T cells that respond to self antigens exist in normal tissues but are, of necessity, stringently controlled in healthy individuals. Autoreactive T cells may be specifically deleted as they develop in the thymus; those that survive and reach the peripheral tissues are kept mitotically quiescent and otherwise unresponsive by stimuli from other immune cells. Together, these two mechanisms, termed central and peripheral tolerance, hold autoreactive T cells in check. Autoimmune disease arises when clones of these cells overcome the usual safeguards, expand, and become activated.

The mechanism behind such an escape from tolerance is uncertain, and defects in both central and peripheral tolerance have been proposed to underlie various disorders. Now, two independent sets of reports establish that both of these mechanisms participate in the pathogenesis of an unusual form of immune disregulation observed in humans and mice. The human disorder, X-linked autoimmunity–allergic disregulation syndrome (XLAAD), presents with a collection of symptoms that are also seen in the Scurfy mouse. With the report by Chatila et al.(1) in a recent issue of the JCI and independent analyses by Brunkow et al.(2), it is now clear that the genes affected are orthologues and encode a transcription factor termed Foxp3, JM2, or scurfin. This parallel offers the prospect of insights into the molecular regulation of human autoimmune diseases. The current findings also suggest that certain allergic diseases arise because of intrinsic defects in CD4+ T cells, leading to Th2-skewing and hyperreactivity to antigens.