cells that recognize the self-proteins are chucked out. In the 1980s, scientists believed that this mechanism—called central immune tolerance—was the only way the immune system trained not to attack the body.
But the surveillance and removal of harmful T cells is not perfect. “Many cells escape into our bodies and there they can still self-react to our own organs and tissues,” said Rickard Sandberg, a cell biologist at the Karolinska Institute and member of the Nobel Prize committee. “That’s why we need a secondary mechanism.”
In 1995, Sakaguchi presented evidence that filled this gap in knowledge.1 While working with mice to understand the development of T cells early in life, he and his colleagues surgically removed the thymus of the animals three days after birth. They expected that the lack of this organ would cause the T cell population to plummet, resulting in a weakened immune system. Contrary to this, the immune system of mice that lacked the thymus went into overdrive and the rodents developed a host of autoimmune disorders. When Sakaguchi injected the thymus-less rodents with T cells from other genetically identical mice, he observed that the newly introduced cells protected the mice from autoimmune disorders. However, it was crucial that these cells expressed the CD25 antigen. Sakaguchi named them regulatory T cells.
Scientists in the field were skeptical of these findings. They needed more information to accept this alternate mechanism of immune tolerance, which came from Brunkow and Ramsdell’s work in 2001. Both scientists worked at Celltech Chiroscience, a company that developed pharmaceuticals for autoimmune diseases. There, they came across a mouse mutant that was riddled with issues from an overactive immune system, ultimately leading to its death within a few weeks of its birth. A deeper analysis of its genome revealed mutations in the Foxp3 gene. Brunkow and Ramsdell also showed that mutations in the human equivalent of this gene caused the immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome, a rare genetic disorder with severe early-onset autoimmunity.2
Subsequent work by Sakaguchi showed that Foxp3 gene is crucial for the development of regulatory T cells, which control other T cells, ensuring the immune system reacts and calms down at appropriate times.
Researchers are conducting various clinical trials to manipulate the numbers of regulatory T cells in the body to tackle different diseases. While ramping up the cell numbers could prove useful to treat autoimmune disorders and improve the viability of transplanted organs, reducing them could aid treatment of cancers that use T cells as a shield from the immune system.
