Abstract
The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific antigens (TSAs) by thymic epithelial cells is critical for this process and depends on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown. Here we identified two Aire-interacting proteins known to be involved in gene repression, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs. Moreover, Mbd1(-/-) mice developed pathological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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AIRE Protein
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Animals
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Autoantigens / immunology
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Central Tolerance / genetics
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Central Tolerance / immunology*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / immunology*
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Flow Cytometry
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Gene Expression Regulation / immunology*
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HEK293 Cells
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Humans
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Immune Tolerance*
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Immunoblotting
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Immunoprecipitation
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Oligonucleotide Array Sequence Analysis
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Protein Binding
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Repressor Proteins / genetics
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Repressor Proteins / immunology*
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription Factors / genetics
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Transcription Factors / immunology*
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Transfection
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Two-Hybrid System Techniques
Substances
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Atf7ip protein, mouse
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Autoantigens
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DNA-Binding Proteins
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Mbd1 protein, mouse
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Repressor Proteins
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Transcription Factors