Figure 1.

Schematic representation of the roles of Aire in TRA gene expression associated with the mTEC differentiation program. Aire-expressing mTECs develop from their progenitor via an immature stage (CD80^lowMHC-2^low) where only limited numbers of TRAs (e.g., and ) are expressed. Aire is expressed at the mature stage (CD80^highMHC-2^high), and the transcription model (upper) suggests that Aire directly activates many target TRA genes within mature mTECs (so-called Aire-dependent TRAs; –). Consequently, lack of Aire results in defective expression of Aire-dependent TRA genes. In contrast, the maturation model suggests that Aire plays an important role in the maturation program of mTECs, and that expression of Aire-dependent TRA genes, such as –, can be accomplished in terminally differentiated mTECs showing a dendritic to fibroblastic morphology that have fully matured with the help of Aire. According to this scenario, lack of Aire causes a halt in mTEC maturation at a stage where promiscuous gene expression in the cells is still not possible (marked as “Aire-KO mTECs”); lack of Aire in mTECs results in premature termination of differentiation, and these CD80^high Aire-less mTECs have a more globular cell shape and lack the transcriptional machinery for Aire-dependent TRA genes (lower). Because Aire-independent TRA genes, such as and , can be expressed before the mature stage, lack of Aire has little impact on their expression.