Abstract
Aire is a transcriptional regulator that induces the promiscuous expression of thousands of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), a step critical for the induction of immunological self-tolerance. Studies have offered molecular insights into how Aire operates, but more comprehensive understanding of this process still remains elusive. Here we found abundant expression of the protein deacetylase Sirtuin-1 (Sirt1) in mature Aire(+) mTECs, wherein it was required for the expression of Aire-dependent TRA-encoding genes and the subsequent induction of immunological self-tolerance. Our study elucidates a previously unknown molecular mechanism for Aire-mediated transcriptional regulation and identifies a unique function for Sirt1 in preventing organ-specific autoimmunity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AIRE Protein
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Acetylation
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Animals
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Antigens / immunology
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Central Tolerance / genetics
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Central Tolerance / immunology*
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Epithelial Cells / immunology
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Epithelial Cells / metabolism
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Flow Cytometry
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HEK293 Cells
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Humans
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Immunoblotting
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Interleukin Receptor Common gamma Subunit / deficiency
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Interleukin Receptor Common gamma Subunit / genetics
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Mice, Transgenic
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Oligonucleotide Array Sequence Analysis
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Organ Specificity / immunology
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Protein Binding / immunology
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Reverse Transcriptase Polymerase Chain Reaction
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Sirtuin 1 / genetics
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Sirtuin 1 / immunology*
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Sirtuin 1 / metabolism
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Thymus Gland / cytology
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Thymus Gland / immunology
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Thymus Gland / metabolism
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Transcription Factors / genetics
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Transcription Factors / immunology*
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Transcription Factors / metabolism
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Transcriptional Activation / immunology*
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Transcriptome / immunology
Substances
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Antigens
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Il2rg protein, mouse
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Interleukin Receptor Common gamma Subunit
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Transcription Factors
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Sirt1 protein, mouse
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Sirtuin 1
Associated data
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GEO/GSE68190
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GEO/GSE68363