title: Canonical microRNAs in thymic epithelial cells promote central tolerance.
abstract: 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 Dgcr8 using a FoxN1-Cre 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 Aire 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.
authors: Diabetes Center, University of California, San Francisco, CA, USA.
authors: Imran S
authors: IS
authors: Khan
authors: Ruth T
authors: RT
authors: Taniguchi
authors: Kayla J
authors: KJ
authors: Fasano
authors: Mark S
authors: MS
authors: Anderson
authors: Lukas T
authors: LT
authors: Jeker
mesh_terms: D000818:Animals; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D000096927:AIRE Protein
chemical_list: D035683:MicroRNAs; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D000096927:AIRE Protein; C474044:Dgcr8 protein, mouse
keywords: Aire; Central tolerance; DGCR8; MicroRNAs; Thymic epithelial cells