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

Nat Immunol. 2014 Mar;15(3):258-65. doi: 10.1038/ni.2820. Epub 2014 Jan 26.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIRE Protein
  • Animals
  • Autoantigens / immunology
  • Central Tolerance / genetics
  • Central Tolerance / immunology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology*
  • Flow Cytometry
  • Gene Expression Regulation / immunology*
  • HEK293 Cells
  • Humans
  • Immune Tolerance*
  • Immunoblotting
  • Immunoprecipitation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oligonucleotide Array Sequence Analysis
  • Protein Binding
  • Repressor Proteins / genetics
  • Repressor Proteins / immunology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / genetics
  • Transcription Factors / immunology*
  • Transfection
  • Two-Hybrid System Techniques

Substances

  • Atf7ip protein, mouse
  • Autoantigens
  • DNA-Binding Proteins
  • Mbd1 protein, mouse
  • Repressor Proteins
  • Transcription Factors

Associated data

  • GEO/GSE52548