title: Differential Features of AIRE-Induced and AIRE-Independent Promiscuous Gene Expression in Thymic Epithelial Cells.
abstract: Establishment of self-tolerance in the thymus depends on promiscuous expression of tissue-restricted Ags (TRA) by thymic epithelial cells (TEC). This promiscuous gene expression (pGE) is regulated in part by the autoimmune regulator (AIRE). To evaluate the commonalities and discrepancies between AIRE-dependent and -independent pGE, we analyzed the transcriptome of the three main TEC subsets in wild-type and Aire knockout mice. We found that the impact of AIRE-dependent pGE is not limited to generation of TRA. AIRE decreases, via non-cell autonomous mechanisms, the expression of genes coding for positive regulators of cell proliferation, and it thereby reduces the number of cortical TEC. In mature medullary TEC, AIRE-driven pGE upregulates non-TRA coding genes that enhance cell-cell interactions (e.g., claudins, integrins, and selectins) and are probably of prime relevance to tolerance induction. We also found that AIRE-dependent and -independent TRA present several distinctive features. In particular, relative to AIRE-induced TRA, AIRE-independent TRA are more numerous and show greater splicing complexity. Furthermore, we report that AIRE-dependent versus -independent TRA project nonredundant representations of peripheral tissues in the thymus.
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec H3C 3J7, Canada; Department of Medicine, University of Montreal, Montreal, Quebec H3C 3J7, Canada; and.
authors.forename: Charles
authors.initials: C
authors.lastname: St-Pierre
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec H3C 3J7, Canada; Department of Medicine, University of Montreal, Montreal, Quebec H3C 3J7, Canada; and Department of Computer Science and Operations Research, University of Montreal, Montreal, Quebec H3C 3J7, Canada.
authors.forename: Assya
authors.initials: A
authors.lastname: Trofimov
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec H3C 3J7, Canada; Department of Medicine, University of Montreal, Montreal, Quebec H3C 3J7, Canada; and.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Brochu
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec H3C 3J7, Canada; Department of Computer Science and Operations Research, University of Montreal, Montreal, Quebec H3C 3J7, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lemieux
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec H3C 3J7, Canada; Department of Medicine, University of Montreal, Montreal, Quebec H3C 3J7, Canada; and claude.perreault@umontreal.ca.
authors.forename: Claude
authors.identifier: http://orcid.org/0000-0001-9453-7383
authors.initials: C
authors.lastname: Perreault
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D057167:Claudins / Q000235:genetics / Q000276:immunology; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016023:Integrins / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019087:Selectins / Q000235:genetics / Q000276:immunology; D017634:Self Tolerance; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D059467:Transcriptome / Q000276:immunology*; D000096927:AIRE Protein
chemical_list: D001324:Autoantigens; D057167:Claudins; D016023:Integrins; D019087:Selectins; D014157:Transcription Factors; D000096927:AIRE Protein