The Thymus as a Mirror of the Body's Gene Expression

The thymus, a complex organ formed by different cell types that establish close interaction, serves a unique function of significant interest. The role played by the thymic stroma is not only a connective tissue or a support structure, but it also involves the stromal thymic epithelial cells (TECs) establishing physical and functional interaction with developing thymocytes. This interaction culminates in the induction of central tolerance, a function that sets this organ apart. The role played by the medullary thymic epithelial cells (mTECs) is noteworthy and is the focus of many studies. The transcriptome of mTEC cells is also very complex. These cells express nearly the functional genome without altering morphological and functional features. Among the thousand mRNAs expressed, a particular set encodes all peripheral tissue antigens (PTAs), representing the body's different tissues and organs. The consequence of ectopic proteins translated from these mRNAs in the thymus is immunological and is associated with self-nonself-discrimination and induction of central tolerance. Due to the wide variety of PTAs, this process was termed promiscuous gene expression (PGE), whose control is shared between autoimmune regulator (human AIRE/murine Aire), a transcriptional modulator, and forebrain-expressed zinc finger 2 (FEZF2/Fezf2), a transcription factor. Therefore, this molecular-genetic process is closely linked to eliminating autoreactive thymocytes in the thymus through negative selection. In this chapter, we review PGE in mTECs and its immunologic implication, the role of the Aire and Fezf2genes, the role of Aire on the expression of miRNAs in mTECs, its consequence on PGE and the manipulation of the Aire expression either by siRNA or by genome editing using the Crispr-Cas9 system.