Autoimmune diseases, including rheumatoid arthritis and lupus, are generally thought to result from an overstimulated immune system. This assumption does not, however, explain why these diseases are more prevalent in sterile western societies or why they often correlate with depleted numbers of T cells. Sarvetnick and colleagues now show that the combination of a depleted and understimulated immune system leads to autoimmunity.
The authors find that a mouse model of autoimmune diabetes has just this combination. These mice make too much of the IL-21 cytokine, which promotes proliferation (like other cytokines) but not survival (unlike other cytokines). Thus, their T cells continually multiply but never fill up the immune system.
These rapidly multiplying T cells (which likely respond to self-antigens from nearby organs) caused autoimmune diabetes. But diabetes was prevented if the mice were injected either with enough T cells to fill the immune system or with bacterial proteins so that multiplying T cells expanded robustly to these non–self-antigens.
“Most people do not want to think of autoimmunity as a form of immunodeficiency,” says Sarvetnick. But T cells in sanitized western children might be faced with a problem: without enough stimulation by foreign antigens to prompt T cell expansion, the T cells that do fill the immune system may have more than the normal share of autoreactive clones. So a bit of play time in the dirt might serve kids well. ▪