Discovering the body's immune 'off switch'

This year's Nobel Prize in Physiology or Medicine honors fundamental discoveries about peripheral immune tolerance, the process that prevents immune cells from turning against the body's own tissues.

The work began with Shimon Sakaguchi, who in the 1980s observed that mice deprived of a small organ called the thymus developed severe autoimmune disease. When he injected immune cells from healthy mice into those animals, the symptoms disappeared. The finding hinted at a hidden class of T cells that acted as peacekeepers in the immune system.

By 1995, Sakaguchi had identified these "regulatory T cells," or T-regs, which act as a brake on other immune cells that might overreact. According to the Associated Press, Sakaguchi "unraveled an additional way the body keeps the system in check," showing that tolerance wasn't limited to the thymus alone.

A few years later, working together at Celltech Chiroscience outside of Seattle, Mary Brunkow and Fred Ramsdell discovered the FOXP3 gene, which controls the development of those same regulatory T cells. Having studied mice that were bred with a severe autoimmune disorder, the researchers found that mutations in FOXP3 caused the condition — mirroring a rare human disease known as IPEX.

Their combined discoveries revealed how the immune system regulates itself and why its failure can lead to chronic autoimmune disorders such as type 1 diabetes, lupus, and rheumatoid arthritis.

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At the prize announcement in Stockholm, Nobel Assembly secretary general Thomas Perlmann said he reached Sakaguchi in his lab. "[Sakaguchi] sounded incredibly grateful … He was quite taken by the news," Perlmann said. He added that he left messages for Brunkow and Ramsdell on the U.S. West Coast.

Committee chair Olle Kämpe called their discoveries "decisive for our understanding of how the immune system functions and why we do not all develop serious autoimmune diseases."

John Wherry, director of the Colton Center for Autoimmunity at the University of Pennsylvania, said that "[t]his is a great recognition of the fundamental importance of distinguishing self from non-self."

The three laureates will share 11 million Swedish kronor, or about $1.17 million, for a body of work that continues to shape medicine's understanding of the immune system's most delicate balance — knowing when to fight, and when to let go.