Canonical microRNAs in thymic epithelial cells promote central tolerance. Issue 5 (20th March 2014)

• Record Type: Journal Article
• Authors: Khan, Imran S.; Taniguchi, Ruth T.; Fasano, Kayla J.; Anderson, Mark S.; Jeker, Lukas T.
• Is Part Of: European journal of immunology. Volume 44:Issue 5(2014:May)
• Page Start: 1313
• Page End: 1319
• Publication Date: 2014-03-20
• Subjects: Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201344079
• Languages: English
• ISSNs: 0014-2980

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Medullary thymic epithelial cells (mTECs) facilitate the deletion of developing self‐reactive T cells by displaying a diverse repertoire of tissue‐specific antigens, a process which largely depends on the expression of the autoimmune regulator (Aire) gene. Mature microRNAs (miRNAs) that regulate gene expression post‐transcriptionally are generated in a multistep process. The microprocessor complex, including DGCR8, cleaves canonical miRNAs, but alternative DGCR8‐independent miRNA biogenesis pathways exist as well. In order to study the role of canonical miRNAs in thymic epithelial cells (TECs), we ablated <italic>Dgcr8</italic> using a <italic>FoxN1‐Cre</italic> transgene. We report that DGCR8‐deficient TECs are unable to maintain proper thymic architecture and exhibit a dramatic loss of thymic cellularity. Importantly, DGCR8‐deficient TECs develop a severe loss of Aire⁺ mTECs. Using a novel immunization approach to amplify and detect self‐reactive T cells within a polyclonal TCR repertoire, we demonstrate a link between the loss of <italic>Aire</italic> expression in DGCR8‐deficient TECs and the breakdown of negative selection in the thymus. Thus, DGCR8 and canonical miRNAs are important in TECs for supporting central tolerance.</p> </abstract>