Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Immunology, 1107 Immunology, 3204 Immunology

Abstract:

Introduction: The Autoimmune Regulator, Aire, mediates central tolerance of peripheral self. Its activity in thymic epithelial cells (TEC) directs the ectopic expression of hundreds of tissue-restricted antigens (TRA), causing the deletion of autoreactive thymocytes. The molecular mechanisms orchestrating this broad transcriptional regulation are unknown. Various models of transcriptional regulation have been proposed, ranging from i) direct DNA binding, ii) non-specific activation of genes within genomic regions, iii) gain of promoter specificity via interaction partners, iv) or recognition of a histone tag left by other proteins. However, none of these models can fully explain how Aire affects expression of hundreds to thousands of genes with vastly different modes of regulation, and yet maintains cell type specificity in the range of genes targeted. One prominent model that might explain both the breadth and specificity of Aire's activity posits that tissue-specific transcription factors induced by Aire in TEC directly activate their canonical targets. Objective: To test a canonical model of Aire transcriptional activity. Methods: We analyzed mice deficient in the pancreatic transcription factor, Pdx1, specifically in TEC, for the expression and tolerance of downstream pancreatic TRA. Results: We observed that lack of Pdx1 in TEC does not reduce the transcription of insulin or somatostatin, nor alter glucagon expression. Conclusion: These findings suggest that Aire's capacity to regulate expression of a huge array of TRA relies solely on an unconventional transcriptional mechanism, without intermediary transcription factors.