The immune system is a master of precision warfare. Its foot soldiers, the T cells, intercept a constant stream of disguised invaders yet rarely shoot down one of their own. The secret is a ruthless process called negative selection. In the training ground of the thymus, T cells that tend to attack host tissues are ordered to kill themselves. Now, a study has uncovered a key protein that kicks off the selection, removing a major obstacle to understanding this crucial process.
All cells deploy one of two biochemical pathways in order to self-destruct. One pathway is triggered by stress, the other by special death receptors that respond to execution orders from other cells. But despite an explosion of research on cell suicide, researchers couldn't figure out which pathway T cells enlist in negative selection. Blocking either pathway seemed to have no effect. Without knowing the pathway, researchers were at an impasse, says Peter Krammer, an immunologist at the German Cancer Research Center in Heidelberg, Germany. "They tended to move on to other things."
But Philippe Bouillet and colleagues Andreas Strasser and Jerry Adams at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, decided to give the problem one more shot. They turned to a line of genetically engineered mice with an autoimmune disease resembling the human disease lupus. The mice lacked a gene called Bim, which codes for a protein in the stress-induced pathway.
To see if these mice suffered from a deficit in T cell suicide, the team first had to magnify the negative selection, which is normally a rare event. So they bred mice in which all T cells attacked host proteins. For instance, in one experiment, they engineered strains of normal mice so that their T cells exclusively attacked a protein found only in males. In males, T cells assaulted tissues and then committed suicide. (T cells in the females didn't attack or self-destruct.) When the team engineered Bim-deficient mice the same way, the aggressive T cells survived in males.
The findings, reported in the 21 February issue of Nature, suggest that Bim is critical to T cell suicide. "That Bim seems to be involved is an extremely interesting finding," says Doug Green, an immunologist at the La Jolla Institute for Allergy and Immunology in California. Krammer predicts that the findings will encourage researchers to eke out the rest of the circuitry involved in negative selection of T cells. "They provide one pearl on the chain, and also show where to look next."