Medullary thymic epithelial cells (mTECs) represent a unique stromal cell population of the thymus which plays an essential role in the establishment of central tolerance. Therefore, mTECs rank among cells relevant for the development of functional mammal immune system.

T cell precursors rise in bone marrow and migrate through the bloodstream to the thymus for further development. During their maturation in the thymus, they undergo a process called V(D)J recombination which conducts the development of T cell receptors (TCRs). The mechanism of this stochastic process enables on one hand the generation of vast repertoire of TCRs, however, on the other hand causes also origin of so called "autoreactive T cells" which recognize self antigens via their TCRs. Autoreactive T cells must be eliminated from the body or skewed into the T Regulatory cells (TRegs) lineage to prevent manifestations of autoimmunity. mTECs possess the ability to deal with these autoreactive clones via mediation of the processes of central tolerance, namely clonal deletion or T regulatory cells selection, respectively.

N.B.: All the below cited references utilized mouse as a model organism.

In 1989, two scientific groups came up with the hypothesis that the thymus expresses genes which are in the periphery, strictly expressed by specific tissues (e.g.: Insulin produced by β cells of the pancreas) to subsequently present these so-called "tissue-restricted antigens" (TRAs) from almost all parts of the body to developing T cells in order to test which TCRs recognize self-tissues and can be therefore harmful to the body. It was found, after more than a decade, that this phenomenon is managed specifically by mTECs in the thymus and was named Promiscuous gene expression (PGE).

Aire is a protein called autoimmune regulator (Aire) which is also specifically expressed by mTECs. and its expression is completely dependent on NF- kappa B signaling pathway. Aire recognizes target genes of TRAs via specific methylation marks and requires about 50 partner molecules for activation of their expression. Moreover, Aire-dependent activation of TRA genes expression is accompanied by formation of DNA double-strand breaks. which probably results in very short lifespan of mTECs between 2–3 days

Mutations of Aire gene in human cause a rare autoimmune disorder called Autoimmune Polyendocrinopathy Candidiasis Ectodermal Distrophy (APECED)., which usually manifests in combination with other autoimmune diseases e.g.: diabetes mellitus type 1. Dysfunction of murine Aire gene results in comparable scenario and therefore mouse is used as the model organism for investigation of APECED.

mTECs as a population are capable to express more than 19000 genes (about 80% of mouse genome) among which approximately 4000 belong to Aire-dependent TRAs. It is important to emphasize that single mTEC expresses about 150 Aire-dependent TRAs and approximately 600 Aire-independent TRAs, indicating that other still unknown PGE regulators exist. Indeed, another protein called Fezf2 was suggested to be the second regulator of PGE.

It was shown that each mTEC expresses stochastically 1-3% of TRA pool. However, more recent studies discovered stable co-expression patterns between TRA genes which are localized in close proximity, suggesting "order in this stochastic process".