Chd4 choreographs self-antigen expression for central immune tolerance

Nat Immunol. 2020 Aug;21(8):892-901. doi: 10.1038/s41590-020-0717-2. Epub 2020 Jun 29.

Abstract

Autoreactive T cells are eliminated in the thymus to prevent autoimmunity by promiscuous expression of tissue-restricted self-antigens in medullary thymic epithelial cells. This expression is dependent on the transcription factor Fezf2, as well as the transcriptional regulator Aire, but the entire picture of the transcriptional program has been obscure. Here, we found that the chromatin remodeler Chd4, also called Mi-2β, plays a key role in the self-antigen expression in medullary thymic epithelial cells. To maximize the diversity of self-antigen expression, Fezf2 and Aire utilized completely distinct transcriptional mechanisms, both of which were under the control of Chd4. Chd4 organized the promoter regions of Fezf2-dependent genes, while contributing to the Aire-mediated induction of self-antigens via super-enhancers. Mice deficient in Chd4 specifically in thymic epithelial cells exhibited autoimmune phenotypes, including T cell infiltration. Thus, Chd4 plays a critical role in integrating Fezf2- and Aire-mediated gene induction to establish central immune tolerance.

Publication types

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

MeSH terms

  • AIRE Protein
  • Animals
  • Autoantigens / biosynthesis
  • Autoantigens / immunology*
  • Central Tolerance / physiology*
  • DNA Helicases / immunology
  • DNA Helicases / metabolism
  • Gene Expression Regulation / immunology*
  • HEK293 Cells
  • Humans
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / immunology*
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Transcription Factors / immunology
  • Transcription Factors / metabolism

Substances

  • Autoantigens
  • CHD4 protein, human
  • Transcription Factors
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex
  • Mi-2beta protein, mouse
  • DNA Helicases