Control of development and tolerogenic properties of thymic epithelial cells by micro RNAs

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Medullary and cortical thymic epithelial cells (cTECs and mTECs) support distinct aspects of positive selection and tolerance induction. For example, terminally differentiated mTECs “promiscuously” express tissue-specific self-antigens and this phenomenon is essential for self-tolerance. To date, the developmental cues and the genetic control mechanisms that orchestrate TEC development and their tolerogenic properties are only incompletely understood. We plan to address an as yet unexplored layer of genetic control in TECs, that is, the role of micro (mi)RNAs. Based upon miRNA expression profiles of different TEC subsets that have recently been established in our lab, we will apply gain and loss of function strategies to test the hypotheses that (a) down-regulated miRNAs may be involved in “promiscuous gene expression”, as their absence may establish a permissive state of “relaxed silencing” of ectopic gene expression, and (b) that up-regulated miRNAs in mTECs may be critical regulators of their tolerogenic properties. The long-term perspective of this project is to obtain an integrated understanding of how gene regulatory networks in TECs impinge on T cell fate decisions.