Identification of a novel cis-regulatory element essential for immune tolerance

• Published in: The Journal of experimental medicine Vol. 212; no. 12; pp. 1993 - 2002
• Main Authors: LaFlam, Taylor N, Seumois, Grégory, Miller, Corey N, Lwin, Wint, Fasano, Kayla J, Waterfield, Michael, Proekt, Irina, Vijayanand, Pandurangan, Anderson, Mark S
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 16.11.2015
• Subjects: AIRE Protein; Animals; Base Sequence; DNA - genetics; DNA - immunology; DNA - metabolism; Epithelial Cells - immunology; Epithelial Cells - metabolism; HEK293 Cells; Humans; Immune Tolerance - genetics; Immune Tolerance - immunology; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Fluorescence; Molecular Sequence Data; NF-kappa B - immunology; NF-kappa B - metabolism; Protein Binding - immunology; Regulatory Sequences, Nucleic Acid - genetics; Regulatory Sequences, Nucleic Acid - immunology; Reverse Transcriptase Polymerase Chain Reaction; Sequence Homology, Nucleic Acid; Thymus Gland - cytology; Thymus Gland - immunology; Thymus Gland - metabolism; Transcription Factors - genetics; Transcription Factors - immunology; Transcription Factors - metabolism; Transcriptome - genetics; Transcriptome - immunology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20151069

Thymic central tolerance is essential to preventing autoimmunity. In medullary thymic epithelial cells (mTECs), the Autoimmune regulator (Aire) gene plays an essential role in this process by driving the expression of a diverse set of tissue-specific antigens (TSAs), which are presented and help tolerize self-reactive thymocytes. Interestingly, Aire has a highly tissue-restricted pattern of expression, with only mTECs and peripheral extrathymic Aire-expressing cells (eTACs) known to express detectable levels in adults. Despite this high level of tissue specificity, the cis-regulatory elements that control Aire expression have remained obscure. Here, we identify a highly conserved noncoding DNA element that is essential for Aire expression. This element shows enrichment of enhancer-associated histone marks in mTECs and also has characteristics of being an NF-κB-responsive element. Finally, we find that this element is essential for Aire expression in vivo and necessary to prevent spontaneous autoimmunity, reflecting the importance of this regulatory DNA element in promoting immune tolerance.