Epithelial cells in the thymus teach T cells what to ignore by presenting them with a comprehensive array of tissue-restricted self-antigens (TRAs) during development. According to Derbinski and colleagues on page 33, this promiscuous expression of TRAs—one of the mechanisms behind central T cell tolerance—increases as the epithelial cells mature.

Self-antigens normally expressed only in individual tissues (labelled) are made in mTECs as they mature.

Teaching T cells how to distinguish self-tissues from foreign invaders is essential for the prevention of autoimmune disease. This education process occurs in the thymus and depends on the presentation of a diverse array of self-antigens to developing thymocytes—a function of medullary thymic epithelial cells (mTECs). T cells that recognize these self-antigens are either deleted or become regulatory T cells.

Recent studies have shown that the transcriptional regulator Aire (autoimmune regulator), which is highly expressed in mTECs, drives the expression of many of these TRAs. But not all TRAs depend on Aire, and Aire expression is not limited to mTECs. Thus, the rules that govern the thymic expression of these tightly regulated genes remain largely mysterious.

Derbinski et al. now show that the expression of a majority of TRAs increases as the mTECs differentiate in the thymus, suggesting an intricate link between mTEC maturity and TRA expression. The level of Aire expression mirrored the increase in TRA expression, consistent with the established role of Aire in this process. The authors confirm, however, that Aire does not act alone, as many TRAs are up-regulated in mature mTECs from mice lacking the transcriptional regulator.

How do differentiating mTECs turn on these genes that are normally expressed only in peripheral tissue? The answer is not completely clear, but Derbinski and colleagues show that regulation occurs at many levels. Some TRAs were expressed by transcriptional read-through of genes that are clustered together in a contiguous chromosomal region. Others depended on de-repression of genes normally silenced by genetic imprinting. But exactly how mTEC differentiation triggers these changes in gene expression remains to be determined.