European Journal of Immunology vol:43 issue:7 pages:1769-1778
The establishment and maintenance of central tolerance depends to a large extent on the ability of medullary thymic epithelial cells (mTECs) to express a variety of tissue-restricted antigens, so-called promiscuous gene expression (pGE). Aire is to date the best characterised transcriptional regulator known to at least partially coordinate pGE. There is accruing evidence that the expression of Aire-dependent and -independent genes is modulated by higher order chromatin configuration, epigenetic modifications and post-transcriptional control. Given the involvement of miRNAs as potent post-transcriptional modulators of gene expression, we investigated their role in the regulation of pGE in purified mouse and human TECs. Microarray profiling of TEC subpopulations revealed evolutionarily conserved cell type- and differentiation-specific miRNA signatures with a subset of miRNAs being significantly up-regulated during terminal mTEC differentiation. The differential regulation of this subset of miRNAs was correlated with Aire expression and some of these miRNAs were misexpressed in the Aire knockout thymus. In turn, the specific absence of miRNAs in TECs resulted in a progressive reduction of Aire expression and pGE, affecting both Aire-dependent and -independent genes. In contrast, the absence of miR-29a only affected the Aire-dependent gene pool. These findings reveal a mutual interdependence of microRNA and Aire.