The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance

• Published in: Nature immunology Vol. 15; no. 3; pp. 258 - 265
• Main Authors: Waterfield, Michael, Khan, Imran S, Cortez, Jessica T, Fan, Una, Metzger, Todd, Greer, Alexandra, Fasano, Kayla, Martinez-Llordella, Marc, Pollack, Joshua L, Erle, David J, Su, Maureen, Anderson, Mark S
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2014; Nature Publishing Group
• Subjects: 13; 13/1; 13/105; 13/109; 13/31; 13/44; 13/51; 13/89; 631/250/38; AIRE Protein; Animals; Autoantigens - immunology; Biomedicine; Central Tolerance - genetics; Central Tolerance - immunology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; Flow Cytometry; Gene Expression Regulation - immunology; HEK293 Cells; Humans; Immune system; Immune Tolerance; Immunoblotting; Immunology; Immunoprecipitation; Infectious Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligonucleotide Array Sequence Analysis; Physiological research; Properties; Protein Binding; Repressor Proteins - genetics; Repressor Proteins - immunology; Reverse Transcriptase Polymerase Chain Reaction; Transcription factors; Transcription Factors - genetics; Transcription Factors - immunology; Transfection; Two-Hybrid System Techniques
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/ni.2820

The transcriptional regulator Aire is required for central tolerance, but how it manages to target tissue-specific genes is unclear. Anderson and colleagues show that Aire achieves such targeting by coopting the ATF7ip-MBD1 repressor complex. 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.