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.
journal_name
Nat Immunoljournal_title
Nature immunologyauthors
Tomofuji Y,Takaba H,Suzuki HI,Benlaribi R,Martinez CDP,Abe Y,Morishita Y,Okamura T,Taguchi A,Kodama T,Takayanagi Hdoi
10.1038/s41590-020-0717-2subject
Has Abstractpub_date
2020-08-01 00:00:00pages
892-901issue
8eissn
1529-2908issn
1529-2916pii
10.1038/s41590-020-0717-2journal_volume
21pub_type
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