How laureates uncovered the body’s immune watchdogs

Our immune system is so powerful that it can sometimes attack parts of our body itself, leading to autoimmune disorders.

- Kabir Firaque

Today, it is well known that the body has a regulatory mechanism, called peripheral immune tolerance, that prevents the immune system from going overboard, but it took a long journey spanning decades before scientists deciphered how that works.

The Nobel Prize for Medicine, announced on Monday, honours three scientists who made pioneering discoveries along that journey. Shimon Shakaguchi, currently with Osaka University, discovered regulatory T cells, the watchdogs that help prevent the immune system from attacking the body. Independently, Mary E Brunkow (Institute for Systems Biology, Seattle) and Frederick J Ramsdell (Sonoma Biotherapeutics, San Francisco) identified a gene which, if mutated, could lead to autoimmune disease. Later, Shakaguchi completed the jigsaw by establishing that the same gene controls the development of regulatory T cells.

Cue from Oppenheimer

For the Nobel laureates, the journey began in the 1980s with Shakaguchi's discovery, and was furthered in the 1990s-2000s by Brunkow and Ramsdell’s work. But the seeds were laid even farther back — in the 1940s, during the Manhattan Project led by Robert J Oppenheimer.

Researchers developing the atomic bomb were studying the consequences of radiation on mice. They found some male mice were born with scaly skin, an extremely enlarged spleen and lymph glands; these lived for just a few weeks.

Since only male mice are affected, it was obvious that the X chromosome must be diseased. A female has two X chromosomes, so if one is defective, the healthy one compensates for it, but she can pass on the mutation to males in future generations.

Five decades later, Brunkow and Ramsdell investigated this mouse strain, named “scurfy”. Then working at a Washington-based biotech company, Celltech Chiroscience, they guessed the scurfy mice could provide clues to pharmaceuticals for autoimmune diseases.