How is tolerance to organ-specific antigens maintained? It was assumed originally that tolerance depends mainly on immunological 'ignorance' or peripheral regulatory mechanisms. However, evidence that organ-specific antigens are expressed by rare thymic medullary epithelial cells has indicated that central-tolerance mechanisms might be important also.

Humans with autoimmune polyendocrinopathy syndrome type 1 — which results from mutations in the autoimmune regulator ( AIRE ) gene — develop a range of organ-specific autoimmune diseases. Chris Goodnow and colleagues are the first to show that self-tolerance might be defective in these patients owing to a failure of negative selection in the thymus. As AIRE seems to be a transcriptional regulator and is expressed mainly by rare thymic stromal cells, this protein is likely to be important for the thymic expression of otherwise organ-specific antigens and their role in central tolerance.

In T-cell receptor (TCR)-transgenic 3A9-insHEL mice, which produce T cells with specificity for hen egg lysozyme (HEL) and express HEL under control of the rat insulin promoter, the TCR-transgenic T cells are deleted in the thymus as a result of thymic antigen expression. To analyse the effects of Aire on this process, the TCR-transgenic mice were crossed with Aire-mutant mice. No difference was observed in the positive selection of TCR-transgenic T cells between Aire+/+ and Aire−/− mice that lacked expression of insHEL. In Aire+/+ 3A9-insHEL mice, few CD4+ T cells were present, indicating efficient negative selection, and those T cells that remained were anergic. However, in Aire−/− 3A9-insHEL mice, normal numbers of mature CD4+ T cells were produced, indicating a failure of thymic deletion.

Reconstitution experiments were used to determine the lineage requirements for expression of Aire. Aire−/− T cells were deleted normally in the thymi of Aire+/+ mice, whereas Aire+/+ T cells were not deleted in Aire−/− mice. Therefore, Aire must be expressed by non-haematopoietic lineages for efficient negative selection.

Levels of HEL protein were too low to detect in 3A9-insHEL mice, so the effects of Aire on thymic expression of HEL could not be measured directly. However, the authors conclude from the lack of HEL-specific thymic deletion in Aire−/− mice that the ectopic expression of HEL depends on Aire. This does not rule out the possibility that Aire is involved in other mechanisms of tolerance induction, but a failure of thymic deletion might be a common explanation for various autoimmune diseases, including multiple sclerosis and diabetes.